From 499f5d900d028abcd66aeffe28db32a23a419b1a Mon Sep 17 00:00:00 2001 From: STRchive bot Date: Mon, 2 Feb 2026 13:24:59 -0700 Subject: [PATCH] Additional OMIM phenotype for NOTCH2NLC --- data/STRchive-loci.json | 20085 +++++++++++++++++++++++++++++--------- 1 file changed, 15290 insertions(+), 4795 deletions(-) diff --git a/data/STRchive-loci.json b/data/STRchive-loci.json index be8f38ee..c31c893e 100644 --- a/data/STRchive-loci.json +++ b/data/STRchive-loci.json @@ -1,4861 +1,15356 @@ [ -{ - "id": "OPDM5_ABCD3", - "disease_id": "OPDM5", - "gene": "ABCD3", - "chrom": "chr1", - "start_hg38": 94418421, - "stop_hg38": 94418444, - "start_hg19": 94883977, - "stop_hg19": 94884000, - "start_t2t": 94266544, - "stop_t2t": 94266567, - "disease": "Oculopharyngodistal myopathy type 5", - "inheritance": ["AD"], - "disease_description": "Oculopharyngodistal myopathy (OPDM) is a rare, adult-onset hereditary muscle disease. People with OPDM present with progressive eye and throat (pharyngeal) problems and involvement of the muscles of the lower legs and arms. Symptoms may include eyelid drooping (ptosis), swallowing difficulty, hoarse and nasal voice, leg and arm weakness, as well as muscle wasting in the face and in the legs and arms. Many people have respiratory problems due to respiratory muscle weakness. In rare cases, there is also hearing loss, as well as severe weakness in muscles of the forearms and thighs. As the disease progresses, other muscles may be affected. A blood exam may show an increased creatine kinase level and an abnormal EMG [@mondo:0025193].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Found in individuals of European, Japanese, and Chinese ancestry [@pmid:38876750; @pmid:34047774].", - "age_onset": "Typical: 24-30; Range: 10-50 [@pmid:39068203]. Age of onset data is limited to 8 families.", - "age_onset_min": 10.0, - "age_onset_max": 50.0, - "typ_age_onset_min": 24.0, - "typ_age_onset_max": 30.0, - "details": "Characterized in eight unrelated families which were used to establish benign (3-44) and pathogenic (118-694) ranges [@pmid:39068203].", - "mechanism": null, - "mechanism_detail": "Potentially over-expression of transcripts [@pmid:39068203].", - "year": "2023 [@pmid:39068203]", - "location_in_gene": "5' UTR", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GCC"], - "pathogenic_motif_reference_orientation": ["GCC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CCG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 3, - "benign_max": 44, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 118, - "pathogenic_max": 694, - "motif_len": 3, - "ref_copies": 7.7, - "novel": "ref", - "gard": ["12592"], - "genereviews": [], - "malacard": [], - "medgen": ["320250"], - "mondo": ["0025193"], - "omim": [], - "orphanet": ["98897"], - "gnomad": ["ABCD3"], - "stripy": [], - "tr_atlas": ["TR5671"], - "webstr_hg38": ["1164141", "6329150"], - "webstr_hg19": ["STR_58687"], - "locus_tags": ["supported_evidence"], - "disease_tags": ["oculopharyngodistal_myopathy"], - "references": ["pmid:39068203", "pmid:38876750", "pmid:34047774", "mondo:0025193"], - "additional_literature": ["pmid:40645757"] -}, -{ - "id": "FRAXE_AFF2", - "disease_id": "FRAXE", - "gene": "AFF2", - "chrom": "chrX", - "start_hg38": 148500604, - "stop_hg38": 148500753, - "start_hg19": 147582124, - "stop_hg19": 147582273, - "start_t2t": 146765190, - "stop_t2t": 146765342, - "disease": "Fragile X syndrome, FRAXE type", - "inheritance": ["XR"], - "disease_description": "A nonsyndromic X-linked mental retardation (NS-XLMR) characterized by mild intellectual deficit. FRAXE is the most common form of NS-XLMR [@mondo:0010659].", - "hpo_terms": null, - "prevalence": "2/50000", - "prevalence_details": "1-4/100,000 males [@url:medlineplus.gov/genetics/condition/fragile-xe-syndrome]; 1/50-100,000 males, more than 50 families [@pmid:11246464]. Found in populations around the globe, including in the UK, US, Canada, Taiwan, Germany, Greece, Cyprus, Spain, and Finland [@pmid:11246464].", - "age_onset": "Typical: 2-10 [@pmid:11246464]. Range: 1-10; developmental delays without physical features can make onset difficult to detect until schooling [@omim:309548].", - "age_onset_min": 1.0, - "age_onset_max": 10.0, - "typ_age_onset_min": 2.0, - "typ_age_onset_max": 10.0, - "details": "Allele ranges (benign:4-39; pathogenic: >200) inferred from The Human Gene Mutation Database [@genereviews:NBK535148]. Intermediate alleles correspond to a premutation [@pmid:23914978]. Non-canonical motifs include: CGG/CCT/GTG/CAG/CTG3 [@pmid:35245110; @pmid:34111553].", - "mechanism": "LoF", - "mechanism_detail": "Loss of function via transcriptional silencing [@pmid:16205714; @pmid:36169768].", - "year": "1993 [@pmid:8334699]", - "location_in_gene": "5' UTR", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GCC"], - "pathogenic_motif_reference_orientation": ["GCC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CCG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 4, - "benign_max": 39, - "intermediate_min": 40, - "intermediate_max": 200, - "pathogenic_min": 201, - "pathogenic_max": 2000, - "motif_len": 3, - "ref_copies": 50.3, - "novel": "ref", - "gard": ["2378"], - "genereviews": ["NBK535148"], - "malacard": ["INT399"], - "medgen": ["155512"], - "mondo": ["0010659"], - "omim": ["309548"], - "orphanet": ["100973"], - "gnomad": ["AFF2"], - "stripy": ["AFF2"], - "tr_atlas": ["TR173976"], - "webstr_hg38": [], - "webstr_hg19": [], - "locus_tags": ["supported_evidence", "somatic_instability", "anticipation", "maternal_expansion", "length_affects_penetrance", "length_affects_severity"], - "disease_tags": [], - "references": ["pmid:11246464", "omim:309548", "pmid:16205714", "pmid:36169768", "genereviews:NBK535148", "pmid:23914978", "pmid:35245110", "pmid:34111553", "url:medlineplus.gov/genetics/condition/fragile-xe-syndrome", "pmid:8334699", "mondo:0010659"], - "additional_literature": ["pmid:41074692", "pmid:40708890", "pmid:35431806", "pmid:28812997", "pmid:25171808", "pmid:24763282", "pmid:22718980", "pmid:21739600", "pmid:21254876", "pmid:21051337", "pmid:17635840", "pmid:17516099", "pmid:16469443", "pmid:11119302", "pmid:10780779", "pmid:10674158", "pmid:10424820", "pmid:9630071", "pmid:9415475", "pmid:9415473", "pmid:9341861", "pmid:8808600", "pmid:8844091", "pmid:8755928", "pmid:8673086", "pmid:7541938", "pmid:7783163", "pmid:7881407", "pmid:7977354", "pmid:8023854", "pmid:8162055", "pmid:8118462"] -}, -{ - "id": "FRA2A_AFF3", - "disease_id": "FRA2A", - "gene": "AFF3", - "chrom": "chr2", - "start_hg38": 100104798, - "stop_hg38": 100104824, - "start_hg19": 100721260, - "stop_hg19": 100721286, - "start_t2t": 100563685, - "stop_t2t": 100563738, - "disease": "Intellectual disability associated with fragile site FRA2A", - "inheritance": ["AD"], - "disease_description": "These expansions are associated with intellectual disability and clinical phenotypes such as delayed motor development or delays in speech/language [@pmid:24763282].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "1/862 (1/654-1266) population prevalence of methylated AFF3 expansions (mild cognitive disability) [@pmid:39313615]. Disease cases observed in South Australia [@pmid:24763282].", - "age_onset": "Early childhood (small sample size) [@pmid:24763282].", - "age_onset_min": 1.0, - "age_onset_max": 7.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "Allele ranges established in study of 3 families; intermediate alleles likely premutations [@pmid:24763282]. Pathogenic threshold may be higher than 300 as this was the largest allele that could be accurately sized by the assay.", - "mechanism": "LoF/methylation", - "mechanism_detail": "Silencing of the FMR2 gene as a consequence of a CCG expansion located upstream of this gene [@malacard:KNS007].", - "year": "2014 [@pmid:24763282]", - "location_in_gene": "Intron 3", - "gene_strand": "-", - "reference_motif_reference_orientation": ["GCC"], - "pathogenic_motif_reference_orientation": ["GCC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CGG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 3, - "benign_max": 20, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 300, - "pathogenic_max": 300, - "motif_len": 3, - "ref_copies": 8.7, - "novel": "ref", - "gard": [], - "genereviews": [], - "malacard": ["KNS007"], - "medgen": [], - "mondo": [], - "omim": ["601464"], - "orphanet": [], - "gnomad": ["AFF3"], - "stripy": [], - "tr_atlas": ["TR252468"], - "webstr_hg38": ["288936"], - "webstr_hg19": [], - "locus_tags": ["supported_evidence"], - "disease_tags": [], - "references": ["pmid:24763282", "malacard:KNS007", "pmid:39313615"], - "additional_literature": ["pmid:40417743", "pmid:37205357"] -}, -{ - "id": "SBMA_AR", - "disease_id": "SBMA", - "gene": "AR", - "chrom": "chrX", - "start_hg38": 67545316, - "stop_hg38": 67545419, - "start_hg19": 66765158, - "stop_hg19": 66765261, - "start_t2t": 65975147, - "stop_t2t": 65975250, - "disease": "Spinal and bulbar muscular atrophy, Kennedy Disease", - "inheritance": ["XR"], - "disease_description": "Kennedy's disease, also known as bulbospinal muscular atrophy (BSMA), is a rare X-linked recessive motor neuron disease characterized by proximal and bulbar muscle wasting [@mondo:0010735].", - "hpo_terms": null, - "prevalence": "1/30000", - "prevalence_details": "1-2/100,000 (population-specific, higher in Finnish population, Canadian population) [@pmid:37628685]; 1/30,000 [@orphanet:481]; mutation frequency of 1:3182 10x more frequent than reported disease prevalence of 1 in 30,000 [@pmid:36797998]. Only documented in patients with European/Asian ancestry, including Scandinavian, English, Belgian, French, Italian, German, Polish, Spanish, Swiss, Moroccan, Turkish, Chinese, Japanese (more common because of a founder effect), East Indian (potentially related to Japanese founder mutation) [@pmid:37578398], Korean, and Vietnamese populations [@genereviews:NBK1333].", - "age_onset": "Typical: 20-49 [@pmid:11436124], Range: 8 [@pmid:15851746] - 83 [@doi:10.17161/2tmg0f25].", - "age_onset_min": 8.0, - "age_onset_max": 83.0, - "typ_age_onset_min": 20.0, - "typ_age_onset_max": 49.0, - "details": "Intermediate alleles indicate reduced penetrance [@genereviews:NBK1333]. Expansions larger than the pathogenic threshold in the AR gene should be evaluated carefully. Interruptions have not been observed in patient cases; it has been proposed that longer alleles with interruptions may not be pathogenic [@pmid:24041967]. Non-canonical motif CAA observed [@pmid:35245110]. Expansions are also detected ten-fold more often in a general population than would be expected by disease prevalence [@pmid:36797998]. Clinical evaluation and phenotypic matching may be necessary to determine diagnosis even in the presence of a pure expanded allele. It has been proposed that contractions may play a role in disease [@pmid:10398229]. Disease may be subclinical in females [@pmid:34922802], and can be clinically heterogeneous even within the same family [@pmid:20184516].", - "mechanism": "GoF", - "mechanism_detail": "Polyglutamine alters protein conformation leading to gain-of-function neurodegeneration [@pmid:29398703; @pmid:36169768]. Transcriptional dysregulation, axonal transport disruption, and mitochondrial dysfunction also play causative roles in the neurodegeneration [@pmid:22609045].", - "year": "1991 [@pmid:2062380]; the first triplet disease to be discovered [@pmid:15313856]", - "location_in_gene": "Coding Exon 1", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GCA"], - "pathogenic_motif_reference_orientation": ["GCA"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["AGC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 9, - "benign_max": 34, - "intermediate_min": 36, - "intermediate_max": 37, - "pathogenic_min": 38, - "pathogenic_max": 68, - "motif_len": 3, - "ref_copies": 34.0, - "novel": "ref", - "gard": ["6818"], - "genereviews": ["NBK1333"], - "malacard": ["SPN404"], - "medgen": ["333282"], - "mondo": ["0010735"], - "omim": ["313200"], - "orphanet": ["481"], - "gnomad": ["AR"], - "stripy": ["AR"], - "tr_atlas": ["TR169377"], - "webstr_hg38": ["859199"], - "webstr_hg19": [], - "locus_tags": ["supported_evidence", "contraction", "somatic_instability", "anticipation", "paternal_expansion", "length_affects_severity", "length_affects_penetrance", "length_affects_onset"], - "disease_tags": [], - "references": ["pmid:11436124", "pmid:15851746", "doi:10.17161/2tmg0f25", "pmid:29398703", "pmid:36169768", "pmid:22609045", "genereviews:NBK1333", "pmid:24041967", "pmid:35245110", "pmid:36797998", "pmid:10398229", "pmid:34922802", "pmid:20184516", "pmid:37628685", "orphanet:481", "pmid:37578398", "pmid:2062380", "pmid:15313856", "mondo:0010735"], - "additional_literature": ["pmid:41361869", "pmid:41246945", "pmid:40912964", "pmid:40614362", "pmid:40585427", "pmid:40488202", "pmid:40450087", "pmid:40371721", "pmid:40366765", "pmid:40031964", "pmid:39755011", "pmid:39729861", "pmid:39694906", "pmid:39570490", "pmid:39189540", "pmid:39140081", "pmid:38976730", "pmid:38860410", "pmid:38737445", "pmid:38701087", "pmid:38585669", "pmid:38284836", "pmid:38171945", "pmid:37936145", "pmid:37718889", "pmid:37715620", "pmid:37422780", "pmid:37269008", "pmid:37045687", "pmid:36988133", "pmid:36717478", "pmid:36701310", "pmid:36622568", "pmid:36599645", "pmid:36585400", "pmid:36142533", "pmid:36137740", "pmid:35982373", "pmid:35876459", "pmid:35872088", "pmid:35867854", "pmid:35661131", "pmid:35599735", "pmid:35571498", "pmid:35237894", "pmid:35230239", "pmid:35189449", "pmid:35182509", "pmid:35165376", "pmid:34914563", "pmid:34744823", "pmid:34723064", "pmid:34407295", "pmid:34390226", "pmid:34372915", "pmid:34006154", "pmid:33865179", "pmid:33738134", "pmid:33714752", "pmid:33261594", "pmid:33191626", "pmid:32989102", "pmid:32856855", "pmid:32468478", "pmid:32216057", "pmid:32166698", "pmid:32152060", "pmid:32070397", "pmid:31901908", "pmid:31522753", "pmid:31446215", "pmid:31303548", 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"pmid:18446630", "pmid:18365230", "pmid:18323476", "pmid:18222439", "pmid:18217192", "pmid:18191848", "pmid:18181049", "pmid:18097504", "pmid:17997416", "pmid:17984450", "pmid:17984063", "pmid:17979523", "pmid:17854832", "pmid:17852020", "pmid:17825390", "pmid:17635942", "pmid:17556727", "pmid:17507624", "pmid:17507457", "pmid:17465263", "pmid:17440439", "pmid:17431729", "pmid:17372242", "pmid:17321486", "pmid:17230529", "pmid:17161354", "pmid:17137601", "pmid:17027356", "pmid:16859836", "pmid:16847812", "pmid:16817826", "pmid:16813680", "pmid:16804045", "pmid:16793958", "pmid:16772330", "pmid:16696857", "pmid:16621916", "pmid:16515589", "pmid:16493814", "pmid:16462497", "pmid:16448271", "pmid:16437189", "pmid:16425097", "pmid:16403814", "pmid:16377095", "pmid:16365010", "pmid:16358333", "pmid:16299230", "pmid:16187285", "pmid:16117826", "pmid:16008071", "pmid:15956082", "pmid:15954500", "pmid:15952987", "pmid:15950642", "pmid:15876692", "pmid:15824176", "pmid:15747808", "pmid:15725470", "pmid:15721279", "pmid:15659427", "pmid:15609126", "pmid:15599941", "pmid:15570555", "pmid:15545219", "pmid:15472213", "pmid:15366384", "pmid:15358199", "pmid:15341991", "pmid:15310009", "pmid:15198988", "pmid:15146455", "pmid:15120698", "pmid:15044606", "pmid:15003169", "pmid:14974917", "pmid:14973115", "pmid:14731580", "pmid:14698481", "pmid:14693242", "pmid:14691592", "pmid:14674723", "pmid:14605819", "pmid:14585317", "pmid:14511217", "pmid:14506156", "pmid:12898143", "pmid:12860943", "pmid:12767946", "pmid:12755998", "pmid:12714591", "pmid:12670590", "pmid:12634316", "pmid:12632109", "pmid:12602915", "pmid:12542725", "pmid:12534937", "pmid:12478141", "pmid:12404104", "pmid:12388541", "pmid:12385020", "pmid:12376473", "pmid:12220434", "pmid:12189490", "pmid:12189162", "pmid:12085360", "pmid:12042281", "pmid:12031042", "pmid:11956643", "pmid:11935317", "pmid:11927493", "pmid:11894978", "pmid:11875046", "pmid:11847524", "pmid:11810651", "pmid:11809726", "pmid:11788641", "pmid:11721964", "pmid:11720249", "pmid:11701709", "pmid:11600555", "pmid:11571732", "pmid:11571725", "pmid:11550169", "pmid:11494335", "pmid:11473958", "pmid:11443190", "pmid:11368874", "pmid:11331662", "pmid:11330644", "pmid:11266016", "pmid:11259089", "pmid:11167027", "pmid:11121465", "pmid:11016637", "pmid:10999852", "pmid:10958659", "pmid:10956560", "pmid:10852984", "pmid:10821498", "pmid:10817350", "pmid:10794490", "pmid:10732798", "pmid:10732754", "pmid:10717532", "pmid:10717003", "pmid:10656235", "pmid:10643885", "pmid:10637497", "pmid:10617922", "pmid:10574254", "pmid:10564878", "pmid:10544298", "pmid:10486315", "pmid:10419869", "pmid:10400640", "pmid:10323251", "pmid:10234512", "pmid:9925917", "pmid:9886069", "pmid:9880240", "pmid:9815849", "pmid:9813160", "pmid:9761394", "pmid:9732460", "pmid:9731888", "pmid:9692387", "pmid:9677254", "pmid:9580659", "pmid:9499423", "pmid:9382110", "pmid:9270598", "pmid:9094973", "pmid:9020849", "pmid:8960833", "pmid:8954049", "pmid:8878435", "pmid:8737374", "pmid:8926495", "pmid:8807333", "pmid:8645957", "pmid:7772520", "pmid:7757084", "pmid:7719348", "pmid:8065934", "pmid:7951325", "pmid:7515106", "pmid:8232348", "pmid:1461383", "pmid:1734865"] -}, -{ - "id": "EIEE1_ARX", - "disease_id": "EIEE1", - "gene": "ARX", - "chrom": "chrX", - "start_hg38": 25013649, - "stop_hg38": 25013697, - "start_hg19": 25031766, - "stop_hg19": 25031814, - "start_t2t": 24597886, - "stop_t2t": 24597934, - "disease": "Early-infantile epileptic encephalopathy", - "inheritance": ["XR"], - "disease_description": "Developmental and epileptic encephalopathy-1 (DEE1) is a severe form of epilepsy characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns, characterized by high-voltage bursts alternating with almost flat suppression phases [@omim:308350].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Found in individuals of multiple ethnicities, including European and Asian ancestry [@pmid:12874418].", - "age_onset": "Typical: 0 [@pmid:21204215; @pmid:9307258]; Range: 0-4; 70% of cases involve infantile spasms, leading to seizures by 3 or 4 years [@pmid:19587282].", - "age_onset_min": 0.0, - "age_onset_max": 4.0, - "typ_age_onset_min": 0.0, - "typ_age_onset_max": 0.0, - "details": "ARX expansions [@genereviews:NBK535148] result in a phenotypic spectrum of conditions including Partington syndrome [@omim:309510], Early Infantile Epileptic Encephalopathy [@omim:308350], Agenesis of Corpus Callosum with Abnormal Genitalia [@omim:300004], and X-Linked Lissencephaly with Ambiguous Genitalia [@omim:300215], described in the literature [@pmid:26029707; @pmid:20506206].", - "mechanism": "LoF", - "mechanism_detail": "Polyalanine expansions lead to reduction in protein product through unclear mechanism [@pmid:36169768; @pmid:38467784]. Apparent aggregation and mis-localisation of mutant protein, increased with expansion length [@genereviews:NBK51932].", - "year": "2002 [@pmid:11889467]", - "location_in_gene": "Coding Exon 2, aa 110-115", - "gene_strand": "-", - "reference_motif_reference_orientation": ["NGC"], - "pathogenic_motif_reference_orientation": ["NGC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CNG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 10, - "benign_max": 16, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 17, - "pathogenic_max": 27, - "motif_len": 3, - "ref_copies": 14.7, - "novel": "ref", - "gard": ["15298"], - "genereviews": ["NBK535148"], - "malacard": ["ERL057"], - "medgen": ["483052"], - "mondo": ["0010632"], - "omim": ["308350", "300419", "300215"], - "orphanet": ["182079"], - "gnomad": ["ARX_1"], - "stripy": ["ARX_1"], - "tr_atlas": ["TR167317"], - "webstr_hg38": ["843651"], - "webstr_hg19": ["STR_1542607"], - "locus_tags": ["supported_evidence", "length_affects_phenotype"], - "disease_tags": ["phenotypic_spectrum"], - "references": ["pmid:21204215", "pmid:9307258", "pmid:19587282", "pmid:36169768", "pmid:38467784", "genereviews:NBK51932", "genereviews:NBK535148", "omim:309510", "omim:308350", "omim:300004", "omim:300215", "pmid:26029707", "pmid:20506206", "pmid:12874418", "pmid:11889467"], - "additional_literature": ["pmid:40608247", "pmid:39933386", "pmid:39123069", "pmid:36571524", "pmid:33847015", "pmid:32033960", "pmid:28627419", "pmid:28602636", "pmid:27798109", "pmid:26571108", "pmid:25171319", "pmid:24236044", "pmid:23968833", "pmid:23246292", "pmid:22628459", "pmid:22108177", "pmid:20376468", "pmid:19018235", "pmid:18823727", "pmid:18462864", "pmid:17668384", "pmid:17664401", "pmid:17480217", "pmid:15533998"] -}, -{ - "id": "PRTS_ARX", - "disease_id": "PRTS", - "gene": "ARX", - "chrom": "chrX", - "start_hg38": 25013529, - "stop_hg38": 25013565, - "start_hg19": 25031646, - "stop_hg19": 25031682, - "start_t2t": 24597766, - "stop_t2t": 24597802, - "disease": "Partington syndrome", - "inheritance": ["XR"], - "disease_description": "A rare neurological condition that is primarily characterized by mild to moderate intellectual disability and dystonia of the hands. Other signs and symptoms may include dysarthria, behavioral abnormalities, recurrent seizures and/or an unusual gait (style of walking). Partington syndrome usually occurs in males; when it occurs in females, the signs and symptoms are often less severe. It is caused by changes (mutations) in the ARX gene and is inherited in an X-linked recessive manner. Treatment is based on the signs and symptoms present in each person [@mondo:0010654].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Limited clinical cases of predominantly European ancestry, such as Welsh/Belgian [@omim:309510].", - "age_onset": "Typical: 1-3; Range: 0-4. Mild phenotypes can make diagnosis difficult (expansions are particularly mild/absent in females) [@omim:309510].", - "age_onset_min": 0.0, - "age_onset_max": 4.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "ARX expansions [@genereviews:NBK535148] result in a phenotypic spectrum of conditions including Partington syndrome [@omim:309510], Early Infantile Epileptic Encephalopathy [@omim:308350], Agenesis of Corpus Callosum with Abnormal Genitalia [@omim:300004], and X-Linked Lissencephaly with Ambiguous Genitalia [@omim:300215], described in the literature [@pmid:26029707; @pmid:20506206].", - "mechanism": "LoF", - "mechanism_detail": "Polyalanine expansions lead to reduction in protein product through unclear mechanism [@pmid:36169768; @pmid:38467784]. Apparent aggregation and mis-localisation of mutan protein, increased with expansion length [@genereviews:NBK51932].", - "year": "2002 [@pmid:11889467]", - "location_in_gene": "Coding Exon 2, aa 144-155", - "gene_strand": "-", - "reference_motif_reference_orientation": ["NGC"], - "pathogenic_motif_reference_orientation": ["NGC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CNG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 12, - "benign_max": 12, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 20, - "pathogenic_max": 20, - "motif_len": 3, - "ref_copies": 12.0, - "novel": "ref", - "gard": ["4235"], - "genereviews": ["NBK535148"], - "malacard": ["PRT003"], - "medgen": ["163237"], - "mondo": ["0010654"], - "omim": ["309510"], - "orphanet": ["94083"], - "gnomad": ["ARX_2"], - "stripy": ["ARX_2"], - "tr_atlas": ["TR167316"], - "webstr_hg38": [], - "webstr_hg19": [], - "locus_tags": ["supported_evidence", "length_affects_phenotype"], - "disease_tags": ["phenotypic_spectrum"], - "references": ["omim:309510", "pmid:36169768", "pmid:38467784", "genereviews:NBK51932", "genereviews:NBK535148", "omim:308350", "omim:300004", "omim:300215", "pmid:26029707", "pmid:20506206", "pmid:11889467", "mondo:0010654"], - "additional_literature": ["pmid:40608247", "pmid:39933386", "pmid:39123069", "pmid:36571524", "pmid:33847015", "pmid:32033960", "pmid:28627419", "pmid:28602636", "pmid:27798109", "pmid:26571108", "pmid:25171319", "pmid:24236044", "pmid:23968833", "pmid:23246292", "pmid:22628459", "pmid:22108177", "pmid:21204215", "pmid:20376468", "pmid:19587282", "pmid:19018235", "pmid:18823727", "pmid:18462864", "pmid:17668384", "pmid:17664401", "pmid:17480217", "pmid:15533998", "pmid:12874418"] -}, -{ - "id": "DRPLA_ATN1", - "disease_id": "DRPLA", - "gene": "ATN1", - "chrom": "chr12", - "start_hg38": 6936716, - "stop_hg38": 6936775, - "start_hg19": 7045879, - "stop_hg19": 7045938, - "start_t2t": 6947903, - "stop_t2t": 6947941, - "disease": "Dentatorubral-Pallidoluysian Atrophy", - "inheritance": ["AD"], - "disease_description": "Dentatorubral pallidoluysian atrophy (DRPLA) is a rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I). It is characterized by involuntary movements, ataxia, epilepsy, mental disorders, cognitive decline and prominent anticipation [@mondo:0007435]. Epilepsy is common in earlier onset cases [@pmid:41147955].", - "hpo_terms": null, - "prevalence": "4.5/1000000", - "prevalence_details": "2-7/1,000,000. More prevalent in Japanese populations; also reported in North America, South America, Europe, and Australia [@genereviews:NBK1491].", - "age_onset": "Typical: 20-40 [@pmid:6808417; @genereviews:NBK1491]. Range: 0 [@pmid:11160976] - 72 [@genereviews:NBK1491].", - "age_onset_min": 0.0, - "age_onset_max": 72.0, - "typ_age_onset_min": 20.0, - "typ_age_onset_max": 40.0, - "details": "Pathogenic expansions (48-93) are fully penetrant with the exception of one documented case of 51 repeats; intermediate alleles (36-47) are associated with a milder phenotype and can expand upon transmission [@genereviews:NBK1491]. CAA interruptions have been observed without known clinical association [@pmid:35245110]. Length of the repeat is inversely associated with age of onset and severe epilepsy phenotype [@pmid:41147955].", - "mechanism": "GoF", - "mechanism_detail": "Polyglutamine expansions leading to gain of function [@genereviews:NBK1491].", - "year": "1994 [@pmid:7842016]", - "location_in_gene": "Coding Exon 5", - "gene_strand": "+", - "reference_motif_reference_orientation": ["CAG"], - "pathogenic_motif_reference_orientation": ["CAG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["AGC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 6, - "benign_max": 35, - "intermediate_min": 36, - "intermediate_max": 47, - "pathogenic_min": 48, - "pathogenic_max": 93, - "motif_len": 3, - "ref_copies": 19.0, - "novel": "ref", - "gard": ["5643"], - "genereviews": ["NBK1491"], - "malacard": ["DNT005"], - "medgen": ["155630"], - "mondo": ["0007435"], - "omim": ["125370"], - "orphanet": ["101"], - "gnomad": ["ATN1"], - "stripy": ["ATN1"], - "tr_atlas": ["TR114246"], - "webstr_hg38": ["5050156"], - "webstr_hg19": ["Expansion_ATN1/DRPLA"], - "locus_tags": ["supported_evidence", "anticipation", "somatic_instability", "paternal_expansion", "length_affects_onset", "length_affects_severity", "length_affects_phenotype"], - "disease_tags": ["ataxia", "epilepsy"], - "references": ["pmid:6808417", "genereviews:NBK1491", "pmid:11160976", "pmid:35245110", "pmid:41147955", "pmid:7842016", "mondo:0007435"], - "additional_literature": ["pmid:41355374", "pmid:41254939", "pmid:41082794", "pmid:40832356", "pmid:40488180", "pmid:40450087", "pmid:40340521", "pmid:40298952", "pmid:40263757", "pmid:40237283", "pmid:39820777", "pmid:39812846", "pmid:39742457", "pmid:39224955", "pmid:38961870", "pmid:38227102", "pmid:38152578", "pmid:37243799", "pmid:36599645", "pmid:36530930", "pmid:35182509", "pmid:34968706", "pmid:34022586", "pmid:33106889", "pmid:32711193", "pmid:32675418", "pmid:32129252", "pmid:31493762", "pmid:30891880", "pmid:30827498", "pmid:30615214", "pmid:30314815", "pmid:30120431", "pmid:29801887", "pmid:29715545", "pmid:29249939", "pmid:28782341", "pmid:28585930", "pmid:27896316", "pmid:27400454", "pmid:26374734", "pmid:26077168", "pmid:25842919", "pmid:25466696", "pmid:24972706", "pmid:24534762", "pmid:23933208", "pmid:23364790", "pmid:23263592", "pmid:23026538", "pmid:22527233", "pmid:22520093", "pmid:22342974", "pmid:22297462", "pmid:21108634", "pmid:20589872", "pmid:19429075", "pmid:19370769", "pmid:19259763", "pmid:19039037", "pmid:18182848", "pmid:17965145", "pmid:17961920", "pmid:17420317", "pmid:16967484", "pmid:16858508", "pmid:16251216", "pmid:16199124", "pmid:15553088", "pmid:15223312", "pmid:15148151", "pmid:15133824", "pmid:14756671", "pmid:12925365", "pmid:12805114", "pmid:12764052", "pmid:12614315", "pmid:12235319", "pmid:12042281", "pmid:11939898", "pmid:11807410", "pmid:11711886", "pmid:11709002", "pmid:11689158", "pmid:11574112", "pmid:11198291", "pmid:10942107", "pmid:10894992", "pmid:10814707", "pmid:10768629", "pmid:10766906", "pmid:10677044", "pmid:10564878", "pmid:10515170", "pmid:10486315", "pmid:10453742", "pmid:10332026", "pmid:10085113", "pmid:10084125", "pmid:9949204", "pmid:9887337", "pmid:9758625", "pmid:9705838", "pmid:9696528", "pmid:9647693", "pmid:9613852", "pmid:9507387", "pmid:9462738", "pmid:9385362", "pmid:9361003", "pmid:9187480", "pmid:9124808", "pmid:9109905", "pmid:9106530", "pmid:9050922", "pmid:9020849", "pmid:8962095", "pmid:9001798", "pmid:8651298", "pmid:8655136", "pmid:8780110", "pmid:8644735", "pmid:8852663", "pmid:8926495", "pmid:8559378", "pmid:8557266", "pmid:7633415", "pmid:7868125", "pmid:7824105", "pmid:7885531", "pmid:8136840", "pmid:8136826", "pmid:7734112"] -}, -{ - "id": "SCA1_ATXN1", - "disease_id": "SCA1", - "gene": "ATXN1", - "chrom": "chr6", - "start_hg38": 16327633, - "stop_hg38": 16327724, - "start_hg19": 16327864, - "stop_hg19": 16327955, - "start_t2t": 16200188, - "stop_t2t": 16200282, - "disease": "Spinocerebellar ataxia type 1", - "inheritance": ["AD"], - "disease_description": "Spinocerebellar ataxia type 1 (SCA1) is a subtype of type I autosomal dominant cerebellar ataxia (ADCA type I) characterized by dysarthria, writing difficulties, limb ataxia, and commonly nystagmus and saccadic abnormalities [@mondo:0008119].", - "hpo_terms": null, - "prevalence": "1.5/100000", - "prevalence_details": "1-2/100,000. Cases have been reported worldwide, although prevalences varies by ancestry/ethnicity [@genereviews:NBK1184].", - "age_onset": "Typical: 20-39 [@url:https://www.uptodate.com/contents/autosomal-dominant-spinocerebellar-ataxias]; Range: 6 [@pmid:3165612] - 63 [@pmid:8825276].", - "age_onset_min": 6.0, - "age_onset_max": 63.0, - "typ_age_onset_min": 20.0, - "typ_age_onset_max": 39.0, - "details": "Penetrance is dependent on sequence purity in addition to expansion length: pure repeats are pathogenic at 39 repeats [@pmid:37906407], while CAT interruptions [@pmid:35245110] can lead to reduced penetrance at comparable lengths [@genereviews:NBK1184]. Regardless, intermediate alleles are considered premutations which may lead to disease upon transmission [@genereviews:NBK1184].", - "mechanism": "GoF/LoF", - "mechanism_detail": "Polyglutamine expansion leading to toxic gain of function with eventual misregulation-based loss of function/dominant negative [@genereviews:NBK1184; @pmid:35573049].", - "year": "1993 [@pmid:8358429]", - "location_in_gene": "Coding Exon 8", - "gene_strand": "-", - "reference_motif_reference_orientation": ["CTG"], - "pathogenic_motif_reference_orientation": ["CTG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["AGC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 6, - "benign_max": 35, - "intermediate_min": 36, - "intermediate_max": 38, - "pathogenic_min": 39, - "pathogenic_max": 91, - "motif_len": 3, - "ref_copies": 30.3, - "novel": "ref", - "gard": ["4071"], - "genereviews": ["NBK1184"], - "malacard": ["SPN294"], - "medgen": ["155703"], - "mondo": ["0008119"], - "omim": ["164400"], - "orphanet": ["98755"], - "gnomad": ["ATXN1"], - "stripy": ["ATXN1"], - "tr_atlas": ["TR63118"], - "webstr_hg38": ["5767842"], - "webstr_hg19": ["Expansion_SCA1/ATXN1"], - "locus_tags": ["supported_evidence", "somatic_instability", "anticipation", "paternal_expansion", "length_affects_onset", "length_affects_penetrance", "length_affects_severity", "motif_affects_instability", "motif_affects_onset", "motif_affects_penetrance", "motif_affects_severity"], - "disease_tags": ["spinocerebellar_ataxia"], - "references": ["url:https://www.uptodate.com/contents/autosomal-dominant-spinocerebellar-ataxias", "pmid:3165612", "pmid:8825276", "genereviews:NBK1184", "pmid:35573049", "pmid:37906407", "pmid:35245110", "pmid:8358429", "mondo:0008119"], - "additional_literature": ["pmid:41435767", "pmid:41426430", "pmid:41254939", "pmid:41149812", "pmid:40900235", "pmid:40488180", "pmid:40450087", "pmid:39820777", "pmid:39456985", "pmid:39289638", "pmid:39211226", "pmid:38961870", "pmid:38626762", "pmid:38585669", "pmid:38308084", "pmid:38125008", "pmid:37827155", "pmid:37776516", "pmid:37397792", "pmid:37146135", "pmid:37043475", "pmid:36599645", "pmid:36549973", "pmid:36291186", "pmid:35869263", "pmid:35525134", "pmid:35182509", "pmid:34830553", "pmid:34635619", "pmid:34600502", "pmid:34372915", "pmid:34179866", "pmid:33502644", "pmid:33276461", "pmid:33159825", "pmid:32954321", "pmid:32761094", "pmid:32580238", "pmid:32339968", "pmid:31940111", "pmid:31810584", "pmid:31645175", "pmid:30891880", "pmid:30729852", "pmid:30615214", "pmid:30324307", "pmid:30314815", "pmid:30120431", "pmid:30108484", "pmid:29845242", "pmid:29656178", "pmid:29497168", "pmid:29274668", "pmid:29249939", "pmid:29057148", "pmid:28585930", "pmid:28444220", "pmid:26077168", "pmid:25595967", "pmid:25344417", "pmid:25255716", "pmid:24972706", "pmid:24594842", "pmid:24534762", "pmid:23197749", "pmid:22884877", "pmid:18337722", "pmid:18301861", "pmid:17961920", "pmid:17420317", "pmid:17116127", "pmid:15300851"] -}, -{ - "id": "SCA10_ATXN10", - "disease_id": "SCA10", - "gene": "ATXN10", - "chrom": "chr22", - "start_hg38": 45795354, - "stop_hg38": 45795424, - "start_hg19": 46191234, - "stop_hg19": 46191304, - "start_t2t": 46280059, - "stop_t2t": 46280134, - "disease": "Spinocerebellar ataxia type 10", - "inheritance": ["AD"], - "disease_description": "Spinocerebellar ataxia type 10 (SCA10) is a subtype of type I autosomal dominant cerebellar ataxia (ADCA type I). It is characterized by slowly progressive cerebellar syndrome and epilepsy, sometimes mild pyramidal signs, peripheral neuropathy and neuropsychological disturbances [@mondo:0011330].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Unknown prevalence, >300 individuals. Cases have been identified in Mexico, Brazil, China, and Japan [@genereviews:NBK1175].", - "age_onset": "Typical: 12-48; Range: 11-83 [@genereviews:NBK1175].", - "age_onset_min": 11.0, - "age_onset_max": 83.0, - "typ_age_onset_min": 12.0, - "typ_age_onset_max": 48.0, - "details": "Unaffected individuals are usually (82%) compound heterozygotes in the benign range [@genereviews:NBK1175]. Intermediate alleles show reduced penetrance, and exact distinction between intermediate and the lower end of the pathogenic range is unclear [@genereviews:NBK1175]. Expansions are frequently interrupted by ATCCT, ATCCC, ATTCC, ATTTCT, ATATTCT, ATTCTTCT, or ATTCTTCT; interruptions of ATTGT, TTTCT, ATTTTCT, ATTCTCT have been noted [@pmid:36199580] as has the interruption ATGCT [@pmid:19234597]. The ATCCT interruption motif is associated with a higher prevalence of epileptic seizures [@pmid:24318420]. Different motif patterns and mixed motif ratios may influence age of onset and anticipation [@doi:10.21203/rs.3.rs-5989910/v1].", - "mechanism": "GoF", - "mechanism_detail": "Transdominant mechanism theorized [@pmid:38467784].", - "year": "2000 [@pmid:11017075]", - "location_in_gene": "Intron 9", - "gene_strand": "+", - "reference_motif_reference_orientation": ["ATTCT"], - "pathogenic_motif_reference_orientation": ["ATTCT"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["ATTCT"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 10, - "benign_max": 32, - "intermediate_min": 33, - "intermediate_max": 850, - "pathogenic_min": 800, - "pathogenic_max": 4500, - "motif_len": 5, - "ref_copies": 14.0, - "novel": "ref", - "gard": ["10474"], - "genereviews": ["NBK1175"], - "malacard": ["SPN314"], - "medgen": ["369786"], - "mondo": ["0011330"], - "omim": ["603516"], - "orphanet": ["98761"], - "gnomad": ["ATXN10"], - "stripy": ["ATXN10"], - "tr_atlas": ["TR165509"], - "webstr_hg38": ["1027359", "4921433"], - "webstr_hg19": ["STR_909210"], - "locus_tags": ["supported_evidence", "somatic_instability", "anticipation", "paternal_expansion", "length_affects_onset", "length_affects_penetrance", "length_affects_phenotype", "motif_affects_instability", "motif_affects_penetrance", "motif_affects_phenotype"], - "disease_tags": ["spinocerebellar_ataxia"], - "references": ["genereviews:NBK1175", "pmid:38467784", "pmid:36199580", "pmid:19234597", "pmid:24318420", "doi:10.21203/rs.3.rs-5989910/v1", "pmid:11017075", "mondo:0011330"], - "additional_literature": ["pmid:41229449", "pmid:41074692", "pmid:40900235", "pmid:40898875", "pmid:40488180", "pmid:40067487", "pmid:39820777", "pmid:38961870", "pmid:38832639", "pmid:36092952", "pmid:35103298", "pmid:34970537", "pmid:33502644", "pmid:32520333", "pmid:32160188", "pmid:31737797", "pmid:31445906", "pmid:31342269", "pmid:29922950", "pmid:29316893", "pmid:28890930", "pmid:28423040", "pmid:27248057", "pmid:26374734", "pmid:26295943", "pmid:26077168", "pmid:26039897", "pmid:25466696", "pmid:24278426", "pmid:24269018", "pmid:23443018", "pmid:23083689", "pmid:23026538", "pmid:22065565", "pmid:22053702", "pmid:21282659", "pmid:20065034", "pmid:19651850", "pmid:19306311", "pmid:19171184", "pmid:19147916", "pmid:17961920", "pmid:17846122", "pmid:16924013", "pmid:16498633", "pmid:16385455", "pmid:15505178", "pmid:15201271", "pmid:15148151", "pmid:15096564", "pmid:12764052", "pmid:12589756", "pmid:11839840", "pmid:11160961", "pmid:9973298"] -}, -{ - "id": "SCA2_ATXN2", - "disease_id": "SCA2", - "gene": "ATXN2", - "chrom": "chr12", - "start_hg38": 111598949, - "stop_hg38": 111599019, - "start_hg19": 112036753, - "stop_hg19": 112036823, - "start_t2t": 111575873, - "stop_t2t": 111575940, - "disease": "Spinocerebellar ataxia type 2", - "inheritance": ["AD", "AR"], - "disease_description": "A subtype of type I autosomal dominant cerebellar ataxia (ADCA type I) characterized by truncal ataxia, dysarthria, slowed saccades and less commonly ophthalmoparesis and chorea [@mondo:0008458].", - "hpo_terms": null, - "prevalence": "1.5/100000", - "prevalence_details": "1-2/100,000 (population-dependent) [@pmid:29100084]. Cases have been found across ethnicities/ancestries, with population-dependent prevalence [@genereviews:NBK1275].", - "age_onset": "Typical: 30-39 [@genereviews:NBK1275]; Range: 2-86 [@omim:183090].", - "age_onset_min": 2.0, - "age_onset_max": 86.0, - "typ_age_onset_min": 30.0, - "typ_age_onset_max": 39.0, - "details": "Full penetrance of single alleles occurs at ~35 repeats [@genereviews:NBK1275; @pmid:37906407] and pathogenic expansions have been documented as large as 500 repeats [@pmid:12116207]. 33-34 length repeats are associated with reduced penetrance and later onset (age >50 years) [@genereviews:NBK1275]. Homozygous 31 repeat alleles may lead to recessive disease [@pmid:30533529], while a single 30-32 repeat is associated with increased ALS risk [@genereviews:NBK1275; @pmid:25285812]. There is some evidence that all CAG-repeat expansions in ATXN2 may be a risk factor for ALS, regardless of length and interruptions [@pmid:39956874]. Interruptions observed include CAA, CGG, CGC, which appear to stabilize the allele in transmission [@genereviews:NBK1275]. May confer risk for amyotrophic lateral sclerosis [@pmid:32954321].", - "mechanism": "GoF/LoF", - "mechanism_detail": "Polyglutamine cytoplasmic aggregates leading to cellular apoptosis; RAN translation implicated [@genereviews:NBK1275].", - "year": "1996 [@pmid:8896556]", - "location_in_gene": "Coding Exon 1", - "gene_strand": "-", - "reference_motif_reference_orientation": ["CTG"], - "pathogenic_motif_reference_orientation": ["CTG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["AGC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 14, - "benign_max": 30, - "intermediate_min": 31, - "intermediate_max": 34, - "pathogenic_min": 35, - "pathogenic_max": 500, - "motif_len": 3, - "ref_copies": 23.3, - "novel": "ref", - "gard": ["4072"], - "genereviews": ["NBK1275"], - "malacard": ["SPN301"], - "medgen": ["155704"], - "mondo": ["0008458"], - "omim": ["183090"], - "orphanet": ["98756"], - "gnomad": ["ATXN2"], - "stripy": ["ATXN2"], - "tr_atlas": ["TR120465"], - "webstr_hg38": ["598560", "5117050"], - "webstr_hg19": ["Expansion_SCA2/ATXN2"], - "locus_tags": ["supported_evidence", "somatic_instability", "anticipation", "paternal_expansion", "maternal_expansion", "length_affects_onset", "length_affects_penetrance", "length_affects_phenotype", "length_affects_severity", "motif_affects_instability", "motif_affects_phenotype", "proposed_modifier"], - "disease_tags": ["spinocerebellar_ataxia"], - "references": ["genereviews:NBK1275", "omim:183090", "pmid:37906407", "pmid:12116207", "pmid:30533529", "pmid:25285812", "pmid:39956874", "pmid:32954321", "pmid:29100084", "pmid:8896556", "mondo:0008458"], - "additional_literature": ["pmid:41435767", "pmid:41426430", "pmid:41373690", "pmid:41359433", "pmid:41310328", "pmid:41298695", "pmid:41196070", "pmid:41149812", "pmid:41082794", "pmid:41077586", "pmid:41071260", "pmid:41009775", "pmid:41001200", "pmid:40908144", "pmid:40906330", "pmid:40900235", "pmid:40746751", "pmid:40684213", "pmid:40556342", "pmid:40488180", "pmid:40346885", "pmid:40220918", "pmid:40004498", "pmid:39940702", "pmid:39820777", "pmid:39812846", "pmid:39804470", "pmid:39571249", "pmid:39521966", "pmid:39512795", "pmid:39457708", "pmid:39420034", "pmid:39317855", "pmid:39209824", "pmid:39200113", "pmid:39048885", "pmid:39004246", "pmid:38961870", "pmid:38715656", "pmid:38667292", "pmid:38642323", "pmid:38626762", "pmid:38585669", "pmid:38419144", "pmid:38397958", "pmid:38340219", "pmid:38239855", "pmid:38227102", "pmid:38165578", "pmid:38152578", "pmid:37848721", "pmid:37821389", "pmid:37397792", "pmid:37379724", "pmid:37202167", "pmid:37146135", "pmid:37070044", "pmid:37043475", "pmid:37003406", "pmid:36894829", "pmid:36823368", "pmid:36618024", "pmid:36530930", "pmid:36209056", "pmid:36008116", "pmid:35989899", "pmid:35962273", "pmid:35869263", "pmid:35787375", "pmid:35599735", "pmid:35525134", "pmid:35521889", "pmid:35297556", "pmid:35188716", "pmid:35182509", "pmid:35052497", "pmid:34565721", "pmid:34430069", "pmid:34390268", "pmid:34372915", "pmid:34350994", "pmid:34298214", "pmid:34284285", "pmid:34179866", "pmid:34168085", "pmid:34159894", "pmid:34077532", "pmid:33688396", "pmid:33625581", "pmid:33548146", "pmid:33502644", "pmid:33414559", "pmid:33377399", "pmid:33284045", "pmid:33159825", "pmid:33115537", "pmid:33070405", "pmid:33058338", "pmid:33029780", "pmid:32989102", "pmid:32932600", "pmid:32870233", "pmid:32822634", "pmid:32340607", "pmid:32307524", "pmid:32124191", "pmid:32082115", "pmid:31940111", "pmid:31898278", "pmid:31812845", "pmid:31810584", "pmid:31766565", "pmid:31619481", "pmid:31522753", "pmid:31432357", "pmid:31343735", "pmid:30920184", "pmid:30891880", "pmid:30847648", "pmid:30615214", "pmid:30611021", "pmid:30591349", "pmid:30417124", "pmid:30342765", "pmid:30342763", "pmid:30314815", "pmid:30196130", "pmid:30123518", "pmid:30120431", "pmid:29959555", "pmid:29934271", "pmid:29895397", "pmid:29848387", "pmid:29801887", "pmid:29801076", "pmid:29756284", "pmid:29715545", "pmid:29666341", "pmid:29665996", "pmid:29553382", "pmid:29497168", "pmid:29468174", "pmid:29462666", "pmid:29249939", "pmid:29080331", "pmid:29057148", "pmid:29046994", "pmid:28923333", "pmid:28782341", "pmid:28642336", "pmid:28585930", "pmid:28534046", "pmid:30363439", "pmid:28527524", "pmid:28525545", "pmid:28444220", "pmid:28263872", "pmid:28124431", "pmid:28017481", "pmid:28017238", "pmid:27896316", "pmid:27848087", "pmid:27774050", "pmid:27531668", "pmid:27333979", "pmid:27245636", "pmid:26846400", "pmid:26777436", "pmid:26733254", "pmid:26599997", "pmid:26551617", "pmid:26377379", "pmid:26374734", "pmid:26362908", "pmid:26354989", "pmid:26095883", "pmid:26086378", "pmid:26077168", "pmid:26054379", "pmid:25893506", "pmid:25790475", "pmid:25721894", "pmid:25634432", "pmid:25527265", "pmid:25466696", "pmid:25189938", "pmid:25189117", "pmid:25111021", "pmid:25098532", "pmid:24972706", "pmid:24908169", "pmid:24866401", "pmid:24780882", "pmid:24780439", "pmid:24718895", "pmid:24534762", "pmid:24269018", "pmid:24209901", "pmid:23959108", "pmid:23844332", "pmid:23635656", "pmid:23634774", "pmid:23368522", "pmid:23197749", "pmid:23047744", "pmid:23026538", "pmid:22868089", "pmid:22831947", "pmid:22650353", "pmid:22520093", "pmid:22507827", "pmid:22425256", "pmid:22297462", "pmid:22053702", "pmid:22035589", "pmid:21889984", "pmid:21880993", "pmid:21832228", "pmid:21741123", "pmid:21610160", "pmid:21600833", "pmid:21562247", "pmid:21537950", "pmid:21479228", "pmid:21329459", "pmid:20960485", "pmid:20740007", "pmid:20095980", "pmid:20070987", "pmid:20069235", "pmid:22353486", "pmid:19676102", "pmid:19672991", "pmid:19473475", "pmid:19429075", "pmid:19049837", "pmid:18990604", "pmid:18759344", "pmid:18685131", "pmid:18418678", "pmid:18297329", "pmid:18182848", "pmid:18028243", "pmid:17961920", "pmid:17923635", "pmid:17712857", "pmid:17620498", "pmid:17568014", "pmid:17440947", "pmid:17420317", "pmid:16687213", "pmid:16436644", "pmid:16389595", "pmid:16000334", "pmid:15911147", "pmid:15747371", "pmid:22473187", "pmid:15553088", "pmid:15533937", "pmid:15504570", "pmid:15300851", "pmid:15265035", "pmid:15148151", "pmid:15133829", "pmid:15080863", "pmid:14967767", "pmid:14966163", "pmid:14756671", "pmid:14732617", "pmid:12853230", "pmid:12812977", "pmid:12810491", "pmid:12764052", "pmid:12682323", "pmid:12671950", "pmid:12614315", "pmid:12490063", "pmid:12235319", "pmid:12039668", "pmid:11939898", "pmid:11889231", "pmid:11839840", "pmid:11804332", "pmid:11719273", "pmid:11689490", "pmid:11591855", "pmid:11502947", "pmid:11448300", "pmid:11374096", "pmid:11160961", "pmid:10369884", "pmid:11030803", "pmid:11030410", "pmid:10953195", "pmid:10942107", "pmid:10915763", "pmid:10894992", "pmid:10785256", "pmid:10768629", "pmid:10766906", "pmid:10642945", "pmid:10573020", "pmid:10525984", "pmid:10525976", "pmid:10453742", "pmid:10219787", "pmid:10210910", "pmid:10050970", "pmid:9973298", "pmid:9855520", "pmid:9779806", "pmid:9776463", "pmid:9762957", "pmid:9758625", "pmid:9748675", "pmid:9741408", "pmid:9710044", "pmid:9696528", "pmid:9674805", "pmid:9613852", "pmid:9588855", "pmid:9577387", "pmid:9549522", "pmid:9507387", "pmid:9436730", "pmid:9385362", "pmid:9403486", "pmid:9403480", "pmid:9339711", "pmid:9339681", "pmid:9259275", "pmid:9225982", "pmid:10735276", "pmid:9106530", "pmid:9020849", "pmid:10464657", "pmid:8968739", "pmid:8896557", "pmid:8896555", "pmid:8559378", "pmid:7477379", "pmid:7762567"] -}, -{ - "id": "SCA3_ATXN3", - "disease_id": "SCA3, MJD", - "gene": "ATXN3", - "chrom": "chr14", - "start_hg38": 92071010, - "stop_hg38": 92071052, - "start_hg19": 92537354, - "stop_hg19": 92537396, - "start_t2t": 86300519, - "stop_t2t": 86300603, - "disease": "Spinocerebellar ataxia type 3/Machado-Joseph disease", - "inheritance": ["AD"], - "disease_description": "Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most common subtype of type 1 autosomal dominant cerebellar ataxia (ADCA type 1), a neurodegenerative disorder, and is characterized by ataxia, external progressive ophthalmoplegia, and other neurological manifestations [@mondo:0007182]. Research suggests that length of ATXN2 expansions may affect the phenotype of SCA3 [@pmid:40684213].", - "hpo_terms": null, - "prevalence": "2.1/100000", - "prevalence_details": "1-5/100,000 [@pmid:29100084]. Most prevalent SCA subtype [@genereviews:NBK557816]. Found worldwide across ancestries/ethnicities [@genereviews:NBK1196].", - "age_onset": "Typical: 10-49 [@genereviews:NBK1196]; 3 [@pmid:40004498] - 73 [@genereviews:NBK1196; @pmid:30414314].", - "age_onset_min": 3.0, - "age_onset_max": 73.0, - "typ_age_onset_min": 10.0, - "typ_age_onset_max": 49.0, - "details": "Benign alleles range from 11-44 repeats [@pmid:37906407], with intermediate alleles (45-59) associated with incomplete penetrance and non-classic phenotypes [@genereviews:NBK1196]. The threshold between incomplete and full penetrance is unclear, but presumed to occur at ~60 repeats [@genereviews:NBK1196; @pmid:37906407]. The interruption CAA has been observed [@pmid:35245110]; AAG is present in hg38 reference sequence. The APOE ε4 allele appears to act as a disease modifier [@pmid:39731318]; GLS expansions may also function as disease modifiers [@pmid:39699045].", - "mechanism": "GoF", - "mechanism_detail": "Polyglutamine expansion leading to gain of function; aggregated and mislocalized proteins in neurons [@pmid:36169768; @genereviews:NBK1196].", - "year": "1994 [@pmid:7874163]", - "location_in_gene": "Coding Exon 10", - "gene_strand": "-", - "reference_motif_reference_orientation": ["CTG"], - "pathogenic_motif_reference_orientation": ["CTG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["AGC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 11, - "benign_max": 44, - "intermediate_min": 45, - "intermediate_max": 59, - "pathogenic_min": 60, - "pathogenic_max": 87, - "motif_len": 3, - "ref_copies": 14.0, - "novel": "ref", - "gard": ["6801"], - "genereviews": ["NBK1196"], - "malacard": ["MCH002"], - "medgen": ["9841"], - "mondo": ["0007182"], - "omim": ["109150"], - "orphanet": ["98757"], - "gnomad": ["ATXN3"], - "stripy": ["ATXN3"], - "tr_atlas": ["TR132758"], - "webstr_hg38": ["5316666", "1481402"], - "webstr_hg19": ["Expansion_SCA3_MJD/ATXN3"], - "locus_tags": ["supported_evidence", "somatic_instability", "anticipation", "paternal_expansion", "maternal_expansion", "length_affects_onset", "length_affects_phenotype", "length_affects_severity"], - "disease_tags": ["spinocerebellar_ataxia"], - "references": ["genereviews:NBK1196", "pmid:40004498", "pmid:30414314", "pmid:36169768", "pmid:37906407", "pmid:35245110", "pmid:39731318", "pmid:39699045", "pmid:29100084", "genereviews:NBK557816", "pmid:7874163", "mondo:0007182", "pmid:40684213"], - "additional_literature": ["pmid:41435767", "pmid:41358280", "pmid:41082794", "pmid:41058593", "pmid:41009775", "pmid:41001200", "pmid:40906330", "pmid:40900235", "pmid:40890629", "pmid:40880681", "pmid:40797466", "pmid:40754098", "pmid:40738252", "pmid:40692435", "pmid:40635703", "pmid:40488202", "pmid:40488180", "pmid:40450087", "pmid:40204795", "pmid:40178277", "pmid:40152810", "pmid:39987589", "pmid:39921113", "pmid:39820777", "pmid:39571249", "pmid:39516744", "pmid:39456985", "pmid:39375222", "pmid:39317855", "pmid:39298485", "pmid:39229124", "pmid:39125643", "pmid:39088078", "pmid:39048885", "pmid:38961870", "pmid:38900277", "pmid:38626762", "pmid:38513302", "pmid:38449714", "pmid:38443995", "pmid:38429929", "pmid:38291334", "pmid:38227102", "pmid:38165578", "pmid:38152578", "pmid:37961108", "pmid:37866221", "pmid:37848721", "pmid:37830620", "pmid:37830611", "pmid:37735371", "pmid:37397792", "pmid:37379724", "pmid:37333326", "pmid:37215811", "pmid:37122622", "pmid:37003406", "pmid:36907537", "pmid:36891289", "pmid:36875652", "pmid:36733922", "pmid:36618024", "pmid:36530930", "pmid:36482247", "pmid:36250694", "pmid:35997830", "pmid:35962273", "pmid:35952620", "pmid:35851059", "pmid:35847233", "pmid:35426475", "pmid:35421843", "pmid:35406787", "pmid:35188716", "pmid:35182509", "pmid:35052497", "pmid:35042771", "pmid:34783886", "pmid:34716557", "pmid:34706018", "pmid:34565721", "pmid:34473252", "pmid:34430069", "pmid:34284285", "pmid:34191270", "pmid:34167352", "pmid:34160773", "pmid:34159894", "pmid:34087977", "pmid:33893204", "pmid:33782863", "pmid:33743045", "pmid:33502644", "pmid:33468086", "pmid:33413375", "pmid:33371889", "pmid:33159825", "pmid:33157084", "pmid:33087504", "pmid:33058338", "pmid:32978817", "pmid:32822634", "pmid:32729243", "pmid:32205441", "pmid:31934455", "pmid:31920494", "pmid:31783119", "pmid:31687087", "pmid:31616370", "pmid:31565539", "pmid:31394429", "pmid:31374463", "pmid:31310802", "pmid:31230722", "pmid:30920184", "pmid:30891880", "pmid:30833927", "pmid:30804982", "pmid:30685895", "pmid:30615214", "pmid:30591349", "pmid:30554804", "pmid:30314815", "pmid:30231063", "pmid:30125433", "pmid:30120431", "pmid:30008965", "pmid:29959555", "pmid:29936336", "pmid:29922950", "pmid:29881950", "pmid:29852360", "pmid:29801869", "pmid:29737427", "pmid:29666341", "pmid:29553382", "pmid:29497168", "pmid:29444500", "pmid:29249939", "pmid:29057148", "pmid:28854700", "pmid:28782341", "pmid:28624196", "pmid:28585930", "pmid:28444220", "pmid:28158474", "pmid:28065793", "pmid:27942452", "pmid:27896316", "pmid:27848087", "pmid:27847820", "pmid:27596958", "pmid:27774050", "pmid:27731380", "pmid:27600091", "pmid:27333979", "pmid:26615955", "pmid:26601773", "pmid:26505994", "pmid:26467707", "pmid:26377379", "pmid:26374734", "pmid:26362908", "pmid:26354989", "pmid:26336829", "pmid:26266536", "pmid:26083476", "pmid:26077168", "pmid:26067219", "pmid:26054379", "pmid:30363545", "pmid:25700012", "pmid:25634432", "pmid:25633985", "pmid:25590633", "pmid:25466696", "pmid:25320121", "pmid:25144244", "pmid:25143392", "pmid:25068645", "pmid:25026993", "pmid:24972706", "pmid:24780882", "pmid:24746364", "pmid:24675225", "pmid:24534762", "pmid:24525517", "pmid:24242192", "pmid:23844332", "pmid:23775343", "pmid:23659897", "pmid:23423669", "pmid:23413156", "pmid:23382971", "pmid:23368522", "pmid:23026538", "pmid:22520093", "pmid:22351852", "pmid:22297462", "pmid:22090366", "pmid:22023810", "pmid:21975858", "pmid:21889984", "pmid:21832228", "pmid:21795378", "pmid:21780213", "pmid:21625753", "pmid:21600833", "pmid:21506152", "pmid:20726892", "pmid:20503052", "pmid:20484674", "pmid:20467850", "pmid:20334689", "pmid:20069235", "pmid:22353486", "pmid:19802879", "pmid:19699305", "pmid:19672991", "pmid:19631275", "pmid:19608203", "pmid:19597981", "pmid:19503814", "pmid:19412185", "pmid:19049837", "pmid:18990604", "pmid:18759344", "pmid:18685131", "pmid:18506570", "pmid:18449188", "pmid:18418678", "pmid:18413477", "pmid:18385100", "pmid:18261802", "pmid:18182848", "pmid:18071041", "pmid:18028243", "pmid:17961920", "pmid:17948873", "pmid:17712857", "pmid:17594286", "pmid:17440947", "pmid:17420317", "pmid:17116127", "pmid:17027034", "pmid:16967484", "pmid:16791428", "pmid:16724006", "pmid:16687213", "pmid:16389595", "pmid:16340213", "pmid:16241973", "pmid:15911147", "pmid:15747371", "pmid:22473187", "pmid:15553088", "pmid:15534186", "pmid:15504352", "pmid:15265035", "pmid:15223312", "pmid:15201448", "pmid:15167689", "pmid:15148151", "pmid:15080863", "pmid:15026782", "pmid:14966163", "pmid:14756671", "pmid:14679302", "pmid:14616293", "pmid:12938149", "pmid:12853230", "pmid:12832059", "pmid:12810491", "pmid:12764052", "pmid:12614315", "pmid:12486728", "pmid:12433269", "pmid:12235319", "pmid:12042281", "pmid:12007862", "pmid:11978767", "pmid:11889231", "pmid:11839840", "pmid:11807410", "pmid:11804332", "pmid:11559318", "pmid:11448300", "pmid:11466410", "pmid:11409435", "pmid:11405804", "pmid:11374096", "pmid:11160961", "pmid:10369884", "pmid:11030803", "pmid:11030410", "pmid:10942107", "pmid:10915763", "pmid:10894992", "pmid:10855623", "pmid:10785256", "pmid:10768629", "pmid:10766906", "pmid:10732811", "pmid:10717003", "pmid:10575843", "pmid:10525976", "pmid:10453742", "pmid:10433966", "pmid:10072437", "pmid:10071104", "pmid:9973298", "pmid:9855520", "pmid:9762957", "pmid:9758625", "pmid:9696528", "pmid:9674805", "pmid:9635424", "pmid:9613852", "pmid:9536097", "pmid:9588850", "pmid:9577387", "pmid:9562258", "pmid:9549522", "pmid:9532283", "pmid:9469848", "pmid:9507387", "pmid:9506544", "pmid:9415538", "pmid:9450899", "pmid:9436730", "pmid:9385362", "pmid:9371900", "pmid:9403486", "pmid:9403480", "pmid:9339702", "pmid:9339681", "pmid:9292723", "pmid:9259275", "pmid:9254842", "pmid:9225982", "pmid:9215676", "pmid:10735276", "pmid:9124808", "pmid:9106530", "pmid:9132496", "pmid:9020849", "pmid:10464657", "pmid:9401013", "pmid:8962095", "pmid:9088110", "pmid:8968739", "pmid:8931692", "pmid:8937340", "pmid:8836972", "pmid:8659514", "pmid:8609925", "pmid:8655136", "pmid:8780110", "pmid:8644735", "pmid:8815156", "pmid:8824876", "pmid:8926495", "pmid:8900536", "pmid:8800925", "pmid:8559378", "pmid:8559377", "pmid:8583215", "pmid:7574470", "pmid:7573040", "pmid:7496771", "pmid:8523034", "pmid:7668288", "pmid:7611296", "pmid:7762567", "pmid:7655453", "pmid:7633439"] -}, -{ - "id": "SCA7_ATXN7", - "disease_id": "SCA7", - "gene": "ATXN7", - "chrom": "chr3", - "start_hg38": 63912684, - "stop_hg38": 63912715, - "start_hg19": 63898360, - "stop_hg19": 63898391, - "start_t2t": 63956302, - "stop_t2t": 63956333, - "disease": "Spinocerebellar ataxia type 7", - "inheritance": ["AD"], - "disease_description": "Spinocerebellar ataxia-7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by adult onset of progressive cerebellar ataxia associated with pigmental macular dystrophy [@omim:164500].", - "hpo_terms": null, - "prevalence": "0.999/300000", - "prevalence_details": "<1/300,000: predominantly found in those with North European and African ancestry [@genereviews:NBK1256].", - "age_onset": "Typical: 4-48 [@pmid:20739808]; Range: 0-90 [@genereviews:NBK1256; @pmid:14571264].", - "age_onset_min": 0.0, - "age_onset_max": 65.0, - "typ_age_onset_min": 4.0, - "typ_age_onset_max": 48.0, - "details": "Benign alleles range from 4-27 [@pmid:37906407], with intermediate alleles ranging from premutations (28-33) to reduced penetrance (34-36) [@genereviews:NBK1256]. Interruptions observed include CAA [@pmid:35245110].", - "mechanism": "GoF", - "mechanism_detail": "Polyglutamine expansion leading to gain of function; toxic misfolded intermediated suspected [@genereviews:NBK1256; @pmid:18418675].", - "year": "1996 [@pmid:8908515]", - "location_in_gene": "Coding Exon 1, 2, or 3 (depending on isoform)", - "gene_strand": "+", - "reference_motif_reference_orientation": ["CAG"], - "pathogenic_motif_reference_orientation": ["CAG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["AGC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [ + { - "motif": "CAG", - "count": null, - "type": "pathogenic_repeat" + "id": "OPDM5_ABCD3", + "disease_id": "OPDM5", + "gene": "ABCD3", + "chrom": "chr1", + "start_hg38": 94418421, + "stop_hg38": 94418444, + "start_hg19": 94883977, + "stop_hg19": 94884000, + "start_t2t": 94266544, + "stop_t2t": 94266567, + "disease": "Oculopharyngodistal myopathy type 5", + "inheritance": [ + "AD" + ], + "disease_description": "Oculopharyngodistal myopathy (OPDM) is a rare, adult-onset hereditary muscle disease. People with OPDM present with progressive eye and throat (pharyngeal) problems and involvement of the muscles of the lower legs and arms. Symptoms may include eyelid drooping (ptosis), swallowing difficulty, hoarse and nasal voice, leg and arm weakness, as well as muscle wasting in the face and in the legs and arms. Many people have respiratory problems due to respiratory muscle weakness. In rare cases, there is also hearing loss, as well as severe weakness in muscles of the forearms and thighs. As the disease progresses, other muscles may be affected. A blood exam may show an increased creatine kinase level and an abnormal EMG [@mondo:0025193].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Found in individuals of European, Japanese, and Chinese ancestry [@pmid:38876750; @pmid:34047774].", + "age_onset": "Typical: 24-30; Range: 10-50 [@pmid:39068203]. Age of onset data is limited to 8 families.", + "age_onset_min": 10, + "age_onset_max": 50, + "typ_age_onset_min": 24, + "typ_age_onset_max": 30, + "details": "Characterized in eight unrelated families which were used to establish benign (3-44) and pathogenic (118-694) ranges [@pmid:39068203].", + "mechanism": null, + "mechanism_detail": "Potentially over-expression of transcripts [@pmid:39068203].", + "year": "2023 [@pmid:39068203]", + "location_in_gene": "5' UTR", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GCC" + ], + "pathogenic_motif_reference_orientation": [ + "GCC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CCG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 3, + "benign_max": 44, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 118, + "pathogenic_max": 694, + "motif_len": 3, + "ref_copies": 7.7, + "novel": "ref", + "gard": [ + "12592" + ], + "genereviews": [], + "malacard": [], + "medgen": [ + "320250" + ], + "mondo": [ + "0025193" + ], + "omim": [], + "orphanet": [ + "98897" + ], + "gnomad": [ + "ABCD3" + ], + "stripy": [], + "tr_atlas": [ + "TR5671" + ], + "webstr_hg38": [ + "1164141", + "6329150" + ], + "webstr_hg19": [ + "STR_58687" + ], + "locus_tags": [ + "supported_evidence" + ], + "disease_tags": [ + "oculopharyngodistal_myopathy" + ], + "references": [ + "pmid:39068203", + "pmid:38876750", + "pmid:34047774", + "mondo:0025193" + ], + "additional_literature": [ + "pmid:40645757" + ] }, { - "motif": "CCG", - "count": 4, - "type": "flank_repeat" - }], - "benign_min": 4, - "benign_max": 27, - "intermediate_min": 28, - "intermediate_max": 35, - "pathogenic_min": 37, - "pathogenic_max": 460, - "motif_len": 3, - "ref_copies": 10.7, - "novel": "ref", - "gard": ["20405"], - "genereviews": ["NBK1256"], - "malacard": ["SPN291"], - "medgen": ["156006"], - "mondo": ["0016163"], - "omim": ["164500"], - "orphanet": ["94147"], - "gnomad": ["ATXN7"], - "stripy": ["ATXN7"], - "tr_atlas": ["TR31879", "TR31880"], - "webstr_hg38": ["4965588"], - "webstr_hg19": ["Expansion_SCA7/ATXN7"], - "locus_tags": ["supported_evidence", "somatic_instability", "anticipation", "paternal_expansion", "length_affects_onset", "length_affects_penetrance", "length_affects_phenotype", "length_affects_severity"], - "disease_tags": ["spinocerebellar_ataxia"], - "references": ["pmid:20739808", "genereviews:NBK1256", "pmid:14571264", "pmid:18418675", "pmid:37906407", "pmid:35245110", "pmid:8908515", "omim:164500"], - "additional_literature": ["pmid:41254939", "pmid:40900235", "pmid:40488180", "pmid:40417743", "pmid:39820777", "pmid:39649105", "pmid:39571249", "pmid:39504355", "pmid:39317855", "pmid:39053472", "pmid:38961870", "pmid:38906973", "pmid:38851031", "pmid:38673939", "pmid:38626762", "pmid:38227102", "pmid:38165578", "pmid:38152578", "pmid:38045332", "pmid:37986914", "pmid:37848721", "pmid:37283503", "pmid:37214832", "pmid:36618024", "pmid:36530930", "pmid:35422034", "pmid:35182509", "pmid:35052497", "pmid:34870541", "pmid:34565721", "pmid:34160002", "pmid:34159894", "pmid:33995769", "pmid:33626063", "pmid:32138195", "pmid:31694722", "pmid:31522753", "pmid:31269856", "pmid:30891880", "pmid:30721448", "pmid:30699348", "pmid:30615214", "pmid:30381411", "pmid:30314815", "pmid:30255962", "pmid:30120431", "pmid:29801887", "pmid:29462666", "pmid:29316893", "pmid:29249939", "pmid:29248324", "pmid:28597910", "pmid:28585930", "pmid:28568901", "pmid:28444220", "pmid:27999335", "pmid:27774050", "pmid:27632585", "pmid:27333979", "pmid:27044733", "pmid:26584329", "pmid:26374734", "pmid:26077168", "pmid:25900954", "pmid:25755283", "pmid:25643591", "pmid:25608122", "pmid:25506882", "pmid:25466696", "pmid:25306109", "pmid:24972706", "pmid:24667781", "pmid:24534762", "pmid:24209901", "pmid:23828024", "pmid:23368522", "pmid:23197655", "pmid:23064575", "pmid:23026538", "pmid:22831947", "pmid:22520093", "pmid:22072678", "pmid:22053702", "pmid:21689595", "pmid:21147232", "pmid:20069235", "pmid:19226466", "pmid:19008940", "pmid:18418678", "pmid:18325672", "pmid:18182848", "pmid:17961920", "pmid:17420317", "pmid:17254003", "pmid:16626296", "pmid:16436644", "pmid:16434483", "pmid:16389941", "pmid:16389595", "pmid:16325416", "pmid:15750685", "pmid:15715978", "pmid:22473187", "pmid:15349877", "pmid:15148151", "pmid:15115762", "pmid:15080863", "pmid:14967767", "pmid:14966163", "pmid:12810491", "pmid:12764052", "pmid:12490531", "pmid:11939898", "pmid:11889231", "pmid:11839840", "pmid:11804332", "pmid:11781712", "pmid:11580893", "pmid:11448300", "pmid:11160961", "pmid:10369884", "pmid:11030825", "pmid:11030806", "pmid:11030410", "pmid:10942107", "pmid:10894992", "pmid:10841760", "pmid:10785256", "pmid:10768629", "pmid:10766906", "pmid:10602364", "pmid:10556295", "pmid:9467013", "pmid:10500272", "pmid:10453742", "pmid:10441328", "pmid:9973298", "pmid:9855520", "pmid:9736784", "pmid:9613852", "pmid:9536097", "pmid:9425224", "pmid:9425223", "pmid:9425222", "pmid:9425905", "pmid:9385362", "pmid:9288099", "pmid:10464657"] -}, -{ - "id": "SCA8_ATXN8OS", - "disease_id": "SCA8", - "gene": "ATXN8OS", - "chrom": "chr13", - "start_hg38": 70139383, - "stop_hg38": 70139429, - "start_hg19": 70713515, - "stop_hg19": 70713561, - "start_t2t": 69361243, - "stop_t2t": 69361270, - "disease": "Spinocerebellar ataxia type 8", - "inheritance": ["AD"], - "disease_description": "Spinocerebellar ataxia type 8 (SCA8) is a subtype of type I autosomal dominant cerebellar ataxia (ADCA type I) characterized by cerebellar ataxia and cognitive dysfunction in almost three quarters of patients and pyramidal and sensory signs in approximately a third of patients [@mondo:0012116].", - "hpo_terms": null, - "prevalence": "0.5/100000", - "prevalence_details": "<1/100,000 [@pmid:29100084]; expansion in 1:100-1200 chromosomes [@genereviews:NBK1268]. Found across ethnicities/ancestries, with population-dependent prevalence [@genereviews:NBK1268].", - "age_onset": "Typical: third to fifth decade (20-49); Range: 0 [@genereviews:NBK1268] - 76 [@doi:10.1101/gr.279634.124].", - "age_onset_min": 0.0, - "age_onset_max": 76.0, - "typ_age_onset_min": 20.0, - "typ_age_onset_max": 49.0, - "details": "Two genes span the CTG/CAG repeat and are expressed in opposite directions: ATXN8, a nearly pure polyglutamine repeat protein in the CAG direction, and ATXN8OS, which is transcribed to a noncoding CUG repeat RNA [@pmid:16804541]. Reduced penetrance is found in alleles of all sizes, although penetrance appears higher at 71+ repeats and repeats at 50-70 appear less likely to result in disease [@genereviews:NBK1268; @pmid:20373340]. Roda et al. suggested that the ATXN8 or ATXN8OS gene should not be evaluated in isolation as a candidate gene for spinocerebellar degenerative disease [@pmid:28451643]. CCG/CGG interruptions in high-penetrance SCA8 families increase RAN translation and protein toxicity [@pmid:34632710]; Interruptions in CTG/CAG expansion by 1 or more CCG/CGG, CTA/TAG, CTC/GAG, CCA/TGG, or CTT/AAG trinucleotides have been observed in full-penetrance repeats [@pmid:16804541; @genereviews:NBK1268].", - "mechanism": "GoF", - "mechanism_detail": "Polyglutamine/toxic gain-of-function [@omim:608768; @genereviews:NBK1268].", - "year": "1999 [@pmid:10192387]", - "location_in_gene": "Coding Exon 1, or 3' UTR depending on transcript", - "gene_strand": "+", - "reference_motif_reference_orientation": ["CTG"], - "pathogenic_motif_reference_orientation": ["CTG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CTG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [ + "id": "FRAXE_AFF2", + "disease_id": "FRAXE", + "gene": "AFF2", + "chrom": "chrX", + "start_hg38": 148500604, + "stop_hg38": 148500753, + "start_hg19": 147582124, + "stop_hg19": 147582273, + "start_t2t": 146765190, + "stop_t2t": 146765342, + "disease": "Fragile X syndrome, FRAXE type", + "inheritance": [ + "XR" + ], + "disease_description": "A nonsyndromic X-linked mental retardation (NS-XLMR) characterized by mild intellectual deficit. FRAXE is the most common form of NS-XLMR [@mondo:0010659].", + "hpo_terms": null, + "prevalence": "2/50000", + "prevalence_details": "1-4/100,000 males [@url:medlineplus.gov/genetics/condition/fragile-xe-syndrome]; 1/50-100,000 males, more than 50 families [@pmid:11246464]. Found in populations around the globe, including in the UK, US, Canada, Taiwan, Germany, Greece, Cyprus, Spain, and Finland [@pmid:11246464].", + "age_onset": "Typical: 2-10 [@pmid:11246464]. Range: 1-10; developmental delays without physical features can make onset difficult to detect until schooling [@omim:309548].", + "age_onset_min": 1, + "age_onset_max": 10, + "typ_age_onset_min": 2, + "typ_age_onset_max": 10, + "details": "Allele ranges (benign:4-39; pathogenic: >200) inferred from The Human Gene Mutation Database [@genereviews:NBK535148]. Intermediate alleles correspond to a premutation [@pmid:23914978]. Non-canonical motifs include: CGG/CCT/GTG/CAG/CTG3 [@pmid:35245110; @pmid:34111553].", + "mechanism": "LoF", + "mechanism_detail": "Loss of function via transcriptional silencing [@pmid:16205714; @pmid:36169768].", + "year": "1993 [@pmid:8334699]", + "location_in_gene": "5' UTR", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GCC" + ], + "pathogenic_motif_reference_orientation": [ + "GCC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CCG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 4, + "benign_max": 39, + "intermediate_min": 40, + "intermediate_max": 200, + "pathogenic_min": 201, + "pathogenic_max": 2000, + "motif_len": 3, + "ref_copies": 50.3, + "novel": "ref", + "gard": [ + "2378" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "INT399" + ], + "medgen": [ + "155512" + ], + "mondo": [ + "0010659" + ], + "omim": [ + "309548" + ], + "orphanet": [ + "100973" + ], + "gnomad": [ + "AFF2" + ], + "stripy": [ + "AFF2" + ], + "tr_atlas": [ + "TR173976" + ], + "webstr_hg38": [], + "webstr_hg19": [], + "locus_tags": [ + "supported_evidence", + "somatic_instability", + "anticipation", + "maternal_expansion", + "length_affects_penetrance", + "length_affects_severity" + ], + "disease_tags": [], + "references": [ + "pmid:11246464", + "omim:309548", + "pmid:16205714", + "pmid:36169768", + "genereviews:NBK535148", + "pmid:23914978", + "pmid:35245110", + "pmid:34111553", + "url:medlineplus.gov/genetics/condition/fragile-xe-syndrome", + "pmid:8334699", + "mondo:0010659" + ], + "additional_literature": [ + "pmid:41074692", + "pmid:40708890", + "pmid:35431806", + "pmid:28812997", + "pmid:25171808", + "pmid:24763282", + "pmid:22718980", + "pmid:21739600", + "pmid:21254876", + "pmid:21051337", + "pmid:17635840", + "pmid:17516099", + "pmid:16469443", + "pmid:11119302", + "pmid:10780779", + "pmid:10674158", + "pmid:10424820", + "pmid:9630071", + "pmid:9415475", + "pmid:9415473", + "pmid:9341861", + "pmid:8808600", + "pmid:8844091", + "pmid:8755928", + "pmid:8673086", + "pmid:7541938", + "pmid:7783163", + "pmid:7881407", + "pmid:7977354", + "pmid:8023854", + "pmid:8162055", + "pmid:8118462" + ] + }, + { + "id": "FRA2A_AFF3", + "disease_id": "FRA2A", + "gene": "AFF3", + "chrom": "chr2", + "start_hg38": 100104798, + "stop_hg38": 100104824, + "start_hg19": 100721260, + "stop_hg19": 100721286, + "start_t2t": 100563685, + "stop_t2t": 100563738, + "disease": "Intellectual disability associated with fragile site FRA2A", + "inheritance": [ + "AD" + ], + "disease_description": "These expansions are associated with intellectual disability and clinical phenotypes such as delayed motor development or delays in speech/language [@pmid:24763282].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "1/862 (1/654-1266) population prevalence of methylated AFF3 expansions (mild cognitive disability) [@pmid:39313615]. Disease cases observed in South Australia [@pmid:24763282].", + "age_onset": "Early childhood (small sample size) [@pmid:24763282].", + "age_onset_min": 1, + "age_onset_max": 7, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "Allele ranges established in study of 3 families; intermediate alleles likely premutations [@pmid:24763282]. Pathogenic threshold may be higher than 300 as this was the largest allele that could be accurately sized by the assay.", + "mechanism": "LoF/methylation", + "mechanism_detail": "Silencing of the FMR2 gene as a consequence of a CCG expansion located upstream of this gene [@malacard:KNS007].", + "year": "2014 [@pmid:24763282]", + "location_in_gene": "Intron 3", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "GCC" + ], + "pathogenic_motif_reference_orientation": [ + "GCC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CGG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 3, + "benign_max": 20, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 300, + "pathogenic_max": 300, + "motif_len": 3, + "ref_copies": 8.7, + "novel": "ref", + "gard": [], + "genereviews": [], + "malacard": [ + "KNS007" + ], + "medgen": [], + "mondo": [], + "omim": [ + "601464" + ], + "orphanet": [], + "gnomad": [ + "AFF3" + ], + "stripy": [], + "tr_atlas": [ + "TR252468" + ], + "webstr_hg38": [ + "288936" + ], + "webstr_hg19": [], + "locus_tags": [ + "supported_evidence" + ], + "disease_tags": [], + "references": [ + "pmid:24763282", + "malacard:KNS007", + "pmid:39313615" + ], + "additional_literature": [ + "pmid:40417743", + "pmid:37205357" + ] + }, + { + "id": "SBMA_AR", + "disease_id": "SBMA", + "gene": "AR", + "chrom": "chrX", + "start_hg38": 67545316, + "stop_hg38": 67545419, + "start_hg19": 66765158, + "stop_hg19": 66765261, + "start_t2t": 65975147, + "stop_t2t": 65975250, + "disease": "Spinal and bulbar muscular atrophy, Kennedy Disease", + "inheritance": [ + "XR" + ], + "disease_description": "Kennedy's disease, also known as bulbospinal muscular atrophy (BSMA), is a rare X-linked recessive motor neuron disease characterized by proximal and bulbar muscle wasting [@mondo:0010735].", + "hpo_terms": null, + "prevalence": "1/30000", + "prevalence_details": "1-2/100,000 (population-specific, higher in Finnish population, Canadian population) [@pmid:37628685]; 1/30,000 [@orphanet:481]; mutation frequency of 1:3182 10x more frequent than reported disease prevalence of 1 in 30,000 [@pmid:36797998]. Only documented in patients with European/Asian ancestry, including Scandinavian, English, Belgian, French, Italian, German, Polish, Spanish, Swiss, Moroccan, Turkish, Chinese, Japanese (more common because of a founder effect), East Indian (potentially related to Japanese founder mutation) [@pmid:37578398], Korean, and Vietnamese populations [@genereviews:NBK1333].", + "age_onset": "Typical: 20-49 [@pmid:11436124], Range: 8 [@pmid:15851746] - 83 [@doi:10.17161/2tmg0f25].", + "age_onset_min": 8, + "age_onset_max": 83, + "typ_age_onset_min": 20, + "typ_age_onset_max": 49, + "details": "Intermediate alleles indicate reduced penetrance [@genereviews:NBK1333]. Expansions larger than the pathogenic threshold in the AR gene should be evaluated carefully. Interruptions have not been observed in patient cases; it has been proposed that longer alleles with interruptions may not be pathogenic [@pmid:24041967]. Non-canonical motif CAA observed [@pmid:35245110]. Expansions are also detected ten-fold more often in a general population than would be expected by disease prevalence [@pmid:36797998]. Clinical evaluation and phenotypic matching may be necessary to determine diagnosis even in the presence of a pure expanded allele. It has been proposed that contractions may play a role in disease [@pmid:10398229]. Disease may be subclinical in females [@pmid:34922802], and can be clinically heterogeneous even within the same family [@pmid:20184516].", + "mechanism": "GoF", + "mechanism_detail": "Polyglutamine alters protein conformation leading to gain-of-function neurodegeneration [@pmid:29398703; @pmid:36169768]. Transcriptional dysregulation, axonal transport disruption, and mitochondrial dysfunction also play causative roles in the neurodegeneration [@pmid:22609045].", + "year": "1991 [@pmid:2062380]; the first triplet disease to be discovered [@pmid:15313856]", + "location_in_gene": "Coding Exon 1", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GCA" + ], + "pathogenic_motif_reference_orientation": [ + "GCA" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "AGC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 9, + "benign_max": 34, + "intermediate_min": 36, + "intermediate_max": 37, + "pathogenic_min": 38, + "pathogenic_max": 68, + "motif_len": 3, + "ref_copies": 34, + "novel": "ref", + "gard": [ + "6818" + ], + "genereviews": [ + "NBK1333" + ], + "malacard": [ + "SPN404" + ], + "medgen": [ + "333282" + ], + "mondo": [ + "0010735" + ], + "omim": [ + "313200" + ], + "orphanet": [ + "481" + ], + "gnomad": [ + "AR" + ], + "stripy": [ + "AR" + ], + "tr_atlas": [ + "TR169377" + ], + "webstr_hg38": [ + "859199" + ], + "webstr_hg19": [], + "locus_tags": [ + "supported_evidence", + "contraction", + "somatic_instability", + "anticipation", + "paternal_expansion", + "length_affects_severity", + "length_affects_penetrance", + "length_affects_onset" + ], + "disease_tags": [], + "references": [ + "pmid:11436124", + "pmid:15851746", + "doi:10.17161/2tmg0f25", + "pmid:29398703", + "pmid:36169768", + "pmid:22609045", + "genereviews:NBK1333", + "pmid:24041967", + "pmid:35245110", + "pmid:36797998", + "pmid:10398229", + "pmid:34922802", + "pmid:20184516", + "pmid:37628685", + "orphanet:481", + "pmid:37578398", + "pmid:2062380", + "pmid:15313856", + "mondo:0010735" + ], + "additional_literature": [ + "pmid:41361869", + "pmid:41246945", + "pmid:40912964", + "pmid:40614362", + "pmid:40585427", + "pmid:40488202", + "pmid:40450087", + "pmid:40371721", + "pmid:40366765", + "pmid:40031964", + "pmid:39755011", + "pmid:39729861", + "pmid:39694906", + "pmid:39570490", + "pmid:39189540", + "pmid:39140081", + "pmid:38976730", + "pmid:38860410", + "pmid:38737445", + "pmid:38701087", + "pmid:38585669", + "pmid:38284836", + "pmid:38171945", + "pmid:37936145", + "pmid:37718889", + "pmid:37715620", + "pmid:37422780", + "pmid:37269008", + "pmid:37045687", + "pmid:36988133", + "pmid:36717478", + "pmid:36701310", + "pmid:36622568", + "pmid:36599645", + "pmid:36585400", + "pmid:36142533", + "pmid:36137740", + "pmid:35982373", + "pmid:35876459", + "pmid:35872088", + "pmid:35867854", + "pmid:35661131", + "pmid:35599735", + "pmid:35571498", + "pmid:35237894", + "pmid:35230239", + "pmid:35189449", + "pmid:35182509", + "pmid:35165376", + "pmid:34914563", + "pmid:34744823", + "pmid:34723064", + "pmid:34407295", + "pmid:34390226", + "pmid:34372915", + "pmid:34006154", + "pmid:33865179", + 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"pmid:8878435", + "pmid:8737374", + "pmid:8926495", + "pmid:8807333", + "pmid:8645957", + "pmid:7772520", + "pmid:7757084", + "pmid:7719348", + "pmid:8065934", + "pmid:7951325", + "pmid:7515106", + "pmid:8232348", + "pmid:1461383", + "pmid:1734865" + ] + }, + { + "id": "EIEE1_ARX", + "disease_id": "EIEE1", + "gene": "ARX", + "chrom": "chrX", + "start_hg38": 25013649, + "stop_hg38": 25013697, + "start_hg19": 25031766, + "stop_hg19": 25031814, + "start_t2t": 24597886, + "stop_t2t": 24597934, + "disease": "Early-infantile epileptic encephalopathy", + "inheritance": [ + "XR" + ], + "disease_description": "Developmental and epileptic encephalopathy-1 (DEE1) is a severe form of epilepsy characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns, characterized by high-voltage bursts alternating with almost flat suppression phases [@omim:308350].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Found in individuals of multiple ethnicities, including European and Asian ancestry [@pmid:12874418].", + "age_onset": "Typical: 0 [@pmid:21204215; @pmid:9307258]; Range: 0-4; 70% of cases involve infantile spasms, leading to seizures by 3 or 4 years [@pmid:19587282].", + "age_onset_min": 0, + "age_onset_max": 4, + "typ_age_onset_min": 0, + "typ_age_onset_max": 0, + "details": "ARX expansions [@genereviews:NBK535148] result in a phenotypic spectrum of conditions including Partington syndrome [@omim:309510], Early Infantile Epileptic Encephalopathy [@omim:308350], Agenesis of Corpus Callosum with Abnormal Genitalia [@omim:300004], and X-Linked Lissencephaly with Ambiguous Genitalia [@omim:300215], described in the literature [@pmid:26029707; @pmid:20506206].", + "mechanism": "LoF", + "mechanism_detail": "Polyalanine expansions lead to reduction in protein product through unclear mechanism [@pmid:36169768; @pmid:38467784]. Apparent aggregation and mis-localisation of mutant protein, increased with expansion length [@genereviews:NBK51932].", + "year": "2002 [@pmid:11889467]", + "location_in_gene": "Coding Exon 2, aa 110-115", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "NGC" + ], + "pathogenic_motif_reference_orientation": [ + "NGC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CNG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 10, + "benign_max": 16, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 17, + "pathogenic_max": 27, + "motif_len": 3, + "ref_copies": 14.7, + "novel": "ref", + "gard": [ + "15298" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "ERL057" + ], + "medgen": [ + "483052" + ], + "mondo": [ + "0010632" + ], + "omim": [ + "308350", + "300419", + "300215" + ], + "orphanet": [ + "182079" + ], + "gnomad": [ + "ARX_1" + ], + "stripy": [ + "ARX_1" + ], + "tr_atlas": [ + "TR167317" + ], + "webstr_hg38": [ + "843651" + ], + "webstr_hg19": [ + "STR_1542607" + ], + "locus_tags": [ + "supported_evidence", + "length_affects_phenotype" + ], + "disease_tags": [ + "phenotypic_spectrum" + ], + "references": [ + "pmid:21204215", + "pmid:9307258", + "pmid:19587282", + "pmid:36169768", + "pmid:38467784", + "genereviews:NBK51932", + "genereviews:NBK535148", + "omim:309510", + "omim:308350", + "omim:300004", + "omim:300215", + "pmid:26029707", + "pmid:20506206", + "pmid:12874418", + "pmid:11889467" + ], + "additional_literature": [ + "pmid:40608247", + "pmid:39933386", + "pmid:39123069", + "pmid:36571524", + "pmid:33847015", + "pmid:32033960", + "pmid:28627419", + "pmid:28602636", + "pmid:27798109", + "pmid:26571108", + "pmid:25171319", + "pmid:24236044", + "pmid:23968833", + "pmid:23246292", + "pmid:22628459", + "pmid:22108177", + "pmid:20376468", + "pmid:19018235", + "pmid:18823727", + "pmid:18462864", + "pmid:17668384", + "pmid:17664401", + "pmid:17480217", + "pmid:15533998" + ] + }, + { + "id": "PRTS_ARX", + "disease_id": "PRTS", + "gene": "ARX", + "chrom": "chrX", + "start_hg38": 25013529, + "stop_hg38": 25013565, + "start_hg19": 25031646, + "stop_hg19": 25031682, + "start_t2t": 24597766, + "stop_t2t": 24597802, + "disease": "Partington syndrome", + "inheritance": [ + "XR" + ], + "disease_description": "A rare neurological condition that is primarily characterized by mild to moderate intellectual disability and dystonia of the hands. Other signs and symptoms may include dysarthria, behavioral abnormalities, recurrent seizures and/or an unusual gait (style of walking). Partington syndrome usually occurs in males; when it occurs in females, the signs and symptoms are often less severe. It is caused by changes (mutations) in the ARX gene and is inherited in an X-linked recessive manner. Treatment is based on the signs and symptoms present in each person [@mondo:0010654].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Limited clinical cases of predominantly European ancestry, such as Welsh/Belgian [@omim:309510].", + "age_onset": "Typical: 1-3; Range: 0-4. Mild phenotypes can make diagnosis difficult (expansions are particularly mild/absent in females) [@omim:309510].", + "age_onset_min": 0, + "age_onset_max": 4, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "ARX expansions [@genereviews:NBK535148] result in a phenotypic spectrum of conditions including Partington syndrome [@omim:309510], Early Infantile Epileptic Encephalopathy [@omim:308350], Agenesis of Corpus Callosum with Abnormal Genitalia [@omim:300004], and X-Linked Lissencephaly with Ambiguous Genitalia [@omim:300215], described in the literature [@pmid:26029707; @pmid:20506206].", + "mechanism": "LoF", + "mechanism_detail": "Polyalanine expansions lead to reduction in protein product through unclear mechanism [@pmid:36169768; @pmid:38467784]. Apparent aggregation and mis-localisation of mutan protein, increased with expansion length [@genereviews:NBK51932].", + "year": "2002 [@pmid:11889467]", + "location_in_gene": "Coding Exon 2, aa 144-155", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "NGC" + ], + "pathogenic_motif_reference_orientation": [ + "NGC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CNG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 12, + "benign_max": 12, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 20, + "pathogenic_max": 20, + "motif_len": 3, + "ref_copies": 12, + "novel": "ref", + "gard": [ + "4235" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "PRT003" + ], + "medgen": [ + "163237" + ], + "mondo": [ + "0010654" + ], + "omim": [ + "309510" + ], + "orphanet": [ + "94083" + ], + "gnomad": [ + "ARX_2" + ], + "stripy": [ + "ARX_2" + ], + "tr_atlas": [ + "TR167316" + ], + "webstr_hg38": [], + "webstr_hg19": [], + "locus_tags": [ + "supported_evidence", + "length_affects_phenotype" + ], + "disease_tags": [ + "phenotypic_spectrum" + ], + "references": [ + "omim:309510", + "pmid:36169768", + "pmid:38467784", + "genereviews:NBK51932", + "genereviews:NBK535148", + "omim:308350", + "omim:300004", + "omim:300215", + "pmid:26029707", + "pmid:20506206", + "pmid:11889467", + "mondo:0010654" + ], + "additional_literature": [ + "pmid:40608247", + "pmid:39933386", + "pmid:39123069", + "pmid:36571524", + "pmid:33847015", + "pmid:32033960", + "pmid:28627419", + "pmid:28602636", + "pmid:27798109", + "pmid:26571108", + "pmid:25171319", + "pmid:24236044", + "pmid:23968833", + "pmid:23246292", + "pmid:22628459", + "pmid:22108177", + "pmid:21204215", + "pmid:20376468", + "pmid:19587282", + "pmid:19018235", + "pmid:18823727", + "pmid:18462864", + "pmid:17668384", + "pmid:17664401", + "pmid:17480217", + "pmid:15533998", + "pmid:12874418" + ] + }, + { + "id": "DRPLA_ATN1", + "disease_id": "DRPLA", + "gene": "ATN1", + "chrom": "chr12", + "start_hg38": 6936716, + "stop_hg38": 6936775, + "start_hg19": 7045879, + "stop_hg19": 7045938, + "start_t2t": 6947903, + "stop_t2t": 6947941, + "disease": "Dentatorubral-Pallidoluysian Atrophy", + "inheritance": [ + "AD" + ], + "disease_description": "Dentatorubral pallidoluysian atrophy (DRPLA) is a rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I). It is characterized by involuntary movements, ataxia, epilepsy, mental disorders, cognitive decline and prominent anticipation [@mondo:0007435]. Epilepsy is common in earlier onset cases [@pmid:41147955].", + "hpo_terms": null, + "prevalence": "4.5/1000000", + "prevalence_details": "2-7/1,000,000. More prevalent in Japanese populations; also reported in North America, South America, Europe, and Australia [@genereviews:NBK1491].", + "age_onset": "Typical: 20-40 [@pmid:6808417; @genereviews:NBK1491]. Range: 0 [@pmid:11160976] - 72 [@genereviews:NBK1491].", + "age_onset_min": 0, + "age_onset_max": 72, + "typ_age_onset_min": 20, + "typ_age_onset_max": 40, + "details": "Pathogenic expansions (48-93) are fully penetrant with the exception of one documented case of 51 repeats; intermediate alleles (36-47) are associated with a milder phenotype and can expand upon transmission [@genereviews:NBK1491]. CAA interruptions have been observed without known clinical association [@pmid:35245110]. Length of the repeat is inversely associated with age of onset and severe epilepsy phenotype [@pmid:41147955].", + "mechanism": "GoF", + "mechanism_detail": "Polyglutamine expansions leading to gain of function [@genereviews:NBK1491].", + "year": "1994 [@pmid:7842016]", + "location_in_gene": "Coding Exon 5", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "CAG" + ], + "pathogenic_motif_reference_orientation": [ + "CAG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "AGC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 6, + "benign_max": 35, + "intermediate_min": 36, + "intermediate_max": 47, + "pathogenic_min": 48, + "pathogenic_max": 93, + "motif_len": 3, + "ref_copies": 19, + "novel": "ref", + "gard": [ + "5643" + ], + "genereviews": [ + "NBK1491" + ], + "malacard": [ + "DNT005" + ], + "medgen": [ + "155630" + ], + "mondo": [ + "0007435" + ], + "omim": [ + "125370" + ], + "orphanet": [ + "101" + ], + "gnomad": [ + "ATN1" + ], + "stripy": [ + "ATN1" + ], + "tr_atlas": [ + "TR114246" + ], + "webstr_hg38": [ + "5050156" + ], + "webstr_hg19": [ + "Expansion_ATN1/DRPLA" + ], + "locus_tags": [ + "supported_evidence", + "anticipation", + "somatic_instability", + "paternal_expansion", + "length_affects_onset", + "length_affects_severity", + "length_affects_phenotype" + ], + "disease_tags": [ + "ataxia", + "epilepsy" + ], + "references": [ + "pmid:6808417", + "genereviews:NBK1491", + "pmid:11160976", + "pmid:35245110", + "pmid:41147955", + "pmid:7842016", + "mondo:0007435" + ], + "additional_literature": [ + "pmid:41355374", + "pmid:41254939", + "pmid:41082794", + "pmid:40832356", + "pmid:40488180", + "pmid:40450087", + "pmid:40340521", + "pmid:40298952", + "pmid:40263757", + "pmid:40237283", + "pmid:39820777", + "pmid:39812846", + "pmid:39742457", + "pmid:39224955", + "pmid:38961870", + "pmid:38227102", + "pmid:38152578", + "pmid:37243799", + "pmid:36599645", + "pmid:36530930", + "pmid:35182509", + "pmid:34968706", + "pmid:34022586", + "pmid:33106889", + "pmid:32711193", + "pmid:32675418", + "pmid:32129252", + "pmid:31493762", + "pmid:30891880", + "pmid:30827498", + "pmid:30615214", + "pmid:30314815", + "pmid:30120431", + "pmid:29801887", + "pmid:29715545", + "pmid:29249939", + "pmid:28782341", + "pmid:28585930", + "pmid:27896316", + "pmid:27400454", + "pmid:26374734", + "pmid:26077168", + "pmid:25842919", + "pmid:25466696", + "pmid:24972706", + "pmid:24534762", + "pmid:23933208", + "pmid:23364790", + "pmid:23263592", + "pmid:23026538", + "pmid:22527233", + "pmid:22520093", + "pmid:22342974", + "pmid:22297462", + "pmid:21108634", + "pmid:20589872", + "pmid:19429075", + "pmid:19370769", + "pmid:19259763", + "pmid:19039037", + "pmid:18182848", + "pmid:17965145", + "pmid:17961920", + "pmid:17420317", + "pmid:16967484", + "pmid:16858508", + "pmid:16251216", + "pmid:16199124", + "pmid:15553088", + "pmid:15223312", + "pmid:15148151", + "pmid:15133824", + "pmid:14756671", + "pmid:12925365", + "pmid:12805114", + "pmid:12764052", + "pmid:12614315", + "pmid:12235319", + "pmid:12042281", + "pmid:11939898", + "pmid:11807410", + "pmid:11711886", + "pmid:11709002", + "pmid:11689158", + "pmid:11574112", + "pmid:11198291", + "pmid:10942107", + "pmid:10894992", + "pmid:10814707", + "pmid:10768629", + "pmid:10766906", + "pmid:10677044", + "pmid:10564878", + "pmid:10515170", + "pmid:10486315", + "pmid:10453742", + "pmid:10332026", + "pmid:10085113", + "pmid:10084125", + "pmid:9949204", + "pmid:9887337", + "pmid:9758625", + "pmid:9705838", + "pmid:9696528", + "pmid:9647693", + "pmid:9613852", + "pmid:9507387", + "pmid:9462738", + "pmid:9385362", + "pmid:9361003", + "pmid:9187480", + "pmid:9124808", + "pmid:9109905", + "pmid:9106530", + "pmid:9050922", + "pmid:9020849", + "pmid:8962095", + "pmid:9001798", + "pmid:8651298", + "pmid:8655136", + "pmid:8780110", + "pmid:8644735", + "pmid:8852663", + "pmid:8926495", + "pmid:8559378", + "pmid:8557266", + "pmid:7633415", + "pmid:7868125", + "pmid:7824105", + "pmid:7885531", + "pmid:8136840", + "pmid:8136826", + "pmid:7734112" + ] + }, + { + "id": "SCA1_ATXN1", + "disease_id": "SCA1", + "gene": "ATXN1", + "chrom": "chr6", + "start_hg38": 16327633, + "stop_hg38": 16327724, + "start_hg19": 16327864, + "stop_hg19": 16327955, + "start_t2t": 16200188, + "stop_t2t": 16200282, + "disease": "Spinocerebellar ataxia type 1", + "inheritance": [ + "AD" + ], + "disease_description": "Spinocerebellar ataxia type 1 (SCA1) is a subtype of type I autosomal dominant cerebellar ataxia (ADCA type I) characterized by dysarthria, writing difficulties, limb ataxia, and commonly nystagmus and saccadic abnormalities [@mondo:0008119].", + "hpo_terms": null, + "prevalence": "1.5/100000", + "prevalence_details": "1-2/100,000. Cases have been reported worldwide, although prevalences varies by ancestry/ethnicity [@genereviews:NBK1184].", + "age_onset": "Typical: 20-39 [@url:https://www.uptodate.com/contents/autosomal-dominant-spinocerebellar-ataxias]; Range: 6 [@pmid:3165612] - 63 [@pmid:8825276].", + "age_onset_min": 6, + "age_onset_max": 63, + "typ_age_onset_min": 20, + "typ_age_onset_max": 39, + "details": "Penetrance is dependent on sequence purity in addition to expansion length: pure repeats are pathogenic at 39 repeats [@pmid:37906407], while CAT interruptions [@pmid:35245110] can lead to reduced penetrance at comparable lengths [@genereviews:NBK1184]. Regardless, intermediate alleles are considered premutations which may lead to disease upon transmission [@genereviews:NBK1184].", + "mechanism": "GoF/LoF", + "mechanism_detail": "Polyglutamine expansion leading to toxic gain of function with eventual misregulation-based loss of function/dominant negative [@genereviews:NBK1184; @pmid:35573049].", + "year": "1993 [@pmid:8358429]", + "location_in_gene": "Coding Exon 8", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "CTG" + ], + "pathogenic_motif_reference_orientation": [ + "CTG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "AGC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 6, + "benign_max": 35, + "intermediate_min": 36, + "intermediate_max": 38, + "pathogenic_min": 39, + "pathogenic_max": 91, + "motif_len": 3, + "ref_copies": 30.3, + "novel": "ref", + "gard": [ + "4071" + ], + "genereviews": [ + "NBK1184" + ], + "malacard": [ + "SPN294" + ], + "medgen": [ + "155703" + ], + "mondo": [ + "0008119" + ], + "omim": [ + "164400" + ], + "orphanet": [ + "98755" + ], + "gnomad": [ + "ATXN1" + ], + "stripy": [ + "ATXN1" + ], + "tr_atlas": [ + "TR63118" + ], + "webstr_hg38": [ + "5767842" + ], + "webstr_hg19": [ + "Expansion_SCA1/ATXN1" + ], + "locus_tags": [ + "supported_evidence", + "somatic_instability", + "anticipation", + "paternal_expansion", + "length_affects_onset", + "length_affects_penetrance", + "length_affects_severity", + "motif_affects_instability", + "motif_affects_onset", + "motif_affects_penetrance", + "motif_affects_severity" + ], + "disease_tags": [ + "spinocerebellar_ataxia" + ], + "references": [ + "url:https://www.uptodate.com/contents/autosomal-dominant-spinocerebellar-ataxias", + "pmid:3165612", + "pmid:8825276", + "genereviews:NBK1184", + "pmid:35573049", + "pmid:37906407", + "pmid:35245110", + "pmid:8358429", + "mondo:0008119" + ], + "additional_literature": [ + "pmid:41435767", + "pmid:41426430", + "pmid:41254939", + "pmid:41149812", + "pmid:40900235", + "pmid:40488180", + "pmid:40450087", + "pmid:39820777", + "pmid:39456985", + "pmid:39289638", + "pmid:39211226", + "pmid:38961870", + "pmid:38626762", + "pmid:38585669", + "pmid:38308084", + "pmid:38125008", + "pmid:37827155", + "pmid:37776516", + "pmid:37397792", + "pmid:37146135", + "pmid:37043475", + "pmid:36599645", + "pmid:36549973", + "pmid:36291186", + "pmid:35869263", + "pmid:35525134", + "pmid:35182509", + "pmid:34830553", + "pmid:34635619", + "pmid:34600502", + "pmid:34372915", + "pmid:34179866", + "pmid:33502644", + "pmid:33276461", + "pmid:33159825", + "pmid:32954321", + "pmid:32761094", + "pmid:32580238", + "pmid:32339968", + "pmid:31940111", + "pmid:31810584", + "pmid:31645175", + "pmid:30891880", + "pmid:30729852", + "pmid:30615214", + "pmid:30324307", + "pmid:30314815", + "pmid:30120431", + "pmid:30108484", + "pmid:29845242", + "pmid:29656178", + "pmid:29497168", + "pmid:29274668", + "pmid:29249939", + "pmid:29057148", + "pmid:28585930", + "pmid:28444220", + "pmid:26077168", + "pmid:25595967", + "pmid:25344417", + "pmid:25255716", + "pmid:24972706", + "pmid:24594842", + "pmid:24534762", + "pmid:23197749", + "pmid:22884877", + "pmid:18337722", + "pmid:18301861", + "pmid:17961920", + "pmid:17420317", + "pmid:17116127", + "pmid:15300851" + ] + }, + { + "id": "SCA10_ATXN10", + "disease_id": "SCA10", + "gene": "ATXN10", + "chrom": "chr22", + "start_hg38": 45795354, + "stop_hg38": 45795424, + "start_hg19": 46191234, + "stop_hg19": 46191304, + "start_t2t": 46280059, + "stop_t2t": 46280134, + "disease": "Spinocerebellar ataxia type 10", + "inheritance": [ + "AD" + ], + "disease_description": "Spinocerebellar ataxia type 10 (SCA10) is a subtype of type I autosomal dominant cerebellar ataxia (ADCA type I). It is characterized by slowly progressive cerebellar syndrome and epilepsy, sometimes mild pyramidal signs, peripheral neuropathy and neuropsychological disturbances [@mondo:0011330].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Unknown prevalence, >300 individuals. Cases have been identified in Mexico, Brazil, China, and Japan [@genereviews:NBK1175].", + "age_onset": "Typical: 12-48; Range: 11-83 [@genereviews:NBK1175].", + "age_onset_min": 11, + "age_onset_max": 83, + "typ_age_onset_min": 12, + "typ_age_onset_max": 48, + "details": "Unaffected individuals are usually (82%) compound heterozygotes in the benign range [@genereviews:NBK1175]. Intermediate alleles show reduced penetrance, and exact distinction between intermediate and the lower end of the pathogenic range is unclear [@genereviews:NBK1175]. Expansions are frequently interrupted by ATCCT, ATCCC, ATTCC, ATTTCT, ATATTCT, ATTCTTCT, or ATTCTTCT; interruptions of ATTGT, TTTCT, ATTTTCT, ATTCTCT have been noted [@pmid:36199580] as has the interruption ATGCT [@pmid:19234597]. The ATCCT interruption motif is associated with a higher prevalence of epileptic seizures [@pmid:24318420]. Different motif patterns and mixed motif ratios may influence age of onset and anticipation [@doi:10.21203/rs.3.rs-5989910/v1].", + "mechanism": "GoF", + "mechanism_detail": "Transdominant mechanism theorized [@pmid:38467784].", + "year": "2000 [@pmid:11017075]", + "location_in_gene": "Intron 9", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "ATTCT" + ], + "pathogenic_motif_reference_orientation": [ + "ATTCT" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "ATTCT" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 10, + "benign_max": 32, + "intermediate_min": 33, + "intermediate_max": 850, + "pathogenic_min": 800, + "pathogenic_max": 4500, + "motif_len": 5, + "ref_copies": 14, + "novel": "ref", + "gard": [ + "10474" + ], + "genereviews": [ + "NBK1175" + ], + "malacard": [ + "SPN314" + ], + "medgen": [ + "369786" + ], + "mondo": [ + "0011330" + ], + "omim": [ + "603516" + ], + "orphanet": [ + "98761" + ], + "gnomad": [ + "ATXN10" + ], + "stripy": [ + "ATXN10" + ], + "tr_atlas": [ + "TR165509" + ], + "webstr_hg38": [ + "1027359", + "4921433" + ], + "webstr_hg19": [ + "STR_909210" + ], + "locus_tags": [ + "supported_evidence", + "somatic_instability", + "anticipation", + "paternal_expansion", + "length_affects_onset", + "length_affects_penetrance", + "length_affects_phenotype", + "motif_affects_instability", + "motif_affects_penetrance", + "motif_affects_phenotype" + ], + "disease_tags": [ + "spinocerebellar_ataxia" + ], + "references": [ + "genereviews:NBK1175", + "pmid:38467784", + "pmid:36199580", + "pmid:19234597", + "pmid:24318420", + "doi:10.21203/rs.3.rs-5989910/v1", + "pmid:11017075", + "mondo:0011330" + ], + "additional_literature": [ + "pmid:41229449", + "pmid:41074692", + "pmid:40900235", + "pmid:40898875", + "pmid:40488180", + "pmid:40067487", + "pmid:39820777", + "pmid:38961870", + "pmid:38832639", + "pmid:36092952", + "pmid:35103298", + "pmid:34970537", + "pmid:33502644", + "pmid:32520333", + "pmid:32160188", + "pmid:31737797", + "pmid:31445906", + "pmid:31342269", + "pmid:29922950", + "pmid:29316893", + "pmid:28890930", + "pmid:28423040", + "pmid:27248057", + "pmid:26374734", + "pmid:26295943", + "pmid:26077168", + "pmid:26039897", + "pmid:25466696", + "pmid:24278426", + "pmid:24269018", + "pmid:23443018", + "pmid:23083689", + "pmid:23026538", + "pmid:22065565", + "pmid:22053702", + "pmid:21282659", + "pmid:20065034", + "pmid:19651850", + "pmid:19306311", + "pmid:19171184", + "pmid:19147916", + "pmid:17961920", + "pmid:17846122", + "pmid:16924013", + "pmid:16498633", + "pmid:16385455", + "pmid:15505178", + "pmid:15201271", + "pmid:15148151", + "pmid:15096564", + "pmid:12764052", + "pmid:12589756", + "pmid:11839840", + "pmid:11160961", + "pmid:9973298" + ] + }, + { + "id": "SCA2_ATXN2", + "disease_id": "SCA2", + "gene": "ATXN2", + "chrom": "chr12", + "start_hg38": 111598949, + "stop_hg38": 111599019, + "start_hg19": 112036753, + "stop_hg19": 112036823, + "start_t2t": 111575873, + "stop_t2t": 111575940, + "disease": "Spinocerebellar ataxia type 2", + "inheritance": [ + "AD", + "AR" + ], + "disease_description": "A subtype of type I autosomal dominant cerebellar ataxia (ADCA type I) characterized by truncal ataxia, dysarthria, slowed saccades and less commonly ophthalmoparesis and chorea [@mondo:0008458].", + "hpo_terms": null, + "prevalence": "1.5/100000", + "prevalence_details": "1-2/100,000 (population-dependent) [@pmid:29100084]. Cases have been found across ethnicities/ancestries, with population-dependent prevalence [@genereviews:NBK1275].", + "age_onset": "Typical: 30-39 [@genereviews:NBK1275]; Range: 2-86 [@omim:183090].", + "age_onset_min": 2, + "age_onset_max": 86, + "typ_age_onset_min": 30, + "typ_age_onset_max": 39, + "details": "Full penetrance of single alleles occurs at ~35 repeats [@genereviews:NBK1275; @pmid:37906407] and pathogenic expansions have been documented as large as 500 repeats [@pmid:12116207]. 33-34 length repeats are associated with reduced penetrance and later onset (age >50 years) [@genereviews:NBK1275]. Homozygous 31 repeat alleles may lead to recessive disease [@pmid:30533529], while a single 30-32 repeat is associated with increased ALS risk [@genereviews:NBK1275; @pmid:25285812]. There is some evidence that all CAG-repeat expansions in ATXN2 may be a risk factor for ALS, regardless of length and interruptions [@pmid:39956874]. Interruptions observed include CAA, CGG, CGC, which appear to stabilize the allele in transmission [@genereviews:NBK1275]. May confer risk for amyotrophic lateral sclerosis [@pmid:32954321].", + "mechanism": "GoF/LoF", + "mechanism_detail": "Polyglutamine cytoplasmic aggregates leading to cellular apoptosis; RAN translation implicated [@genereviews:NBK1275].", + "year": "1996 [@pmid:8896556]", + "location_in_gene": "Coding Exon 1", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "CTG" + ], + "pathogenic_motif_reference_orientation": [ + "CTG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "AGC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 14, + "benign_max": 30, + "intermediate_min": 31, + "intermediate_max": 34, + "pathogenic_min": 35, + "pathogenic_max": 500, + "motif_len": 3, + "ref_copies": 23.3, + "novel": "ref", + "gard": [ + "4072" + ], + "genereviews": [ + "NBK1275" + ], + "malacard": [ + "SPN301" + ], + "medgen": [ + "155704" + ], + "mondo": [ + "0008458" + ], + "omim": [ + "183090" + ], + "orphanet": [ + "98756" + ], + "gnomad": [ + "ATXN2" + ], + "stripy": [ + "ATXN2" + ], + "tr_atlas": [ + "TR120465" + ], + "webstr_hg38": [ + "598560", + "5117050" + ], + "webstr_hg19": [ + "Expansion_SCA2/ATXN2" + ], + "locus_tags": [ + "supported_evidence", + "somatic_instability", + "anticipation", + "paternal_expansion", + "maternal_expansion", + "length_affects_onset", + "length_affects_penetrance", + "length_affects_phenotype", + "length_affects_severity", + "motif_affects_instability", + "motif_affects_phenotype", + "proposed_modifier" + ], + "disease_tags": [ + "spinocerebellar_ataxia" + ], + "references": [ + "genereviews:NBK1275", + "omim:183090", + "pmid:37906407", + "pmid:12116207", + "pmid:30533529", + "pmid:25285812", + "pmid:39956874", + "pmid:32954321", + "pmid:29100084", + "pmid:8896556", + "mondo:0008458" + ], + "additional_literature": [ + "pmid:41435767", + "pmid:41426430", + "pmid:41373690", + "pmid:41359433", + "pmid:41310328", + "pmid:41298695", + "pmid:41196070", + "pmid:41149812", + "pmid:41082794", + "pmid:41077586", + "pmid:41071260", + "pmid:41009775", + "pmid:41001200", + "pmid:40908144", + "pmid:40906330", + "pmid:40900235", + "pmid:40746751", + "pmid:40684213", + "pmid:40556342", + "pmid:40488180", + "pmid:40346885", + "pmid:40220918", + "pmid:40004498", + "pmid:39940702", + "pmid:39820777", + "pmid:39812846", + "pmid:39804470", + "pmid:39571249", + "pmid:39521966", + "pmid:39512795", + "pmid:39457708", + "pmid:39420034", + "pmid:39317855", + "pmid:39209824", + "pmid:39200113", + "pmid:39048885", + "pmid:39004246", + "pmid:38961870", + "pmid:38715656", + "pmid:38667292", + "pmid:38642323", + "pmid:38626762", + "pmid:38585669", + "pmid:38419144", + "pmid:38397958", + "pmid:38340219", + "pmid:38239855", + "pmid:38227102", + "pmid:38165578", + "pmid:38152578", + "pmid:37848721", + "pmid:37821389", + "pmid:37397792", + "pmid:37379724", + 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"pmid:9741408", + "pmid:9710044", + "pmid:9696528", + "pmid:9674805", + "pmid:9613852", + "pmid:9588855", + "pmid:9577387", + "pmid:9549522", + "pmid:9507387", + "pmid:9436730", + "pmid:9385362", + "pmid:9403486", + "pmid:9403480", + "pmid:9339711", + "pmid:9339681", + "pmid:9259275", + "pmid:9225982", + "pmid:10735276", + "pmid:9106530", + "pmid:9020849", + "pmid:10464657", + "pmid:8968739", + "pmid:8896557", + "pmid:8896555", + "pmid:8559378", + "pmid:7477379", + "pmid:7762567" + ] + }, + { + "id": "SCA3_ATXN3", + "disease_id": "SCA3, MJD", + "gene": "ATXN3", + "chrom": "chr14", + "start_hg38": 92071010, + "stop_hg38": 92071052, + "start_hg19": 92537354, + "stop_hg19": 92537396, + "start_t2t": 86300519, + "stop_t2t": 86300603, + "disease": "Spinocerebellar ataxia type 3/Machado-Joseph disease", + "inheritance": [ + "AD" + ], + "disease_description": "Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most common subtype of type 1 autosomal dominant cerebellar ataxia (ADCA type 1), a neurodegenerative disorder, and is characterized by ataxia, external progressive ophthalmoplegia, and other neurological manifestations [@mondo:0007182]. Research suggests that length of ATXN2 expansions may affect the phenotype of SCA3 [@pmid:40684213].", + "hpo_terms": null, + "prevalence": "2.1/100000", + "prevalence_details": "1-5/100,000 [@pmid:29100084]. Most prevalent SCA subtype [@genereviews:NBK557816]. Found worldwide across ancestries/ethnicities [@genereviews:NBK1196].", + "age_onset": "Typical: 10-49 [@genereviews:NBK1196]; 3 [@pmid:40004498] - 73 [@genereviews:NBK1196; @pmid:30414314].", + "age_onset_min": 3, + "age_onset_max": 73, + "typ_age_onset_min": 10, + "typ_age_onset_max": 49, + "details": "Benign alleles range from 11-44 repeats [@pmid:37906407], with intermediate alleles (45-59) associated with incomplete penetrance and non-classic phenotypes [@genereviews:NBK1196]. The threshold between incomplete and full penetrance is unclear, but presumed to occur at ~60 repeats [@genereviews:NBK1196; @pmid:37906407]. The interruption CAA has been observed [@pmid:35245110]; AAG is present in hg38 reference sequence. The APOE ε4 allele appears to act as a disease modifier [@pmid:39731318]; GLS expansions may also function as disease modifiers [@pmid:39699045].", + "mechanism": "GoF", + "mechanism_detail": "Polyglutamine expansion leading to gain of function; aggregated and mislocalized proteins in neurons [@pmid:36169768; @genereviews:NBK1196].", + "year": "1994 [@pmid:7874163]", + "location_in_gene": "Coding Exon 10", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "CTG" + ], + "pathogenic_motif_reference_orientation": [ + "CTG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "AGC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 11, + "benign_max": 44, + "intermediate_min": 45, + "intermediate_max": 59, + "pathogenic_min": 60, + "pathogenic_max": 87, + "motif_len": 3, + "ref_copies": 14, + "novel": "ref", + "gard": [ + "6801" + ], + "genereviews": [ + "NBK1196" + ], + "malacard": [ + "MCH002" + ], + "medgen": [ + "9841" + ], + "mondo": [ + "0007182" + ], + "omim": [ + "109150" + ], + "orphanet": [ + "98757" + ], + "gnomad": [ + "ATXN3" + ], + "stripy": [ + "ATXN3" + ], + "tr_atlas": [ + "TR132758" + ], + "webstr_hg38": [ + "5316666", + "1481402" + ], + "webstr_hg19": [ + "Expansion_SCA3_MJD/ATXN3" + ], + "locus_tags": [ + "supported_evidence", + "somatic_instability", + "anticipation", + "paternal_expansion", + "maternal_expansion", + "length_affects_onset", + "length_affects_phenotype", + "length_affects_severity" + ], + "disease_tags": [ + "spinocerebellar_ataxia" + ], + "references": [ + "genereviews:NBK1196", + "pmid:40004498", + "pmid:30414314", + "pmid:36169768", + "pmid:37906407", + "pmid:35245110", + "pmid:39731318", + "pmid:39699045", + "pmid:29100084", + "genereviews:NBK557816", + "pmid:7874163", + "mondo:0007182", + "pmid:40684213" + ], + "additional_literature": [ + "pmid:41435767", + "pmid:41358280", + "pmid:41082794", + "pmid:41058593", + "pmid:41009775", + "pmid:41001200", + "pmid:40906330", + "pmid:40900235", + "pmid:40890629", + "pmid:40880681", + "pmid:40797466", + "pmid:40754098", + "pmid:40738252", + "pmid:40692435", + "pmid:40635703", + "pmid:40488202", + "pmid:40488180", + "pmid:40450087", + "pmid:40204795", + "pmid:40178277", + "pmid:40152810", + "pmid:39987589", + "pmid:39921113", + "pmid:39820777", + "pmid:39571249", + "pmid:39516744", + "pmid:39456985", + "pmid:39375222", + "pmid:39317855", + "pmid:39298485", + "pmid:39229124", + "pmid:39125643", + "pmid:39088078", + "pmid:39048885", + "pmid:38961870", + "pmid:38900277", + "pmid:38626762", + "pmid:38513302", + "pmid:38449714", + "pmid:38443995", + "pmid:38429929", + "pmid:38291334", + "pmid:38227102", + "pmid:38165578", + "pmid:38152578", + "pmid:37961108", + "pmid:37866221", + "pmid:37848721", + "pmid:37830620", + "pmid:37830611", + "pmid:37735371", + "pmid:37397792", + 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"pmid:15201448", + "pmid:15167689", + "pmid:15148151", + "pmid:15080863", + "pmid:15026782", + "pmid:14966163", + "pmid:14756671", + "pmid:14679302", + "pmid:14616293", + "pmid:12938149", + "pmid:12853230", + "pmid:12832059", + "pmid:12810491", + "pmid:12764052", + "pmid:12614315", + "pmid:12486728", + "pmid:12433269", + "pmid:12235319", + "pmid:12042281", + "pmid:12007862", + "pmid:11978767", + "pmid:11889231", + "pmid:11839840", + "pmid:11807410", + "pmid:11804332", + "pmid:11559318", + "pmid:11448300", + "pmid:11466410", + "pmid:11409435", + "pmid:11405804", + "pmid:11374096", + "pmid:11160961", + "pmid:10369884", + "pmid:11030803", + "pmid:11030410", + "pmid:10942107", + "pmid:10915763", + "pmid:10894992", + "pmid:10855623", + "pmid:10785256", + "pmid:10768629", + "pmid:10766906", + "pmid:10732811", + "pmid:10717003", + "pmid:10575843", + "pmid:10525976", + "pmid:10453742", + "pmid:10433966", + "pmid:10072437", + "pmid:10071104", + "pmid:9973298", + "pmid:9855520", + "pmid:9762957", + "pmid:9758625", + "pmid:9696528", + "pmid:9674805", + "pmid:9635424", + "pmid:9613852", + "pmid:9536097", + "pmid:9588850", + "pmid:9577387", + "pmid:9562258", + "pmid:9549522", + "pmid:9532283", + "pmid:9469848", + "pmid:9507387", + "pmid:9506544", + "pmid:9415538", + "pmid:9450899", + "pmid:9436730", + "pmid:9385362", + "pmid:9371900", + "pmid:9403486", + "pmid:9403480", + "pmid:9339702", + "pmid:9339681", + "pmid:9292723", + "pmid:9259275", + "pmid:9254842", + "pmid:9225982", + "pmid:9215676", + "pmid:10735276", + "pmid:9124808", + "pmid:9106530", + "pmid:9132496", + "pmid:9020849", + "pmid:10464657", + "pmid:9401013", + "pmid:8962095", + "pmid:9088110", + "pmid:8968739", + "pmid:8931692", + "pmid:8937340", + "pmid:8836972", + "pmid:8659514", + "pmid:8609925", + "pmid:8655136", + "pmid:8780110", + "pmid:8644735", + "pmid:8815156", + "pmid:8824876", + "pmid:8926495", + "pmid:8900536", + "pmid:8800925", + "pmid:8559378", + "pmid:8559377", + "pmid:8583215", + "pmid:7574470", + "pmid:7573040", + "pmid:7496771", + "pmid:8523034", + "pmid:7668288", + "pmid:7611296", + "pmid:7762567", + "pmid:7655453", + "pmid:7633439" + ] + }, + { + "id": "SCA7_ATXN7", + "disease_id": "SCA7", + "gene": "ATXN7", + "chrom": "chr3", + "start_hg38": 63912684, + "stop_hg38": 63912715, + "start_hg19": 63898360, + "stop_hg19": 63898391, + "start_t2t": 63956302, + "stop_t2t": 63956333, + "disease": "Spinocerebellar ataxia type 7", + "inheritance": [ + "AD" + ], + "disease_description": "Spinocerebellar ataxia-7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by adult onset of progressive cerebellar ataxia associated with pigmental macular dystrophy [@omim:164500].", + "hpo_terms": null, + "prevalence": "0.999/300000", + "prevalence_details": "<1/300,000: predominantly found in those with North European and African ancestry [@genereviews:NBK1256].", + "age_onset": "Typical: 4-48 [@pmid:20739808]; Range: 0-90 [@genereviews:NBK1256; @pmid:14571264].", + "age_onset_min": 0, + "age_onset_max": 65, + "typ_age_onset_min": 4, + "typ_age_onset_max": 48, + "details": "Benign alleles range from 4-27 [@pmid:37906407], with intermediate alleles ranging from premutations (28-33) to reduced penetrance (34-36) [@genereviews:NBK1256]. Interruptions observed include CAA [@pmid:35245110].", + "mechanism": "GoF", + "mechanism_detail": "Polyglutamine expansion leading to gain of function; toxic misfolded intermediated suspected [@genereviews:NBK1256; @pmid:18418675].", + "year": "1996 [@pmid:8908515]", + "location_in_gene": "Coding Exon 1, 2, or 3 (depending on isoform)", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "CAG" + ], + "pathogenic_motif_reference_orientation": [ + "CAG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "AGC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [ + { + "motif": "CAG", + "count": null, + "type": "pathogenic_repeat" + }, + { + "motif": "CCG", + "count": 4, + "type": "flank_repeat" + } + ], + "benign_min": 4, + "benign_max": 27, + "intermediate_min": 28, + "intermediate_max": 35, + "pathogenic_min": 37, + "pathogenic_max": 460, + "motif_len": 3, + "ref_copies": 10.7, + "novel": "ref", + "gard": [ + "20405" + ], + "genereviews": [ + "NBK1256" + ], + "malacard": [ + "SPN291" + ], + "medgen": [ + "156006" + ], + "mondo": [ + "0016163" + ], + "omim": [ + "164500" + ], + "orphanet": [ + "94147" + ], + "gnomad": [ + "ATXN7" + ], + "stripy": [ + "ATXN7" + ], + "tr_atlas": [ + "TR31879", + "TR31880" + ], + "webstr_hg38": [ + "4965588" + ], + "webstr_hg19": [ + "Expansion_SCA7/ATXN7" + ], + "locus_tags": [ + "supported_evidence", + "somatic_instability", + "anticipation", + "paternal_expansion", + "length_affects_onset", + "length_affects_penetrance", + "length_affects_phenotype", + "length_affects_severity" + ], + "disease_tags": [ + "spinocerebellar_ataxia" + ], + "references": [ + "pmid:20739808", + "genereviews:NBK1256", + "pmid:14571264", + "pmid:18418675", + "pmid:37906407", + "pmid:35245110", + "pmid:8908515", + "omim:164500" + ], + "additional_literature": [ + "pmid:41254939", + "pmid:40900235", + "pmid:40488180", + "pmid:40417743", + "pmid:39820777", + "pmid:39649105", + "pmid:39571249", + "pmid:39504355", + "pmid:39317855", + "pmid:39053472", + "pmid:38961870", + "pmid:38906973", + "pmid:38851031", + "pmid:38673939", + "pmid:38626762", + "pmid:38227102", + "pmid:38165578", + "pmid:38152578", + "pmid:38045332", + "pmid:37986914", + "pmid:37848721", + "pmid:37283503", + "pmid:37214832", + "pmid:36618024", + "pmid:36530930", + "pmid:35422034", + "pmid:35182509", + "pmid:35052497", + "pmid:34870541", + "pmid:34565721", + "pmid:34160002", + "pmid:34159894", + "pmid:33995769", + "pmid:33626063", + "pmid:32138195", + "pmid:31694722", + "pmid:31522753", + "pmid:31269856", + "pmid:30891880", + "pmid:30721448", + "pmid:30699348", + "pmid:30615214", + "pmid:30381411", + "pmid:30314815", + "pmid:30255962", + "pmid:30120431", + "pmid:29801887", + "pmid:29462666", + "pmid:29316893", + "pmid:29249939", + "pmid:29248324", + "pmid:28597910", + "pmid:28585930", + "pmid:28568901", + "pmid:28444220", + "pmid:27999335", + "pmid:27774050", + "pmid:27632585", + "pmid:27333979", + "pmid:27044733", + "pmid:26584329", + "pmid:26374734", + "pmid:26077168", + "pmid:25900954", + "pmid:25755283", + "pmid:25643591", + "pmid:25608122", + "pmid:25506882", + "pmid:25466696", + "pmid:25306109", + "pmid:24972706", + "pmid:24667781", + "pmid:24534762", + "pmid:24209901", + "pmid:23828024", + "pmid:23368522", + "pmid:23197655", + "pmid:23064575", + "pmid:23026538", + "pmid:22831947", + "pmid:22520093", + "pmid:22072678", + "pmid:22053702", + "pmid:21689595", + "pmid:21147232", + "pmid:20069235", + "pmid:19226466", + "pmid:19008940", + "pmid:18418678", + "pmid:18325672", + "pmid:18182848", + "pmid:17961920", + "pmid:17420317", + "pmid:17254003", + "pmid:16626296", + "pmid:16436644", + "pmid:16434483", + "pmid:16389941", + "pmid:16389595", + "pmid:16325416", + "pmid:15750685", + "pmid:15715978", + "pmid:22473187", + "pmid:15349877", + "pmid:15148151", + "pmid:15115762", + "pmid:15080863", + "pmid:14967767", + "pmid:14966163", + "pmid:12810491", + "pmid:12764052", + "pmid:12490531", + "pmid:11939898", + "pmid:11889231", + "pmid:11839840", + "pmid:11804332", + "pmid:11781712", + "pmid:11580893", + "pmid:11448300", + "pmid:11160961", + "pmid:10369884", + "pmid:11030825", + "pmid:11030806", + "pmid:11030410", + "pmid:10942107", + "pmid:10894992", + "pmid:10841760", + "pmid:10785256", + "pmid:10768629", + "pmid:10766906", + "pmid:10602364", + "pmid:10556295", + "pmid:9467013", + "pmid:10500272", + "pmid:10453742", + "pmid:10441328", + "pmid:9973298", + "pmid:9855520", + "pmid:9736784", + "pmid:9613852", + "pmid:9536097", + "pmid:9425224", + "pmid:9425223", + "pmid:9425222", + "pmid:9425905", + "pmid:9385362", + "pmid:9288099", + "pmid:10464657" + ] + }, + { + "id": "SCA8_ATXN8OS", + "disease_id": "SCA8", + "gene": "ATXN8OS", + "chrom": "chr13", + "start_hg38": 70139383, + "stop_hg38": 70139429, + "start_hg19": 70713515, + "stop_hg19": 70713561, + "start_t2t": 69361243, + "stop_t2t": 69361270, + "disease": "Spinocerebellar ataxia type 8", + "inheritance": [ + "AD" + ], + "disease_description": "Spinocerebellar ataxia type 8 (SCA8) is a subtype of type I autosomal dominant cerebellar ataxia (ADCA type I) characterized by cerebellar ataxia and cognitive dysfunction in almost three quarters of patients and pyramidal and sensory signs in approximately a third of patients [@mondo:0012116].", + "hpo_terms": null, + "prevalence": "0.5/100000", + "prevalence_details": "<1/100,000 [@pmid:29100084]; expansion in 1:100-1200 chromosomes [@genereviews:NBK1268]. Found across ethnicities/ancestries, with population-dependent prevalence [@genereviews:NBK1268].", + "age_onset": "Typical: third to fifth decade (20-49); Range: 0 [@genereviews:NBK1268] - 76 [@doi:10.1101/gr.279634.124].", + "age_onset_min": 0, + "age_onset_max": 76, + "typ_age_onset_min": 20, + "typ_age_onset_max": 49, + "details": "Two genes span the CTG/CAG repeat and are expressed in opposite directions: ATXN8, a nearly pure polyglutamine repeat protein in the CAG direction, and ATXN8OS, which is transcribed to a noncoding CUG repeat RNA [@pmid:16804541]. Reduced penetrance is found in alleles of all sizes, although penetrance appears higher at 71+ repeats and repeats at 50-70 appear less likely to result in disease [@genereviews:NBK1268; @pmid:20373340]. Roda et al. suggested that the ATXN8 or ATXN8OS gene should not be evaluated in isolation as a candidate gene for spinocerebellar degenerative disease [@pmid:28451643]. CCG/CGG interruptions in high-penetrance SCA8 families increase RAN translation and protein toxicity [@pmid:34632710]; Interruptions in CTG/CAG expansion by 1 or more CCG/CGG, CTA/TAG, CTC/GAG, CCA/TGG, or CTT/AAG trinucleotides have been observed in full-penetrance repeats [@pmid:16804541; @genereviews:NBK1268].", + "mechanism": "GoF", + "mechanism_detail": "Polyglutamine/toxic gain-of-function [@omim:608768; @genereviews:NBK1268].", + "year": "1999 [@pmid:10192387]", + "location_in_gene": "Coding Exon 1, or 3' UTR depending on transcript", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "CTG" + ], + "pathogenic_motif_reference_orientation": [ + "CTG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CTG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [ + { + "motif": "CTA", + "count": 10, + "type": "flank_repeat" + }, + { + "motif": "CTG", + "count": null, + "type": "pathogenic_repeat" + } + ], + "benign_min": 15, + "benign_max": 50, + "intermediate_min": 50, + "intermediate_max": 70, + "pathogenic_min": 71, + "pathogenic_max": 1300, + "motif_len": 3, + "ref_copies": 15.3, + "novel": "ref", + "gard": [ + "4956" + ], + "genereviews": [ + "NBK1268" + ], + "malacard": [ + "SPN304" + ], + "medgen": [ + "332457" + ], + "mondo": [ + "0012116" + ], + "omim": [ + "608768" + ], + "orphanet": [ + "98760" + ], + "gnomad": [ + "ATXN8OS" + ], + "stripy": [ + "ATXN8OS" + ], + "tr_atlas": [ + "TR125263", + "TR125264" + ], + "webstr_hg38": [ + "5356762" + ], + "webstr_hg19": [ + "Expansion_SCA8/ATXN8" + ], + "locus_tags": [ + "supported_evidence", + "somatic_instability", + "anticipation", + "maternal_expansion", + "motif_affects_onset", + "motif_affects_penetrance" + ], + "disease_tags": [ + "spinocerebellar_ataxia" + ], + "references": [ + "genereviews:NBK1268", + "doi:10.1101/gr.279634.124", + "omim:608768", + "pmid:16804541", + "pmid:20373340", + "pmid:28451643", + "pmid:34632710", + "pmid:29100084", + "pmid:10192387", + "mondo:0012116" + ], + "additional_literature": [ + "pmid:41353794", + "pmid:41082794", + "pmid:41079917", + "pmid:41074692", + "pmid:41001200", + "pmid:40906330", + "pmid:40890648", + "pmid:40844737", + "pmid:40765612", + "pmid:40488180", + "pmid:40007153", + "pmid:38961870", + "pmid:38227102", + "pmid:38165578", + "pmid:38152578", + "pmid:37906407", + "pmid:37848721", + "pmid:37146135", + "pmid:37003406", + "pmid:36703300", + "pmid:36530930", + "pmid:34622207", + "pmid:34600502", + "pmid:34284285", + "pmid:33526774", + "pmid:33502644", + "pmid:31471687", + "pmid:30109267", + "pmid:29316893", + "pmid:29111027", + "pmid:28782341", + "pmid:28229454", + "pmid:27896316", + "pmid:26374734", + "pmid:26077168", + "pmid:25466696", + "pmid:23711133", + "pmid:23026538", + "pmid:22581592", + "pmid:22520093", + "pmid:22297462", + "pmid:22053702", + "pmid:21173221", + "pmid:20403608", + "pmid:19259763", + "pmid:19229559", + "pmid:18684474", + "pmid:18418692", + "pmid:17961920", + "pmid:17005861", + "pmid:16184604", + "pmid:16054804", + "pmid:15553088", + "pmid:15148151", + "pmid:15080863", + "pmid:14972680", + "pmid:14966163", + "pmid:14960773", + "pmid:14756671", + "pmid:12838526", + "pmid:12764052", + "pmid:12545428", + "pmid:12505613", + "pmid:12470185", + "pmid:12431257", + "pmid:12372061", + "pmid:12140678", + "pmid:12042281", + "pmid:11939898", + "pmid:11839840", + "pmid:11807410", + "pmid:11708995", + "pmid:11591855", + "pmid:11448300", + "pmid:11160961", + "pmid:11121196", + "pmid:11102643", + "pmid:11030410", + "pmid:10976642", + "pmid:10958651", + "pmid:10785256", + "pmid:10712198", + "pmid:10700168", + "pmid:10690991" + ] + }, + { + "id": "SCA31_BEAN1", + "disease_id": "SCA31", + "gene": "BEAN1", + "chrom": "chr16", + "start_hg38": 66490396, + "stop_hg38": 66490466, + "start_hg19": 66524299, + "stop_hg19": 66524369, + "start_t2t": 72284666, + "stop_t2t": 72284761, + "disease": "Spinocerebellar ataxia type 31", + "inheritance": [ + "AD" + ], + "disease_description": "Spinocerebellar ataxia type 31 (SCA31) is a very rare subtype of autosomal dominant cerebellar ataxia type III (ADCA type III) characterized by the late-onset of cerebral ataxia, dysarthria and horizontal gaze nystagmus, and that is occasionally accompanied by pyramidal signs, tremor, decreased vibration sense and hearing difficulties [@mondo:0007296].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Has been found in Japanese populations [@omim:117210] and then once respectively in a Korean and a Chinese family [@pmid:36563608].", + "age_onset": "Typical: 56-62 [@pmid:36563608]; Range: 8-83 [@pmid:23331413].", + "age_onset_min": 8, + "age_onset_max": 83, + "typ_age_onset_min": 56, + "typ_age_onset_max": 62, + "details": "This locus is a novel STR-containing insertion, not present in reference genome; the pathogenic threshold (110-760) is based on the pure repeat of the pathogenic motif within the insertion [@pmid:19878914].", + "mechanism": "GoF", + "mechanism_detail": "RNA toxicity and gain of function leading to neurodegeneration [@pmid:36371266]. Role in heterochromatin or chromosomal structure theorized [@omim:117210].", + "year": "2009 [@pmid:19878914]", + "location_in_gene": "Intron 4/4", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "AATAA" + ], + "pathogenic_motif_reference_orientation": [ + "TGGAA", + "TAGAA" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [ + "AAAAA", + "AAAAC", + "AAATG", + "AGAAA", + "ATAAG", + "TAAAC", + "TAACA", + "TACAA", + "TCAAA", + "TGCAA" + ], + "pathogenic_motif_gene_orientation": [ + "AATGG", + "AATAG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [ + "AAAAA", + "AAAAC", + "AAATG", + "AAAAG", + "AAGAT", + "AAACT", + "AACAT", + "AATAC", + "AAATC", + "AATGC" + ], + "locus_structure": [], + "benign_min": null, + "benign_max": null, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 110, + "pathogenic_max": 760, + "motif_len": 5, + "ref_copies": 14.4, + "novel": "novel", + "gard": [ + "9975" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "SPN103" + ], + "medgen": [ + "348439" + ], + "mondo": [ + "0007296" + ], + "omim": [ + "117210" + ], + "orphanet": [ + "217012" + ], + "gnomad": [ + "BEAN1" + ], + "stripy": [ + "BEAN1" + ], + "tr_atlas": [ + "TR141992" + ], + "webstr_hg38": [ + "812447", + "5971756" + ], + "webstr_hg19": [ + "STR_539736" + ], + "locus_tags": [ + "supported_evidence", + "anticipation", + "motif_affects_onset", + "motif_affects_penetrance" + ], + "disease_tags": [ + "spinocerebellar_ataxia" + ], + "references": [ + "pmid:36563608", + "pmid:23331413", + "pmid:36371266", + "omim:117210", + "pmid:19878914", + "mondo:0007296" + ], + "additional_literature": [ + "pmid:41426430", + "pmid:40765612", + "pmid:40488180", + "pmid:38961870", + "pmid:38152578", + "pmid:37848721", + "pmid:36970617", + "pmid:36092952", + "pmid:35084690", + "pmid:33785066", + "pmid:33431896", + "pmid:32066831", + "pmid:31737797", + "pmid:29111027", + "pmid:28343865", + "pmid:24215022", + "pmid:23607545" + ] + }, + { + "id": "FTDALS1_C9orf72", + "disease_id": "FTDALS1", + "gene": "C9orf72", + "chrom": "chr9", + "start_hg38": 27573484, + "stop_hg38": 27573546, + "start_hg19": 27573482, + "stop_hg19": 27573544, + "start_t2t": 27584063, + "stop_t2t": 27584155, + "disease": "Frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS)", + "inheritance": [ + "AD" + ], + "disease_description": "Pure frontotemporal dementia, pure amyotrophic lateral sclerosis or combination of the two [@pmid:39349043]. Nominal associations with risk of Parkinson's have also been reported [@pmid:41074692].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "The expansion of a hexanucleotide repeat GGGGCC in C9orf72 is the most common known cause of ALS accounting for ~ 40% familial cases and ~ 7% sporadic cases in the European population; overall ALS incidence is 1-2/100,000 person-years, point prevalence is 3-5/100,000 (Europe/US); lifetime risk is 1 in 300 [@pmid:31315673]. Related individuals to patients with C9orf72-ALS appear at an increased risk of disease regardless of carrier status [@pmid:38149039; @pmid:39315390]. C9orf72-FTD is estimated to be 0.04-134:100,000 [@genereviews:NBK268647], and by our estimates 0.65-1.56/100,000 for C9orf72-ALS. The expansion has been found across ethnicities/ancestries, with population-dependent prevalence, highest in those with northern European ancestry [@genereviews:NBK268647].", + "age_onset": "Typical: 50-64; Range: 20-91 [@genereviews:NBK268647].", + "age_onset_min": 20, + "age_onset_max": 91, + "typ_age_onset_min": 50, + "typ_age_onset_max": 64, + "details": "FTD and ALS form a clinical spectrum [@pmid:37388914; @pmid:22406228]. The clinical ranges of the C9orf72 locus remain ambiguous [@stripy:C9ORF72]: most healthy controls have alleles up to 24 repeats [@pmid:28319737] yet 24-30 repeats are associated with ALS [@pmid:31315673] and while 60 repeats is frequently used as a threshold for uncertain alleles, the exact threshold of pathogenicity remains unclear [@genereviews:NBK268647; @pmid:38099605]. Repeats of 80 motifs and lower appear to have delayed onset for any phenotype [@pmid:28319737]. >250 repeats are associated with a full FTD/ALS disease state [@pmid:31048495], but pathogenic alleles can range from 30 to more than 4000 repeats [@pmid:38099605; @pmid:39709476]. Penetrance appears to also be age-dependent, with environmental factors and specific phenotypes associated with sex and age at onset [@pmid:28522837]. Methylation appears to increase with expansion length and age [@pmid:39709476].", + "mechanism": "Ambiguous", + "mechanism_detail": "The HRE forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA/DNA hybrids (R-loops). The structural polymorphism causes a repeat length-dependent accumulation of transcripts aborted in the HRE region [@omim:105500]. Addiitonal mechanisms theorized include protein loss of function and RNA gain of function [@pmid:37847372]. Multiple cell types in the prefrontal cortex, including oligodendrocytes, microglia, astrocytes, and neurons, appear impacted during pathogenesis [@pmid:39999167].", + "year": "2011 [@pmid:21944778]", + "location_in_gene": "Intron 1 or 5' UTR depending on transcript", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "GGCCCC" + ], + "pathogenic_motif_reference_orientation": [ + "GGCCCC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CCGGGG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 2, + "benign_max": 23, + "intermediate_min": 24, + "intermediate_max": 60, + "pathogenic_min": 251, + "pathogenic_max": 4088, + "motif_len": 6, + "ref_copies": 10.8, + "novel": "ref", + "gard": [ + "18396" + ], + "genereviews": [ + "NBK268647" + ], + "malacard": [ + "FRN044" + ], + "medgen": [ + "1830423" + ], + "mondo": [ + "0007105" + ], + "omim": [ + "105500" + ], + "orphanet": [ + "275872" + ], + "gnomad": [ + "C9ORF72" + ], + "stripy": [ + "C9ORF72" + ], + "tr_atlas": [ + "TR92417" + ], + "webstr_hg38": [ + "5877863", + "1502453" + ], + "webstr_hg19": [ + "STR_1475506" + ], + "locus_tags": [ + "supported_evidence", + "length_affects_phenotype", + "length_affects_onset" + ], + "disease_tags": [ + "phenotypic_spectrum" + ], + "references": [ + "genereviews:NBK268647", + "omim:105500", + "pmid:37847372", + "pmid:39999167", + "pmid:37388914", + "pmid:22406228", + "stripy:C9ORF72", + "pmid:28319737", + "pmid:31315673", + "pmid:38099605", + "pmid:31048495", + "pmid:39709476", + "pmid:28522837", + "pmid:38149039", + "pmid:39315390", + "pmid:21944778", + "pmid:39349043", + "pmid:41074692" + ], + "additional_literature": [ + "pmid:41440030", + "pmid:41437053", + "pmid:41426430", + "pmid:41423553", + "pmid:41394713", + "pmid:41394638", + "pmid:41379346", + "pmid:41366786", + "pmid:41359433", + 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Ao, et al. has proposed that this expansion may have effects on chronotype, differing by sex and menopausal status, as well as depresssion severity [@pmid:41358280].", + "hpo_terms": null, + "prevalence": "2.65/100000", + "prevalence_details": "13-15% of global SCA prevalence, estimated to be 0.02-31/100,000 [@genereviews:NBK1140; @pmid:29100084]: resultant estimate is 0.3-5/100,000. Found across ethnicities/ancestries, with population-dependent prevalence [@genereviews:NBK1140].", + "age_onset": "Typical: 43-52 [@genereviews:NBK1140]; Range: 16 [@pmid:23331413] - 73 [@genereviews:NBK1140].", + "age_onset_min": 16, + "age_onset_max": 73, + "typ_age_onset_min": 43, + "typ_age_onset_max": 52, + "details": "The intermediate range (19-20 motifs) [@doi:10.1212/NXG.0000000000200245; @genereviews:NBK1140] can be associated with a premutation, reduced penetrance, atypical phenotype, or a disease state when homozygous [@genereviews:NBK1140]. When the longer allele is > 22 motifs, the short allele does not play a role in pathogenicity/age of onset, but expansions of 21-22 motifs have age of onset influenced by the smaller allele [@doi:10.1212/NXG.0000000000200245]. For individuals with a longest allele of 19-20, the presence of a second allele of 19-20 likely increases the risk of developing SCA6 [@doi:10.1212/NXG.0000000000200245].", + "mechanism": "GoF/LoF", + "mechanism_detail": "Polyglutamine expansions associated increased expression of altered product leading to impaired gene binding and transcription factor function as well as cellular toxicity [@genereviews:NBK1140].", + "year": "1997 [@pmid:8988170]", + "location_in_gene": "Coding, Last Exon: 47 or 48", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "CTG" + ], + "pathogenic_motif_reference_orientation": [ + "CTG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "AGC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 4, + "benign_max": 18, + "intermediate_min": 19, + "intermediate_max": 20, + "pathogenic_min": 21, + "pathogenic_max": 33, + "motif_len": 3, + "ref_copies": 13.3, + "novel": "ref", + "gard": [ + "10351" + ], + "genereviews": [ + "NBK1140" + ], + "malacard": [ + "SPN309" + ], + "medgen": [ + "148458" + ], + "mondo": [ + "0008457" + ], + "omim": [ + "183086" + ], + "orphanet": [ + "98758" + ], + "gnomad": [ + "CACNA1A" + ], + "stripy": [ + "CACNA1A" + ], + "tr_atlas": [ + "TR154515" + ], + "webstr_hg38": [ + "5624835" + ], + "webstr_hg19": [ + "Expansion_SCA6/CACNA1A" + ], + "locus_tags": [ + "supported_evidence", + "length_affects_phenotype", + "length_affects_penetrance", + "length_affects_onset" + ], + "disease_tags": [ + "spinocerebellar_ataxia" + ], + "references": [ + "genereviews:NBK1140", + "pmid:23331413", + "doi:10.1212/NXG.0000000000200245", + "pmid:29100084", + "pmid:8988170", + "mondo:0008457", + "pmid:41358280" + ], + "additional_literature": [ + "pmid:41358280", + "pmid:41082794", + "pmid:41009775", + "pmid:40906330", + "pmid:40900235", + "pmid:40879304", + "pmid:40746751", + "pmid:40488180", + "pmid:40189664", + "pmid:39812846", + "pmid:39571249", + "pmid:39152783", + "pmid:39048885", + "pmid:38961870", + "pmid:38227102", + "pmid:38165578", + "pmid:38152578", + "pmid:37848721", + "pmid:37307504", + "pmid:37301203", + "pmid:36618024", + "pmid:36599645", + "pmid:36530930", + "pmid:35962273", + "pmid:35188716", + "pmid:35182509", + "pmid:35052497", + "pmid:34647648", + "pmid:34600502", + "pmid:34565721", + "pmid:34371182", + "pmid:34159894", + "pmid:33502644", + "pmid:33121221", + "pmid:32888184", + "pmid:32822634", + "pmid:31522753", + "pmid:30891880", + "pmid:30591349", + "pmid:30342765", + "pmid:30314815", + "pmid:30120431", + "pmid:30078120", + "pmid:29959555", + "pmid:29553382", + "pmid:29367260", + "pmid:29316893", + "pmid:29249939", + "pmid:29111027", + "pmid:29057148", + "pmid:28946818", + "pmid:28782341", + "pmid:28585930", + "pmid:28444220", + "pmid:28131213", + "pmid:27979829", + "pmid:27896316", + "pmid:27848087", + "pmid:27806289", + "pmid:27412786", + "pmid:27400454", + "pmid:27333979", + "pmid:26730403", + "pmid:26377379", + "pmid:26374734", + "pmid:26354989", + "pmid:26077168", + "pmid:26054379", + "pmid:25634432", + "pmid:25624155", + "pmid:25466696", + "pmid:24780882", + "pmid:24534762", + "pmid:24486772", + "pmid:24209901", + "pmid:23423669", + "pmid:23407676", + "pmid:23368522", + "pmid:23026538", + "pmid:22520093", + "pmid:26859398", + "pmid:26676458", + "pmid:21832228", + "pmid:21550405", + "pmid:20069235", + "pmid:19631275", + "pmid:19429075", + "pmid:19259763", + "pmid:19224313", + "pmid:18949263", + "pmid:18759344", + "pmid:18687887", + "pmid:18685131", + "pmid:18684474", + "pmid:18506570", + "pmid:18418678", + "pmid:18285829", + "pmid:18074367", + "pmid:17961920", + "pmid:17682009", + "pmid:17516099", + "pmid:17420317", + "pmid:16396623", + "pmid:16389595", + "pmid:16310805", + "pmid:16000334", + "pmid:15875905", + "pmid:15747371", + "pmid:15553088", + "pmid:15148151", + "pmid:15080863", + "pmid:15026782", + "pmid:14967767", + "pmid:14966163", + "pmid:14756671", + "pmid:14534930", + "pmid:12810491", + "pmid:12764052", + "pmid:12676347", + "pmid:12614315", + "pmid:12545428", + "pmid:11939898", + "pmid:11889231", + "pmid:11839840", + "pmid:11804332", + "pmid:11717352", + "pmid:11708993", + "pmid:11448300", + "pmid:11355155", + "pmid:11341481", + "pmid:11311290", + "pmid:11176970", + "pmid:11160961", + "pmid:10369884", + "pmid:11081813", + "pmid:11030410", + "pmid:10985694", + "pmid:10964945", + "pmid:10945665", + "pmid:10942107", + "pmid:10894992", + "pmid:10785256", + "pmid:10768629", + "pmid:10766906", + "pmid:10690991", + "pmid:10674974", + "pmid:10601803", + "pmid:10453742", + "pmid:10442462", + "pmid:10369863", + "pmid:10369828", + "pmid:10366652", + "pmid:10225349", + "pmid:9973298", + "pmid:9915947", + "pmid:9879686", + "pmid:9855520", + "pmid:9779664", + "pmid:9758625", + "pmid:9741473", + "pmid:9696528", + "pmid:9674805", + "pmid:9613852", + "pmid:9600677", + "pmid:9559993", + "pmid:9507387", + "pmid:9436730", + "pmid:9385362", + "pmid:9371901", + "pmid:9371900", + "pmid:9403486", + "pmid:9403480", + "pmid:9345107", + "pmid:9339681", + "pmid:9302278", + "pmid:9311738", + "pmid:9259275", + "pmid:9259274", + "pmid:10464657", + "pmid:9043864" + ] + }, + { + "id": "JBS_CBL", + "disease_id": "JBS", + "gene": "CBL", + "chrom": "chr11", + "start_hg38": 119206289, + "stop_hg38": 119206323, + "start_hg19": 119076999, + "stop_hg19": 119077033, + "start_t2t": 119226662, + "stop_t2t": 119226696, + "disease": "Jacobsen syndrome (FRAX11B fragile site)", + "inheritance": [ + "AD" + ], + "disease_description": "A multiple congenital anomaly/intellectual disability contiguous gene syndrome caused by partial deletion of the long arm of chromosome 11 [@mondo:0007838].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "1/100,000 births; female/male ratio 2:1 [@pmid:19267933]. Found across ancestries/ethnicities [@omim:147791].", + "age_onset": "Condition at birth.", + "age_onset_min": 0, + "age_onset_max": 0, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "70% of individuals have 11 repeats [@pmid:7603564], but pathogenic expansion can span hundreds of motifs [@pmid:10767345]. The CGG repeat expansion can lead to a fragile site and subsequent deletion of 11q (shown in 2 cases) but total causality is unclear; intermediate alleles are associated with a premutation [@pmid:19267933].", + "mechanism": "Hypermethylation", + "mechanism_detail": "DNA hypermethylation/11q deletion in sporadic cases [@pmid:38467784].", + "year": "1995 [@pmid:7603564]", + "location_in_gene": "5' UTR", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "CGG" + ], + "pathogenic_motif_reference_orientation": [ + "CGG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CGG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 5, + "benign_max": 79, + "intermediate_min": 80, + "intermediate_max": 100, + "pathogenic_min": 101, + "pathogenic_max": 300, + "motif_len": 3, + "ref_copies": 11.3, + "novel": "ref", + "gard": [ + "307" + ], + "genereviews": [], + "malacard": [ + "JCB001" + ], + "medgen": [ + "162878" + ], + "mondo": [ + "0007838" + ], + "omim": [ + "147791" + ], + "orphanet": [ + "2308" + ], + "gnomad": [ + "CBL" + ], + "stripy": [ + "CBL" + ], + "tr_atlas": [ + "TR112816" + ], + "webstr_hg38": [ + "6166081", + "430025" + ], + "webstr_hg19": [ + "STR_266122" + ], + "locus_tags": [ + "supported_evidence" + ], + "disease_tags": [], + "references": [ + "pmid:38467784", + "pmid:7603564", + "pmid:10767345", + "pmid:19267933", + "omim:147791", + "mondo:0007838" + ], + "additional_literature": [ + "pmid:37422244", + "pmid:22131879", + "pmid:22084433", + "pmid:16474167" + ] + }, + { + "id": "DM2_CNBP", + "disease_id": "DM2", + "gene": "CNBP", + "chrom": "chr3", + "start_hg38": 129172576, + "stop_hg38": 129172656, + "start_hg19": 128891419, + "stop_hg19": 128891499, + "start_t2t": 131917482, + "stop_t2t": 131917557, + "disease": "Myotonic dystrophy type 2", + "inheritance": [ + "AD" + ], + "disease_description": "Myotonic dystrophy type 2 (MD2), also known as proximal myotonic myopathy, is a very rare genetic multi-system disorder of late childhood or adult-onset characterized by mild myotonia, muscle weakness, and rarely cardiac conduction disorders [@mondo:0011266].", + "hpo_terms": null, + "prevalence": "2.29/100000", + "prevalence_details": "2.29/100,000 [@pmid:35483324]; population specific prevalence [@genereviews:NBK1466]. Most cases have European ancestry, but disease has been reported worldwide [@genereviews:NBK1466].", + "age_onset": "Typical: 28-56 [@pmid:29086017]; Range: 0-73 [@pmid:31159885].", + "age_onset_min": 0, + "age_onset_max": 73, + "typ_age_onset_min": 28, + "typ_age_onset_max": 56, + "details": "Detailed overview of disease locus through 2024 by Rimoldi et al [@pmid:39643839]. ≤30 uninterrupted CCTG repeats or 11-26 CCTG repeats with GCTC/TCTG interruptions are considered benign; 27-29 repeats with interruptions have currently unknown significance, ~30-~54 repeats are considered premutations, ~55-74 repeats are premutations with possible reduced penetrance, and >74 repeat alleles are considered pathogenic [@genereviews:NBK1466]. Penetrance is age-dependent and approaches 100%. Locus structure is (TG)n(TCTG)n(CCTG)n. CCTG expansion causes DM2 but the other repeat units are also variable. Interruptions include GCTG/TCTG/GGCT [@pmid:35245110]. The effect of the (TCTG)n repeat remains to be determined, but it is potentially common in the repeat structure of this locus [@pmid:39703464].", + "mechanism": "GoF", + "mechanism_detail": "Aberrant splicing, RAN translation [@pmid:22140091; @pmid:38467784].", + "year": "2001 [@pmid:11486088]", + "location_in_gene": "Intron 1", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "CAGG" + ], + "pathogenic_motif_reference_orientation": [ + "CAGG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [ + "CAGA" + ], + "pathogenic_motif_gene_orientation": [ + "CCTG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [ + "CTGT" + ], + "locus_structure": [ + { + "motif": "CAGG", + "count": null, + "type": "pathogenic_repeat" + }, + { + "motif": "CAGA", + "count": 10, + "type": "flank_repeat" + }, + { + "motif": "CA", + "count": 19, + "type": "flank_repeat" + } + ], + "benign_min": 11, + "benign_max": 26, + "intermediate_min": 27, + "intermediate_max": 74, + "pathogenic_min": 75, + "pathogenic_max": 11000, + "motif_len": 4, + "ref_copies": 20.8, + "novel": "ref", + "gard": [ + "9728" + ], + "genereviews": [ + "NBK1466" + ], + "malacard": [ + "MYT020" + ], + "medgen": [ + "419137" + ], + "mondo": [ + "0011266" + ], + "omim": [ + "602668" + ], + "orphanet": [ + "606" + ], + "gnomad": [ + "CNBP" + ], + "stripy": [ + "CNBP" + ], + "tr_atlas": [ + "TR35563", + "TR35564", + "TR35565" + ], + "webstr_hg38": [ + "741073" + ], + "webstr_hg19": [], + "locus_tags": [ + "supported_evidence", + "somatic_instability", + "motif_affects_instability" + ], + "disease_tags": [ + "myotonic_dystrophy" + ], + "references": [ + "pmid:29086017", + "pmid:31159885", + "pmid:22140091", + "pmid:38467784", + "pmid:39643839", + "genereviews:NBK1466", + "pmid:35245110", + "pmid:39703464", + "pmid:35483324", + "pmid:11486088", + "mondo:0011266" + ], + "additional_literature": [ + "pmid:41074692", + "pmid:40113266", + "pmid:39894140", + "pmid:39240646", + "pmid:39119544", + "pmid:38922834", + "pmid:37950892", + "pmid:37461657", + "pmid:37146135", + "pmid:36778282", + "pmid:36018009", + "pmid:35945246", + "pmid:35567413", + "pmid:34101465", + "pmid:34024776", + "pmid:33595997", + "pmid:31981476", + "pmid:31927948", + "pmid:30984523", + "pmid:30140252", + "pmid:30100878", + "pmid:29973908", + "pmid:29291944", + "pmid:28623239", + "pmid:28491317", + "pmid:28130447", + "pmid:27727437", + "pmid:27222292", + "pmid:26586700", + "pmid:25443993", + "pmid:25186227", + "pmid:24907641", + "pmid:23570879", + "pmid:22723857", + "pmid:22643181", + "pmid:22587749", + "pmid:22459146", + "pmid:22332444", + "pmid:22062891", + "pmid:21303839", + "pmid:21224892", + "pmid:21204798", + "pmid:20971734", + "pmid:20491895", + "pmid:20174632", + "pmid:19683984", + "pmid:19632331", + "pmid:19218442", + "pmid:18804219", + "pmid:18213375", + "pmid:16927100", + "pmid:16624843", + "pmid:16376058", + "pmid:15718211", + "pmid:15704146", + "pmid:15322428", + "pmid:15231584", + "pmid:15215218", + "pmid:15114529", + "pmid:15019706", + "pmid:14505273", + "pmid:12970845", + "pmid:12601109" + ] + }, + { + "id": "EDM1-PSACH_COMP", + "disease_id": "EDM1, PSACH", + "gene": "COMP", + "chrom": "chr19", + "start_hg38": 18786034, + "stop_hg38": 18786050, + "start_hg19": 18896844, + "stop_hg19": 18896860, + "start_t2t": 18921630, + "stop_t2t": 18921645, + "disease": "Multiple epiphyseal dysplasia, Pseudoachondroplasia", + "inheritance": [ + "AD" + ], + "disease_description": "Pseudoachondroplasia is characterized by severe growth deficiency and deformations such as bow legs and hyperlordosis.; Multiple epiphyseal dysplasia type 1 (MED 1) is a form of multiple epiphyseal dysplasia that is characterized by normal or mild short stature, pain in the hips and/or knees, progressive deformity of extremities and early-onset osteoarthrosis. Specific features to MED 1 include a more pronounced involvement of hip joints and gait abnormality and a shorter adult height. MED1 is allelic to pseudoachondroplasia with which it shares clinical and radiological features. The disease follows an autosomal dominant mode of transmission [@mondo:0008322; @mondo:0007561].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Specific contribution of COMP repeats to EDM1 is unknown (~300 COMP mutation variants for both phenotypes); likely 1:90,000 prevalence for COMP-PSACH that is repeat-specific. Found across ancestries/ethnicities [@genereviews:NBK1123; @genereviews:NBK1487].", + "age_onset": "Typical: 0-2 (COMP-PSACH)/ 1-12 (EDM1); Range: 0 (PSACH) - 13 (EDM1). 3-13 specific to trinucleotide expansions (duplications) [@pmid:29530484], several contractions but unknown exact AoO [@genereviews:NBK1123; @genereviews:NBK1487].", + "age_onset_min": 3, + "age_onset_max": 13, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "Both expansions to (GTC)6-7 and contractions to (GTC)4 are associated with disease [@genereviews:NBK1487].", + "mechanism": "LoF/GoF?", + "mechanism_detail": "Poly-aspartic acid expansions, domain dependent [@pmid:29530484]; may involve misfolding but still unestablished [@genereviews:NBK1123].", + "year": "1999 [@pmid:9887340]", + "location_in_gene": "Coding Exon 13", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "GTC" + ], + "pathogenic_motif_reference_orientation": [ + "GTC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "ACG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 5, + "benign_max": 5, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 6, + "pathogenic_max": 7, + "motif_len": 3, + "ref_copies": 5, + "novel": "ref", + "gard": [ + "4540", + "2180" + ], + "genereviews": [ + "NBK1123", + "NBK1487" + ], + "malacard": [ + "EPP017", + "PSD012" + ], + "medgen": [ + "98378", + "325376" + ], + "mondo": [ + "0008322", + "0007561" + ], + "omim": [ + "132400", + "177170" + ], + "orphanet": [ + "750", + "93308" + ], + "gnomad": [ + "COMP" + ], + "stripy": [ + "COMP" + ], + "tr_atlas": [ + "TR155017" + ], + "webstr_hg38": [ + "1317658" + ], + "webstr_hg19": [ + "STR_673389" + ], + "locus_tags": [ + "supported_evidence", + "contraction" + ], + "disease_tags": [ + "phenotypic_spectrum" + ], + "references": [ + "pmid:29530484", + "genereviews:NBK1123", + "genereviews:NBK1487", + "pmid:9887340", + "mondo:0008322", + "mondo:0007561" + ], + "additional_literature": [ + "pmid:32097846", + "pmid:28924040", + "pmid:21644213", + "pmid:18353302", + "pmid:15014436", + "pmid:12483437" + ] + }, + { + "id": "EPM1_CSTB", + "disease_id": "EPM1", + "gene": "CSTB", + "chrom": "chr21", + "start_hg38": 43776442, + "stop_hg38": 43776479, + "start_hg19": 45196323, + "stop_hg19": 45196360, + "start_t2t": 42132054, + "stop_t2t": 42132091, + "disease": "Progressive Myoclonic Epilepsy Type 1 (EPM1), a.k.a Unverricht-Lundborg Disease (ULD)", + "inheritance": [ + "AR" + ], + "disease_description": "Unverricht-Lundborg disease (ULD) is a rare progressive myoclonic epilepsy disorder characterized by action- and stimulus-sensitive myoclonus, and tonic-clonic seizures with ataxia, but with only a mild cognitive decline over time [@mondo:0009698].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Worldwide prevalence unknown; Finland prevalence 2-4/100,000. Found across ethnicities/ancestries, with population-dependent prevalence; highest in Tunisia, Algeria, Morocco, and Finland [@genereviews:NBK1142].", + "age_onset": "Typical: 6-15 [@genereviews:NBK1142]; Range: 6-18 [@pmid:18325013].", + "age_onset_min": 6, + "age_onset_max": 18, + "typ_age_onset_min": 6, + "typ_age_onset_max": 15, + "details": "Affected individuals have an unstable 12-nucleotide (dodecomer) repeat expansion. Alleles containing 2-3 motifs are considered benign, while alleles with 30-125 repeats are fully penetrant [@pmid:18325013]. Alleles in the range 12-17 repeats have been observed, however the individuals carrying them have not undergone clinical evaluation. Alleles in the range 4-11 and 18-29 repeats have not been reported to date.", + "mechanism": "LoF", + "mechanism_detail": "The repeat expanison causes significantly reduced expression of cystatin-B protein [@genereviews:NBK1142].", + "year": "1997 [@pmid:9126745]", + "location_in_gene": "5' UTR", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "CGCGGGGCGGGG" + ], + "pathogenic_motif_reference_orientation": [ + "CGCGGGGCGGGG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CCCCGCCCCGCG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 2, + "benign_max": 3, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 30, + "pathogenic_max": 125, + "motif_len": 12, + "ref_copies": null, + "novel": null, + "gard": [ + "3876" + ], + "genereviews": [ + "NBK1142" + ], + "malacard": [ + "MYC080" + ], + "medgen": [ + "155923" + ], + "mondo": [ + "0009698" + ], + "omim": [ + "254800" + ], + "orphanet": [ + "308" + ], + "gnomad": [ + "CSTB" + ], + "stripy": [], + "tr_atlas": [ + "TR163552" + ], + "webstr_hg38": [ + "5547429" + ], + "webstr_hg19": [ + "STR_886261" + ], + "locus_tags": [ + "supported_evidence", + "length_affects_onset", + "length_affects_severity" + ], + "disease_tags": [ + "ataxia" + ], + "references": [ + "genereviews:NBK1142", + "pmid:18325013", + "pmid:9126745", + "mondo:0009698" + ], + "additional_literature": [ + "pmid:41268177", + "pmid:41147955", + "pmid:41074692", + "pmid:40442775", + "pmid:40340521", + "pmid:39156922", + "pmid:38135787", + "pmid:36398398", + "pmid:36359887", + "pmid:34474241", + "pmid:32920378", + "pmid:32875576", + "pmid:29352102", + "pmid:25752200", + "pmid:23883076", + "pmid:22581592", + "pmid:21757863", + "pmid:21075014", + "pmid:18358403", + "pmid:17003839", + "pmid:16379547", + "pmid:15483648", + "pmid:14517952", + "pmid:14510831", + "pmid:12215838", + "pmid:11790146", + "pmid:11697734", + "pmid:11571333", + "pmid:11524486", + "pmid:11240124", + "pmid:10927802", + "pmid:10721698", + "pmid:10660338", + "pmid:10515170", + "pmid:10441345", + "pmid:9529356", + "pmid:9090386", + "pmid:9054946", + "pmid:9012407", + "pmid:7885531" + ] + }, + { + "id": "SCA37_DAB1", + "disease_id": "SCA37", + "gene": "DAB1", + "chrom": "chr1", + "start_hg38": 57367043, + "stop_hg38": 57367121, + "start_hg19": 57832715, + "stop_hg19": 57832793, + "start_t2t": 57245935, + "stop_t2t": 57245973, + "disease": "Spinocerebellar ataxia type 37", + "inheritance": [ + "AD" + ], + "disease_description": "Spinocerebellar ataxia type 37 (SCA37) is a subtype of autosomal dominant cerebellar ataxia type 1 (ADCA type 1), characterized by a cerebellar syndrome along with altered vertical eye movements [@mondo:0014410].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "0.20/100,000 specific to Portugal; not yet found in other geographic regions. Founder effect from Iberian Peninsula [@genereviews:NBK541729].", + "age_onset": "Typical: 33-53; Range: 18-64 [@genereviews:NBK541729].", + "age_onset_min": 18, + "age_onset_max": 64, + "typ_age_onset_min": 33, + "typ_age_onset_max": 53, + "details": "Pathogenicity only associated with pathogenic motif >30 repeats, flanked by at least 58 repeats of reference motif on either side; reference repeat (AAAAT) can range from 1 to 400 repeats, although typically less than 30 [@genereviews:NBK541729]. The pathogenic motif is unstable, particularly when transmitted by the father [@genereviews:NBK541729].", + "mechanism": "GoF", + "mechanism_detail": "Toxic gain-of-function mechanism in protein, associated with alternative splicing, an RNA switch, and an upregulation of reelin-DAB1 signalling [@omim:615945; @pmid:30284037].", + "year": "2017 [@pmid:28686858]", + "location_in_gene": "Intron 1 (most isoforms)", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "AAAAT" + ], + "pathogenic_motif_reference_orientation": [ + "GAAAT" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [ + "AAAAA" + ], + "pathogenic_motif_gene_orientation": [ + "ATTTC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [ + "TTTTT" + ], + "locus_structure": [ + { + "motif": "AAAAT", + "count": 7, + "type": "internal_repeat" + }, + { + "motif": "GAAAT", + "count": null, + "type": "pathogenic_repeat" + } + ], + "benign_min": 0, + "benign_max": 30, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 31, + "pathogenic_max": 75, + "motif_len": 5, + "ref_copies": 0, + "novel": "novel", + "gard": [ + "12368" + ], + "genereviews": [ + "NBK541729" + ], + "malacard": [ + "SPN283" + ], + "medgen": [ + "855217" + ], + "mondo": [ + "0014410" + ], + "omim": [ + "615945" + ], + "orphanet": [ + "363710" + ], + "gnomad": [ + "DAB1" + ], + "stripy": [ + "DAB1" + ], + "tr_atlas": [ + "TR3445" + ], + "webstr_hg38": [ + "1144531" + ], + "webstr_hg19": [ + "STR_39393" + ], + "locus_tags": [ + "supported_evidence", + "maternal_expansion", + "paternal_expansion", + "motif_affects_onset", + "motif_affects_penetrance" + ], + "disease_tags": [ + "spinocerebellar_ataxia" + ], + "references": [ + "genereviews:NBK541729", + "omim:615945", + "pmid:30284037", + "pmid:28686858", + "mondo:0014410" + ], + "additional_literature": [ + "pmid:41426430", + "pmid:38961870", + "pmid:36622139", + "pmid:36148898", + "pmid:36092952", + "pmid:32582864", + "pmid:30588707" + ] + }, + { + "id": "FRA12A_DIP2B", + "disease_id": "FRA12A", + "gene": "DIP2B", + "chrom": "chr12", + "start_hg38": 50505001, + "stop_hg38": 50505024, + "start_hg19": 50898784, + "stop_hg19": 50898807, + "start_t2t": 50468095, + "stop_t2t": 50468118, + "disease": "Intellectual developmental disorder, FRA12A type", + "inheritance": [ + "AD" + ], + "disease_description": "...impaired intellectual development with or without other anomalies has been described in patients with over 40% of cells expressing FRA12A [@omim:136630].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Appears to occur in those of European ancestry/ethnicity [@omim:136630].", + "age_onset": "Typical: 0-1 (small sample size) [@pmid:3742859]. Range: 0-3 [@pmid:4042396].", + "age_onset_min": 0, + "age_onset_max": 3, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "Repeat ranges reflect affected and unaffected individuals from a cohort study of 70 controls (6-23 repeats), unaffected carriers representing the intermediate alleles (139-206), and affected individuals (273-306) [@pmid:17236128]. Unmethylated expansions may correspond to movement-related phenotypes (chorea, dystonia, and ataxia) [@pmid:39854091].", + "mechanism": "LoF", + "mechanism_detail": "Hypermethylation leading to decreased expression, although unmethylated expansion leads to increased expression [@omim:136630; @doi:10.1101/2022.09.12.22279739].", + "year": "2007 [@pmid:17236128]", + "location_in_gene": "5' UTR", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GGC" + ], + "pathogenic_motif_reference_orientation": [ + "GGC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CGG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 6, + "benign_max": 23, + "intermediate_min": 139, + "intermediate_max": 206, + "pathogenic_min": 273, + "pathogenic_max": 306, + "motif_len": 3, + "ref_copies": 7, + "novel": "ref", + "gard": [], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "INT482" + ], + "medgen": [ + "369613" + ], + "mondo": [ + "0007634" + ], + "omim": [ + "136630" + ], + "orphanet": [], + "gnomad": [ + "DIP2B" + ], + "stripy": [ + "DIP2B" + ], + "tr_atlas": [ + "TR116656" + ], + "webstr_hg38": [ + "5075695" + ], + "webstr_hg19": [ + "Expansion_FRA12A_MR/DIP2B" + ], + "locus_tags": [ + "limited_evidence" + ], + "disease_tags": [], + "references": [ + "pmid:3742859", + "pmid:4042396", + "omim:136630", + "doi:10.1101/2022.09.12.22279739", + "pmid:17236128", + "pmid:39854091" + ], + "additional_literature": [ + "pmid:38418263", + "pmid:37248219", + "pmid:37090938", + "pmid:34622207" + ] + }, + { + "id": "DMD_DMD", + "disease_id": "DMD", + "gene": "DMD", + "chrom": "chrX", + "start_hg38": 31284557, + "stop_hg38": 31284605, + "start_hg19": 31302674, + "stop_hg19": 31302722, + "start_t2t": 30882677, + "stop_t2t": 30882743, + "disease": "Duchenne muscular dystrophy", + "inheritance": [ + "XR" + ], + "disease_description": "Duchenne muscular dystrophy (DMD) is a neuromuscular disease characterized by rapidly progressive muscle weakness and wasting due to degeneration of skeletal, smooth and cardiac muscle [@mondo:0010679].", + "hpo_terms": null, + "prevalence": "4.8/100000", + "prevalence_details": "Believed to be 0 for disease specific to STR expansion. 1/3500-4700 male births (incidence) for overall DMD (one of the most common and severe congenital myopathies) [@genereviews:NBK1119]. 4.8/100,000 prevalence [@pmid:35168641]. DMD repeat locus expansion only identified in one Greek family [@pmid:27417533].", + "age_onset": "Typical: 6-7 (usual disease is 0-3) [@pmid:27417533].", + "age_onset_min": 6, + "age_onset_max": 7, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "There is conflicting evidence for the association between this repeat expansion and Duchenne muscular dystrophy. The association was reported in a single family, from which the benign and pathogenic ranges were inferred from affected and unaffected family members [@pmid:27417533]. The population frequency of the proposed pathogenic allele is much higher than expected for a highly penetrant early-onset condition.", + "mechanism": "LoF", + "mechanism_detail": "Functional defect in dystrophin/dystroglycan [@pmid:16969582].", + "year": "2016 [@pmid:27417533]", + "location_in_gene": "Intron 62", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "TTC" + ], + "pathogenic_motif_reference_orientation": [ + "TTC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "AAG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [ + { + "motif": "TTC", + "count": null, + "type": "pathogenic_repeat" + }, + { + "motif": "T", + "count": 8, + "type": "flank_repeat" + } + ], + "benign_min": 16, + "benign_max": 33, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 59, + "pathogenic_max": 82, + "motif_len": 3, + "ref_copies": 16.7, + "novel": "ref", + "gard": [ + "6291" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "MSC157" + ], + "medgen": [ + "3925" + ], + "mondo": [ + "0010679" + ], + "omim": [ + "310200" + ], + "orphanet": [ + "98896" + ], + "gnomad": [ + "DMD" + ], + "stripy": [ + "DMD" + ], + "tr_atlas": [ + "TR167703" + ], + "webstr_hg38": [], + "webstr_hg19": [ + "STR_1545664" + ], + "locus_tags": [ + "contradictory_evidence" + ], + "disease_tags": [], + "references": [ + "pmid:27417533", + "pmid:16969582", + "genereviews:NBK1119", + "pmid:35168641", + "mondo:0010679" + ], + "additional_literature": [ + "pmid:41244984", + "pmid:41173008", + "pmid:39874107", + "pmid:39803454", + "pmid:39713478", + "pmid:39251998", + "pmid:38290145", + "pmid:37829280", + "pmid:37270548", + "pmid:37090938", + "pmid:36975100", + "pmid:36048237", + "pmid:35615378", + "pmid:35093299", + "pmid:34371182", + "pmid:34238289", + "pmid:33349121", + "pmid:30914715", + "pmid:30349485", + "pmid:29687370", + "pmid:27924830", + "pmid:27178005", + "pmid:27529242", + "pmid:27276190", + "pmid:24411039", + "pmid:25804023", + "pmid:24191945", + "pmid:23894429", + "pmid:23695957", + "pmid:23659897", + "pmid:23574351", + "pmid:23538453", + "pmid:21901138", + "pmid:21305566", + "pmid:22830166", + "pmid:19927354", + "pmid:19907931", + "pmid:19309270", + "pmid:19158820", + "pmid:19108751", + "pmid:18393226", + "pmid:18359022", + "pmid:17439955", + "pmid:16553208", + "pmid:16415967", + "pmid:12132577", + "pmid:11807410", + "pmid:11593558", + "pmid:11280167", + "pmid:11185740", + "pmid:10445321", + "pmid:9894797", + "pmid:8588583", + "pmid:7633442", + "pmid:7705851" + ] + }, + { + "id": "DM1_DMPK", + "disease_id": "DM1", + "gene": "DMPK", + "chrom": "chr19", + "start_hg38": 45770204, + "stop_hg38": 45770266, + "start_hg19": 46273462, + "stop_hg19": 46273524, + "start_t2t": 48597739, + "stop_t2t": 48597756, + "disease": "Myotonic dystrophy type 1", + "inheritance": [ + "AD" + ], + "disease_description": "Steinert disease, also known as myotonic dystrophy type 1, is a muscle disease characterized by myotonia and by multiorgan damage that combines various degrees of muscle weakness, arrhythmia and/or cardiac conduction disorders, cataract, endocrine damage, sleep disorders and baldness [@mondo:0008056]. It has also been linked to Autism and related traits, especially in individuals with earlier onset [@pmid:40259070; @pmid:29361396; @pmid:8810716; @pmid:27695335; @pmid:29871899; @pmid:37209486].", + "hpo_terms": null, + "prevalence": "9.27/100000", + "prevalence_details": "5-20/100,000 [@genereviews:NBK1165]. 0.5-18.1/100,000 [@pmid:29100084]; 6.5/100,000 [@pmid:31159885]. 9.27 cases (95% CI: 4.73-15.21) per 100,000, ranging from 0.37 to 36.29 cases per 100,000 [@pmid:35483324]. Found across ethnicities/ancestries, with population-dependent prevalence [@genereviews:NBK1165].", + "age_onset": "Typical: 10-30 [@genereviews:NBK1165]; Range: 0-74 [@pmid:38454488].", + "age_onset_min": 0, + "age_onset_max": 74, + "typ_age_onset_min": 10, + "typ_age_onset_max": 30, + "details": "Overview of disease locus through 2024, including largest pathogenic allele of 4,000, described in Rimoldi et al review [@pmid:39643839]. Intermediate alleles (35-49) associated with premutation [@genereviews:NBK1165]. 3%-8% of DM1 expansions contain interrupting variant repeats such as CCG and CGG, associated with later onset and milder phenotype; the variant repeat GCGGCA has also been reported [@pmid:32851192; @doi:10.1016/j.mcp.2024.102005]. In another study, interruptions of the CTG repeat with CCG, GGC, CTC or CAG motifs are estimated to occur in 3-11% of DM1 patients [@pmid:35741732]. Expansions within gene ZNF850 may function as DM1 modifiers [@doi:10.1093/hmg/ddae186].", + "mechanism": "GoF", + "mechanism_detail": "RNA gain-of-function: RNA gelation leading to misregulation of alternative splicing [@pmid:36169768]. Expanded-repeat RNA sequesters the muscleblind-like (MBNL) family of RNA-binding proteins as part of the disruption of pre-mRNA processing, contributing to cardiac phenotypes [@pmid:39932794]. Loss of MBNL proteins has been linked to mis-splicing of Autism spectrum-risk genes such as SCN2A, ANK2, and SHANK2, possibly leading to Autism-related traits [@pmid:40259070]", + "year": "1992 [@pmid:1310900]", + "location_in_gene": "3' UTR", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "CAG" + ], + "pathogenic_motif_reference_orientation": [ + "CAG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CTG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 5, + "benign_max": 34, + "intermediate_min": 35, + "intermediate_max": 49, + "pathogenic_min": 50, + "pathogenic_max": 4000, + "motif_len": 3, + "ref_copies": 20.7, + "novel": "ref", + "gard": [ + "8310" + ], + "genereviews": [ + "NBK1165" + ], + "malacard": [ + "MYT021" + ], + "medgen": [ + "886881" + ], + "mondo": [ + "0008056" + ], + "omim": [ + "160900" + ], + "orphanet": [ + "273" + ], + "gnomad": [ + "DMPK" + ], + "stripy": [ + "DMPK" + ], + "tr_atlas": [ + "TR156684" + ], + "webstr_hg38": [ + "5650727" + ], + "webstr_hg19": [ + "Expansion_DM1/DMPK" + ], + "locus_tags": [ + "supported_evidence", + "somatic_instability", + "anticipation", + "maternal_expansion", + "length_affects_onset", + "length_affects_phenotype", + "length_affects_severity", + "motif_affects_instability", + "motif_affects_onset", + "motif_affects_phenotype", + "motif_affects_severity" + ], + "disease_tags": [ + "myotonic_dystrophy" + ], + "references": [ + "genereviews:NBK1165", + "pmid:38454488", + "pmid:36169768", + "pmid:39932794", + "pmid:40259070", + "pmid:39643839", + "pmid:32851192", + "doi:10.1016/j.mcp.2024.102005", + "pmid:35741732", + "doi:10.1093/hmg/ddae186", + "pmid:29100084", + "pmid:31159885", + "pmid:35483324", + "pmid:1310900", + "mondo:0008056", + "pmid:29361396", + "pmid:8810716", + "pmid:27695335", + "pmid:29871899", + "pmid:37209486" + ], + "additional_literature": [ + "pmid:41379996", + "pmid:41260620", + "pmid:41250834", + "pmid:41226829", + "pmid:41212113", + "pmid:41161721", + "pmid:41074692", + "pmid:40903903", + "pmid:40896579", + "pmid:40879030", + "pmid:40712995", + "pmid:40606545", + "pmid:40599975", + "pmid:40417743", + "pmid:40296143", + "pmid:40113266", + "pmid:40092662", + "pmid:40004498", + "pmid:39710066", + "pmid:39679849", + "pmid:39492694", + "pmid:39433769", + "pmid:39415708", + "pmid:39391712", + "pmid:39383229", + "pmid:39278936", + "pmid:39267217", + "pmid:39273681", + "pmid:39232665", + "pmid:39180495", + "pmid:39126705", + "pmid:38709060", + "pmid:38704930", + "pmid:38490135", + "pmid:38314057", + "pmid:37829280", + "pmid:37744174", + "pmid:37645891", + "pmid:37638448", + "pmid:37521782", + "pmid:37397246", + "pmid:37373276", + "pmid:37352653", + "pmid:37200862", + "pmid:37146135", + "pmid:37143315", + "pmid:36892629", + "pmid:36778282", + "pmid:36701310", + "pmid:36627397", + "pmid:36352383", + "pmid:36230978", + "pmid:36222125", + "pmid:36099027", + "pmid:36084803", + "pmid:36011377", + "pmid:35770133", + "pmid:35767654", + "pmid:35567413", + "pmid:35328504", + "pmid:35243403", + "pmid:35182509", + "pmid:34976437", + "pmid:34915310", + "pmid:34513303", + "pmid:34472530", + "pmid:34432028", + "pmid:34386887", + "pmid:34372915", + "pmid:34371182", + "pmid:34262431", + "pmid:34114350", + "pmid:34025359", + "pmid:33682722", + "pmid:33624941", + "pmid:33575482", + "pmid:33526774", + "pmid:33497365", + "pmid:33363709", + "pmid:33362853", + "pmid:33235377", + "pmid:32929188", + "pmid:32823742", + "pmid:32717741", + "pmid:32656337", + "pmid:32607474", + "pmid:32350131", + "pmid:32203199", + "pmid:32109384", + "pmid:32063450", + "pmid:31996899", + "pmid:31873063", + "pmid:31759551", + "pmid:31649961", + "pmid:31624084", + "pmid:31570586", + "pmid:31395669", + "pmid:31334355", + "pmid:31316546", + "pmid:31253581", + "pmid:31227653", + "pmid:31220271", + "pmid:31164682", + "pmid:31027145", + "pmid:30891637", + "pmid:30700578", + "pmid:30615214", + "pmid:30546383", + "pmid:30425655", + "pmid:30304901", + "pmid:30216892", + "pmid:30140252", + "pmid:29967337", + "pmid:29947794", + "pmid:29592894", + "pmid:29551391", + "pmid:29381654", + "pmid:29334465", + "pmid:29274549", + "pmid:29246312", + "pmid:29114849", + "pmid:28942489", + "pmid:28886202", + "pmid:28810563", + "pmid:28782311", + "pmid:28623239", + "pmid:28435090", + "pmid:28363916", + "pmid:28211918", + "pmid:28129118", + "pmid:28102759", + "pmid:27854230", + "pmid:27727437", + "pmid:27358583", + "pmid:27245480", + "pmid:27222292", + "pmid:26708183", + "pmid:26640575", + "pmid:26586700", + "pmid:26498872", + "pmid:26190529", + "pmid:25958258", + "pmid:25712547", + "pmid:25655594", + "pmid:25606394", + "pmid:25307018", + "pmid:25303993", + "pmid:25168381", + "pmid:24824895", + "pmid:24795756", + "pmid:24781112", + "pmid:24715907", + "pmid:24705798", + "pmid:24455202", + "pmid:24269018", + "pmid:24196578", + "pmid:24092878", + "pmid:23811192", + "pmid:23570879", + "pmid:23308382", + "pmid:26317000", + "pmid:23263591", + "pmid:23209425", + "pmid:23183533", + "pmid:23161457", + "pmid:23159592", + "pmid:23139243", + "pmid:22643181", + "pmid:22595968", + "pmid:22459146", + "pmid:22427994", + "pmid:22078098", + "pmid:22062891", + "pmid:21971425", + "pmid:21949239", + "pmid:21511730", + "pmid:21303839", + "pmid:21245981", + "pmid:21204798", + "pmid:21103235", + "pmid:20801043", + "pmid:20635151", + "pmid:20603324", + "pmid:20346670", + "pmid:20228473", + "pmid:20179953", + "pmid:20171614", + "pmid:20074967", + "pmid:19946639", + "pmid:19715468", + "pmid:19632331", + "pmid:19516957", + "pmid:19470458", + "pmid:18798829", + "pmid:18729234", + "pmid:18611984", + "pmid:18563724", + "pmid:18561181", + "pmid:18559347", + "pmid:18299519", + "pmid:18228241", + "pmid:18213375", + "pmid:17987120", + "pmid:17950578", + "pmid:17877752", + "pmid:17728322", + "pmid:17487865", + "pmid:17158949", + "pmid:17150182", + "pmid:17145685", + "pmid:17114933", + "pmid:16978612", + "pmid:16927100", + "pmid:16716318", + "pmid:16624843", + "pmid:16401743", + "pmid:16376058", + "pmid:16193250", + "pmid:16027111", + "pmid:15972723", + "pmid:15961406", + "pmid:15750273", + "pmid:15684391", + "pmid:15576360", + "pmid:15489504", + "pmid:15462191", + "pmid:15459182", + "pmid:15336691", + "pmid:15215218", + "pmid:15114529", + "pmid:15019706", + "pmid:14734627", + "pmid:14597103", + "pmid:12970845", + "pmid:12630069", + "pmid:12614928", + "pmid:12427866", + "pmid:11978764", + "pmid:11809728", + "pmid:11793472", + "pmid:11726559", + "pmid:11686919", + "pmid:11592825", + "pmid:11590133", + "pmid:11555624", + "pmid:11526199", + "pmid:11260612", + "pmid:11124939", + "pmid:11013451", + "pmid:11001736", + "pmid:10970838", + "pmid:10958655", + "pmid:10951446", + "pmid:10909850", + "pmid:10802668", + "pmid:10802667", + "pmid:10767343", + "pmid:10699184", + "pmid:10668800", + "pmid:10480373", + "pmid:10454725", + "pmid:10435210", + "pmid:10332037", + "pmid:10332033", + "pmid:9950368", + "pmid:9887331", + "pmid:9858828", + "pmid:9668171", + "pmid:9537423", + "pmid:9402536", + "pmid:9401353", + "pmid:9371827", + "pmid:9294109", + "pmid:9241283", + "pmid:9241282", + "pmid:9207101", + "pmid:8948631", + "pmid:8923304", + "pmid:8673131", + "pmid:8659513", + "pmid:8784809", + "pmid:8595416", + "pmid:7626046", + "pmid:7590731", + "pmid:7726160", + "pmid:7896884", + "pmid:8288237" + ] + }, + { + "id": "RCPS_EIF4A3", + "disease_id": "RCPS", + "gene": "EIF4A3", + "chrom": "chr17", + "start_hg38": 80147009, + "stop_hg38": 80147139, + "start_hg19": 78120808, + "stop_hg19": 78120938, + "start_t2t": 81047404, + "stop_t2t": 81047534, + "disease": "Richieri-Costa-Pereira syndrome", + "inheritance": [ + "AR" + ], + "disease_description": "Richieri Costa-Pereira syndrome is characterized by short stature, Robin sequence, cleft mandible, pre/postaxial hand anomalies (including hypoplastic thumbs), and clubfoot. It has been described in 14 Brazilian families and in one unrelated French patient. Prominent low set ears and a highly arched palate were also observed. Transmission is autosomal recessive [@mondo:0009998].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "49 cases as of Nov 2023 [@doi:10.1016/j.omsc.2023.100340]. Found in Brazilian families and one unrelated French patient [@mondo:0009998].", + "age_onset": "0 (birth)", + "age_onset_min": 0, + "age_onset_max": 0, + "typ_age_onset_min": 0, + "typ_age_onset_max": 0, + "details": "Complex repeat of 18-20 nucleotides expands to cause disease: disease is found in individuals with 14-16 repeats [@pmid:24360810], while controls have typically 3-12 repeats with as low as 1 repeat [@genereviews:NBK535148; @gnomad:EIF4A3]. Significance of intermediate alleles is unknown [@pmid:29112243].", + "mechanism": "LoF", + "mechanism_detail": "LoF from a hypomorphic allele [@pmid:24360810].", + "year": "2014 [@pmid:24360810]; syndrome described in 1992 [@pmid:1632438]", + "location_in_gene": "5' UTR", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "CCTCGCTGTGCCGCTGCCGA" + ], + "pathogenic_motif_reference_orientation": [ + "CCTCGCTGTGCCGCTGCCGA" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "ACAGCGAGGTCGGCAGCGGC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 1, + "benign_max": 12, + "intermediate_min": 13, + "intermediate_max": 13, + "pathogenic_min": 14, + "pathogenic_max": 16, + "motif_len": 20, + "ref_copies": null, + "novel": "ref", + "gard": [ + "4718" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "RBN014" + ], + "medgen": [ + "336581" + ], + "mondo": [ + "0009998" + ], + "omim": [ + "268305" + ], + "orphanet": [ + "3102" + ], + "gnomad": [ + "EIF4A3" + ], + "stripy": [], + "tr_atlas": [ + "TR148462" + ], + "webstr_hg38": [], + "webstr_hg19": [], + "locus_tags": [ + "supported_evidence" + ], + "disease_tags": [], + "references": [ + "pmid:24360810", + "genereviews:NBK535148", + "gnomad:EIF4A3", + "pmid:29112243", + "doi:10.1016/j.omsc.2023.100340", + "mondo:0009998", + "pmid:1632438" + ], + "additional_literature": [] + }, + { + "id": "SCA27B_FGF14", + "disease_id": "SCA27B", + "gene": "FGF14", + "chrom": "chr13", + "start_hg38": 102161574, + "stop_hg38": 102161726, + "start_hg19": 102813924, + "stop_hg19": 102814076, + "start_t2t": 101377549, + "stop_t2t": 101377792, + "disease": "Spinocerebellar ataxia 27B", + "inheritance": [ + "AD" + ], + "disease_description": "Late-onset ataxia, may have episodic onset, downbeat nystagmus, vertigo, neuropathy [@pmid:39349043]. Involvement of the superior cerebellar peduncles is frequent and may aid in diagnostic efforts [@doi:10.1212/NXG.0000000000200253].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Intermediate expansions 1-2% of population, but non-GAA-pure without relation to ataxia [@genereviews:NBK599589]. Found in multiple ethnicities [@pmid:38876750]; diagnosed patients in America, Brazil, Japan, Germany, Spain, Canada, France, Austria, Australia, and Italy [@genereviews:NBK599589; @pmid:38886208; @pmid:37267898].", + "age_onset": "Typical: 42-70; Range: 21-87 [@genereviews:NBK599589; @pmid:39263992].", + "age_onset_min": 21, + "age_onset_max": 87, + "typ_age_onset_min": 42, + "typ_age_onset_max": 70, + "details": "Higher repeat size is associated with earlier age of onset [@pmid:39263992]. The 250-300 repeats range is linked to incomplete penetrance and >300 repeats with complete penetrance in some studies and resources [@genereviews:NBK599589; @pmid:37399286; @pmid:39227614]. However, our thresholds are taken from suggestions made by Mohren et al upon evaluation of 169 cases and 802 controls; the authors propose lower thresholds based on pathogenic cases of shorter pure repeats [@pmid:39227614]. Additionally, this study suggests that benign motifs may disrupt the formation of secondary structures in DNA/RNA, leading to reduced pathogenicity. The affect of interruptions on penetrance and onset has been shown in patients, with uninterrupted expansions apparently necessary for disease [@pmid:40007153]. Variation in flanking regions appear to correlate with repeat size [@pmid:39227614; @pmid:38937606]. Intermediate alleles make pose as susceptibility factors or be associated with a phenotypic spectrum (multiple system atrophy) [@pmid:39227614; @pmid:39604554]. Finally, a complex (TTC/TGC) ≥300 repeat expansion has been associated as a risk factor for Parkinson's disease [@pmid:41327893; @pmid:41277530].", + "mechanism": "LoF", + "mechanism_detail": "Reduced transcript 2 [@pmid:36516086].", + "year": "2023 [@pmid:36493768]", + "location_in_gene": "Intron 1", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "GAA" + ], + "pathogenic_motif_reference_orientation": [ + "GAA" + ], + "benign_motif_reference_orientation": [ + "GAAGGA", + "GAAGAAGAAGAAGCA" + ], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CTT" + ], + "benign_motif_gene_orientation": [ + "CCTTCT", + "CTGCTTCTTCTTCTT" + ], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 8, + "benign_max": 179, + "intermediate_min": 180, + "intermediate_max": 319, + "pathogenic_min": 320, + "pathogenic_max": 937, + "motif_len": 3, + "ref_copies": 50.3, + "novel": "ref", + "gard": [], + "genereviews": [ + "NBK599589" + ], + "malacard": [ + "SPN469" + ], + "medgen": [ + "1824051" + ], + "mondo": [ + "0859340" + ], + "omim": [ + "620174" + ], + "orphanet": [ + "675216" + ], + "gnomad": [ + "FGF14" + ], + "stripy": [ + "FGF14" + ], + "tr_atlas": [], + "webstr_hg38": [ + "1272528" + ], + "webstr_hg19": [], + "locus_tags": [ + "supported_evidence", + "maternal_expansion", + "length_affects_onset", + "length_affects_penetrance", + "motif_affects_penetrance", + "length_affects_phenotype" + ], + "disease_tags": [ + "spinocerebellar_ataxia" + ], + "references": [ + "genereviews:NBK599589", + "pmid:39263992", + "pmid:36516086", + "pmid:37399286", + "pmid:39227614", + "pmid:40007153", + "pmid:38937606", + "pmid:39604554", + "pmid:41327893", + "pmid:41277530", + "pmid:38876750", + "pmid:38886208", + "pmid:37267898", + "pmid:36493768", + "pmid:39349043", + "doi:10.1212/NXG.0000000000200253" + ], + "additional_literature": [ + "pmid:41327893", + "pmid:41277530", + "pmid:41118032", + "pmid:41065930", + "pmid:41055766", + "pmid:40974444", + "pmid:40906330", + "pmid:40898875", + "pmid:40894141", + "pmid:40879304", + "pmid:40835733", + "pmid:40679574", + "pmid:40637932", + "pmid:40623333", + "pmid:40579842", + "pmid:40556471", + "pmid:40488180", + "pmid:40379261", + "pmid:40273470", + "pmid:40239008", + "pmid:40191983", + "pmid:40141365", + "pmid:40024931", + "pmid:40017559", + "pmid:39996128", + "pmid:39821862", + "pmid:39801711", + "pmid:39723156", + "pmid:39666057", + "pmid:39666053", + "pmid:39574782", + "pmid:39571249", + "pmid:39392764", + "pmid:39378335", + "pmid:39152783", + "pmid:39006414", + "pmid:38976084", + "pmid:38949032", + "pmid:38866925", + "pmid:38816190", + "pmid:38513302", + "pmid:38487929", + "pmid:38472396", + "pmid:38405699", + "pmid:38381176", + "pmid:38221848", + "pmid:38170134", + "pmid:38150853", + "pmid:38058854", + "pmid:37916889", + "pmid:37646005", + "pmid:37578187", + "pmid:37577458", + "pmid:37322040", + "pmid:37165652", + "pmid:32717741", + "pmid:30017992", + "pmid:28444220", + "pmid:26677414", + "pmid:26149656", + "pmid:15470364", + "pmid:15148151" + ] + }, + { + "id": "FXS_FMR1", + "disease_id": "FXS, FXTAS, POF1", + "gene": "FMR1", + "chrom": "chrX", + "start_hg38": 147912049, + "stop_hg38": 147912111, + "start_hg19": 146993567, + "stop_hg19": 146993629, + "start_t2t": 146176677, + "stop_t2t": 146176769, + "disease": "Fragile X syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency FXPOI/POF1", + "inheritance": [ + "XD" + ], + "disease_description": "A genetic syndrome caused by mutations in the FMR1 gene which is responsible for the expression of the fragile X mental retardation 1 protein. This protein participates in neural development. This syndrome is manifested with mental, emotional, behavioral, physical, and learning disabilities.; Any primary ovarian failure in which the cause of the disease is a mutation in the FMR1 gene.; Fragile X-associated tremor/ataxia syndrome (FXTAS) is a rare neurodegenerative disorder characterized by adult-onset progressive intention tremor and gait ataxia [@mondo:0010383; @mondo:0010706; @mondo:0010382].", + "hpo_terms": null, + "prevalence": "14/100000", + "prevalence_details": "Incidence of full mutation in males 19/100,000; prevalence 14/100,000 [@genereviews:NBK1384]. Female prevalence 9/100,000 [@pmid:24700618]. Known carrier frequency is approximately 300-500/100,000 but detected was 11/100,000 [@pmid:29100084]. FXS prevalence 1:7000 males, 1:11,000 females; FX premutation carriers 1:290-855 males, 1:148-300 females [@isbn:978-3-031-66932-3]. Found worldwide [@genereviews:NBK1384]. In Thailand, 1 in 600 women carry a premutation, and 1 in 400 carry a 'gray zone' allele [@pmid:39320553].", + "age_onset": "Typical: FXS 1 to 'first several years of life', FXTAS 60-65 [@genereviews:NBK1384]; Range: 0 [@url:https://www.uptodate.com/contents/fragile-x-syndrome-clinical-features-and-diagnosis-in-children-and-adolescents] - 78 [@pmid:17427188]; detailed description of typical symptom onset and diagnosis available from Arnold et al [@isbn:978-3-031-66932-3].", + "age_onset_min": 0, + "age_onset_max": 78, + "typ_age_onset_min": 1, + "typ_age_onset_max": 65, + "details": "Intermediate or 'gray zone' occur at 45-54 alleles and may be unstable enough to expand into the premutation range, as well as associate with parkinsonism [@pmid:32463542; @genereviews:NBK1384]. FXTAS/POI occurs at 55-200 repeats, FXS >200, late onset; AGG and CTG interruptions documented [@genereviews:NBK1384; @pmid:29868108].", + "mechanism": "LoF/GoF", + "mechanism_detail": "Loss of function via transcriptional silencing in FXS, RNA gain of function in FXTAS/FXPOI [@pmid:16205714; @pmid:36169768].", + "year": "1992 [@pmid:1605194]; causative gene discovered in 1991 [@pmid:1710175]", + "location_in_gene": "5' UTR", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "CGG" + ], + "pathogenic_motif_reference_orientation": [ + "CGG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CGG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 5, + "benign_max": 44, + "intermediate_min": 45, + "intermediate_max": 200, + "pathogenic_min": 201, + "pathogenic_max": 2000, + "motif_len": 3, + "ref_copies": 20.6667, + "novel": "ref", + "gard": [ + "6464", + "16806" + ], + "genereviews": [ + "NBK1384" + ], + "malacard": [ + "FRG001", + "FRG008", + "PRM405" + ], + "medgen": [ + "8912", + "1644269", + "333403" + ], + "mondo": [ + "0010383", + "0010706", + "0010382" + ], + "omim": [ + "300624", + "300623" + ], + "orphanet": [ + "908", + "642691", + "93256" + ], + "gnomad": [ + "FMR1" + ], + "stripy": [ + "FMR1" + ], + "tr_atlas": [ + "TR173944" + ], + "webstr_hg38": [ + "885222" + ], + "webstr_hg19": [ + "Expansion_FXS/FMR1" + ], + "locus_tags": [ + "supported_evidence", + "somatic_instability", + "anticipation", + "maternal_expansion", + "length_affects_onset", + "length_affects_penetrance", + "length_affects_phenotype", + "length_affects_severity", + "motif_affects_instability" + ], + "disease_tags": [ + "phenotypic_spectrum", + "ataxia" + ], + "references": [ + "genereviews:NBK1384", + "url:https://www.uptodate.com/contents/fragile-x-syndrome-clinical-features-and-diagnosis-in-children-and-adolescents", + "pmid:17427188", + "isbn:978-3-031-66932-3", + "pmid:16205714", + "pmid:36169768", + "pmid:32463542", + "pmid:29868108", + "pmid:24700618", + "pmid:29100084", + "pmid:39320553", + "pmid:1605194", + "pmid:1710175", + "mondo:0010383", + "mondo:0010706", + "mondo:0010382" + ], + "additional_literature": [ + "pmid:41409170", + "pmid:41386846", + "pmid:41385812", + "pmid:41372183", + "pmid:41351347", + "pmid:41278766", + "pmid:41256123", + "pmid:41167304", + "pmid:41145158", + "pmid:41120736", + "pmid:41098569", + "pmid:41074692", + "pmid:41028987", + "pmid:41015363", + "pmid:40980401", + "pmid:40940631", + "pmid:40877251", + "pmid:40869951", + "pmid:40879637", + "pmid:40778130", + "pmid:40653294", + "pmid:40600017", + "pmid:40534679", + "pmid:40488180", + "pmid:40480633", + "pmid:40459253", + "pmid:40455869", + "pmid:40418066", + "pmid:40417743", + "pmid:40296143", + 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"start_hg19": 138664861, + "stop_hg19": 138664904, + "start_t2t": 141687011, + "stop_t2t": 141687054, + "disease": "Blepharophimosis, epicanthus inversus, and ptosis", + "inheritance": [ + "AD", + "AR" + ], + "disease_description": "Blepharophimosis, Ptosis, and Epicanthus Inversus syndrome (BPES) is an ophthalmic disorder characterized by blepharophimosis, ptosis, epicanthus inversus, and telecanthus, that can appear associated with (type I) or without premature ovarian failure (POF) (type II) [@mondo:0007201].", + "hpo_terms": null, + "prevalence": "0.3/50000", + "prevalence_details": "1 in 50,000 births globally for all BPES, with FOXL2 expansions ~30% of pathogenic variants [@genereviews:NBK1441; @genereviews:NBK535148; @pmid:12529855]. Found worldwide, without differences in prevalence based on sex/ethnicity [@genereviews:NBK1441].", + "age_onset": "0 (birth)", + "age_onset_min": 0, + "age_onset_max": 0, + "typ_age_onset_min": 0, + "typ_age_onset_max": 0, + "details": "14 repeats appears highly constrained in humans: homozygous expansions from 14 polyalanines to 19 leads to disease, which can be limited to isolated palpebral defects [@pmid:15591279]. Heterozygous expansions to 24 polyalanines also lead to disease [@pmid:15591279]. Locus start can differ between catalogs, which can affect genotyping.", + "mechanism": "GoF/LoF", + "mechanism_detail": "Polyalanine expansion leads to haploinsufficiency, likely due to decreased protein availibility due to mislocalization following nuclear inclusion [@genereviews:NBK1441; @pmid:15591279]", + "year": "2003 [@pmid:12529855]", + "location_in_gene": "Coding Exon 1", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "NGC" + ], + "pathogenic_motif_reference_orientation": [ + "NGC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CNG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 14, + "benign_max": 14, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 15, + "pathogenic_max": 24, + "motif_len": 3, + "ref_copies": 14, + "novel": "ref", + "gard": [ + "23" + ], + "genereviews": [ + "NBK1441" + ], + "malacard": [ + "BLP046" + ], + "medgen": [ + "66312" + ], + "mondo": [ + "0007201" + ], + "omim": [ + "110100" + ], + "orphanet": [ + "126" + ], + "gnomad": [ + "FOXL2" + ], + "stripy": [ + "FOXL2" + ], + "tr_atlas": [ + "TR36092" + ], + "webstr_hg38": [], + "webstr_hg19": [], + "locus_tags": [ + "supported_evidence" + ], + "disease_tags": [], + "references": [ + "genereviews:NBK1441", + "pmid:15591279", + "genereviews:NBK535148", + "pmid:12529855", + "mondo:0007201" + ], + "additional_literature": [ + "pmid:22926839", + "pmid:18158309", + "pmid:17089161", + "pmid:7633459" + ] + }, + { + "id": "FRDA_FXN", + "disease_id": "FRDA", + "gene": "FXN", + "chrom": "chr9", + "start_hg38": 69037286, + "stop_hg38": 69037304, + "start_hg19": 71652202, + "stop_hg19": 71652220, + "start_t2t": 81210834, + "stop_t2t": 81210861, + "disease": "Friedreich ataxia", + "inheritance": [ + "AR" + ], + "disease_description": "Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia with associated limb muscle weakness, absent lower limb reflexes, extensor plantar responses, dysarthria, and decreased vibratory sense and proprioception. Onset is usually in the first or second decade, before the end of puberty [@omim:229300].", + "hpo_terms": null, + "prevalence": "1/50000", + "prevalence_details": "1/50,000 [@omim:229300; @pmid:29100084]: Known carrier frequency 1000/100,000; observed 421/100,000. Most common inherited ataxia in Europe, the Middle East, India, and North Africa; not documented in Southeast Asia, in sub-Saharan Africa, or among Native Americans [@genereviews:NBK1281].", + "age_onset": "Typical: 10-15; Range: 2-80 [@genereviews:NBK1281].", + "age_onset_min": 2, + "age_onset_max": 80, + "typ_age_onset_min": 10, + "typ_age_onset_max": 15, + "details": "96% of FA patients have biallelic GAA expansions in intron 1 (compared to compound heterozygous with another mutation type), in which the reference allele is conventionally 5-33 repeats [@genereviews:NBK1281]. Intermediate alleles (34-55) are associated with premutations, but may lead to disease as exact pathogenicity/penetrance thresholds have not been demarcated [@genereviews:NBK1281]. The expanded repeats can interrupted either with GAAGAG, GAAGGA, or GAAGAAAA sequences, leading to differential phenotypes [@pmid:11748752]. Allele size is correlated with disease severity and inversely correlated to age of onset, and expansions can reach 1700 repeats [@pmid:8815938].", + "mechanism": "LoF", + "mechanism_detail": "Loss of function via transcriptional silencing [@pmid:16205714; @pmid:36169768].", + "year": "1996 [@pmid:8596916]", + "location_in_gene": "Intron 1", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GAA" + ], + "pathogenic_motif_reference_orientation": [ + "GAA" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "AAG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [ + { + "motif": "A", + "count": 16, + "type": "flank_repeat" + }, + { + "motif": "GAA", + "count": null, + "type": "pathogenic_repeat" + } + ], + "benign_min": 5, + "benign_max": 33, + "intermediate_min": 34, + "intermediate_max": 55, + "pathogenic_min": 56, + "pathogenic_max": 1700, + "motif_len": 3, + "ref_copies": 6, + "novel": "ref", + "gard": [ + "6468" + ], + "genereviews": [ + "NBK1281" + ], + "malacard": [ + "FRD001" + ], + "medgen": [ + "383962" + ], + "mondo": [ + "0100340" + ], + "omim": [ + "229300" + ], + "orphanet": [ + "95" + ], + "gnomad": [ + "FXN" + ], + "stripy": [ + "FXN" + ], + "tr_atlas": [ + "TR93516" + ], + "webstr_hg38": [ + "1509872" + ], + "webstr_hg19": [], + "locus_tags": [ + "supported_evidence", + "somatic_instability", + "maternal_expansion", + "length_affects_onset", + "length_affects_phenotype", + "motif_affects_instability", + "motif_affects_onset", + "motif_affects_penetrance" + ], + "disease_tags": [ + "ataxia" + ], + "references": [ + "genereviews:NBK1281", + "pmid:16205714", + "pmid:36169768", + "pmid:11748752", + "pmid:8815938", + "omim:229300", + "pmid:29100084", + "pmid:8596916" + ], + "additional_literature": [ + "pmid:41432640", + "pmid:41426430", + "pmid:41318543", + "pmid:41301739", + "pmid:41278766", + "pmid:41176519", + "pmid:41137390", + "pmid:41074692", + "pmid:41014100", + "pmid:40994821", + "pmid:40970480", + "pmid:40898875", + "pmid:40880907", + "pmid:40507780", + "pmid:40488180", + "pmid:40419681", + "pmid:40404357", + "pmid:40296143", + "pmid:40141365", + "pmid:39812846", + "pmid:39810753", + "pmid:39574782", + "pmid:39571249", + "pmid:39519164", + "pmid:39496895", + "pmid:39324476", + "pmid:39235665", + "pmid:39219417", + "pmid:39062522", + "pmid:38936158", + "pmid:38495102", + "pmid:38484450", + "pmid:38396238", + "pmid:38367363", + "pmid:38352270", + "pmid:38141359", + "pmid:38063871", + "pmid:38014032", + "pmid:37891254", + "pmid:37585105", + "pmid:37006329", + "pmid:36928898", + "pmid:36800320", + "pmid:36780807", + "pmid:36777637", + "pmid:36638893", + "pmid:36635061", + "pmid:36618024", + "pmid:36511872", + "pmid:36369844", + "pmid:36133907", + "pmid:36036008", + "pmid:35850241", + "pmid:35708503", + "pmid:35595154", + "pmid:35301072", + "pmid:35182509", + "pmid:34920960", + "pmid:34849883", + "pmid:34786480", + "pmid:34747814", + "pmid:34687355", + "pmid:34643298", + "pmid:34600502", + "pmid:34408077", + "pmid:34372915", + "pmid:34299126", + "pmid:34214898", + "pmid:33820410", + "pmid:33629768", + "pmid:33624863", + "pmid:33599954", + "pmid:33592237", + "pmid:33529321", + "pmid:33354116", + "pmid:33151022", + "pmid:33028632", + "pmid:32746884", + "pmid:32744307", + "pmid:32717741", + "pmid:32608417", + "pmid:32586831", + "pmid:32582297", + "pmid:32481586", + "pmid:32385683", + "pmid:32291635", + "pmid:31911468", + "pmid:31904895", + "pmid:31877117", + "pmid:31673878", + "pmid:31650522", + "pmid:31446150", + "pmid:31279523", + "pmid:30874991", + "pmid:30828501", + "pmid:30761510", + "pmid:30635474", + "pmid:30596685", + "pmid:30590615", + "pmid:30552117", + "pmid:30519163", + "pmid:30464193", + "pmid:30425621", + "pmid:30358880", + "pmid:30237783", + "pmid:30159187", + "pmid:30097477", + "pmid:30076049", + "pmid:30065630", + "pmid:29666341", + "pmid:29529236", + "pmid:29261783", + "pmid:29125828", + "pmid:29070698", + "pmid:28904984", + "pmid:28812047", + "pmid:28716278", + "pmid:28451558", + "pmid:28282710", + "pmid:28109580", + "pmid:27518705", + "pmid:27668106", + "pmid:27648458", + "pmid:27644330", + "pmid:27522354", + "pmid:27425605", + "pmid:27386501", + "pmid:27228352", + "pmid:27206881", + "pmid:27142428", + "pmid:26906906", + "pmid:26896803", + "pmid:28392990", + "pmid:26704351", + "pmid:26414159", + "pmid:26401053", + "pmid:26393353", + "pmid:26379101", + "pmid:26339677", + "pmid:26338206", + "pmid:26301374", + "pmid:26149656", + "pmid:26099177", + "pmid:25845763", + "pmid:25831023", + "pmid:25814655", + "pmid:25758173", + "pmid:25685137", + "pmid:25681319", + "pmid:25616511", + "pmid:25207996", + "pmid:25198290", + "pmid:25112975", + "pmid:25022367", + "pmid:24971578", + "pmid:24962209", + "pmid:24858524", + "pmid:24819921", + "pmid:24816001", + "pmid:24787137", + "pmid:24714088", + "pmid:24691413", + "pmid:24667739", + "pmid:24665325", + "pmid:24613765", + "pmid:24586819", + "pmid:24455203", + "pmid:24371004", + "pmid:24327207", + "pmid:24209901", + "pmid:24023969", + "pmid:23996585", + "pmid:23943791", + "pmid:23925595", + "pmid:23922695", + "pmid:23879205", + "pmid:23838345", + "pmid:23775342", + "pmid:23691127", + "pmid:23640016", + "pmid:23625326", + "pmid:23474817", + "pmid:23418481", + "pmid:23382970", + "pmid:23280845", + "pmid:25499576", + "pmid:23269675", + "pmid:23242090", + "pmid:23071719", + "pmid:22798143", + "pmid:22787155", + "pmid:22764244", + "pmid:22752483", + "pmid:22691228", + "pmid:22447512", + "pmid:22414340", + "pmid:22409940", + "pmid:22289650", + "pmid:22262734", + "pmid:21830088", + "pmid:21776984", + "pmid:21745819", + "pmid:21652007", + "pmid:21486239", + "pmid:21397024", + "pmid:21181307", + "pmid:21127046", + "pmid:21051337", + "pmid:21040903", + "pmid:20675166", + "pmid:20559546", + "pmid:20506029", + "pmid:20373285", + "pmid:20098685", + "pmid:20090835", + "pmid:19956589", + "pmid:19876374", + "pmid:19733517", + "pmid:19485941", + "pmid:19370769", + "pmid:19259763", + "pmid:19043662", + "pmid:18820300", + "pmid:18697824", + "pmid:18597733", + "pmid:18045775", + "pmid:17703324", + "pmid:17498922", + "pmid:28182935", + "pmid:17262846", + "pmid:17235301", + "pmid:17024371", + "pmid:16989817", + "pmid:16919418", + "pmid:16857735", + "pmid:16764889", + "pmid:16644517", + "pmid:16120311", + "pmid:15376485", + "pmid:15340363", + "pmid:15233994", + "pmid:15201464", + "pmid:15180699", + "pmid:14978261", + "pmid:14962663", + "pmid:12516053", + "pmid:12112211", + "pmid:11939898", + "pmid:11843702", + "pmid:11809170", + "pmid:11428460", + "pmid:11340071", + "pmid:11325966", + "pmid:11240567", + "pmid:11071107", + "pmid:11054139", + "pmid:10982543", + "pmid:10982187", + "pmid:10969848", + "pmid:10896266", + "pmid:10732799", + "pmid:10681084", + "pmid:10556290", + "pmid:10230399", + "pmid:10102712", + "pmid:10077729", + "pmid:9811933", + "pmid:9779809", + "pmid:9737785", + "pmid:9667602", + "pmid:9577387", + "pmid:9443873", + "pmid:9486868", + "pmid:9448568", + "pmid:9416816", + "pmid:9409356", + "pmid:9326946", + "pmid:9339708", + "pmid:9339680", + "pmid:9270667", + "pmid:9270608", + "pmid:9241271", + "pmid:9177790", + "pmid:9153531", + "pmid:9153129", + "pmid:10464657", + "pmid:9331900", + "pmid:8751856" + ] + }, + { + "id": "OPDM2_GIPC1", + "disease_id": "OPDM2", + "gene": "GIPC1", + "chrom": "chr19", + "start_hg38": 14496041, + "stop_hg38": 14496075, + "start_hg19": 14606853, + "stop_hg19": 14606887, + "start_t2t": 14622655, + "stop_t2t": 14622692, + "disease": "Oculopharyngodistal myopathy type 2", + "inheritance": [ + "AD" + ], + "disease_description": "Ptosis, external ophthalmoplegia, facial weakness, and pharyngeal and distal limb weakness [@pmid:38876750]; Slowly progressive distal weakness, ophthalmoplegia, facial and bulbar weakness [@pmid:39349043].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Population dependent; presumed rare. Predominantly found in individuals of East Asian ancestry [@pmid:38876750].", + "age_onset": "Typical: 20-34 [@pmid:32413282]; Range: 14 [@pmid:32413282] - 70 [@pmid:33374016].", + "age_onset_min": 14, + "age_onset_max": 70, + "typ_age_onset_min": 20, + "typ_age_onset_max": 34, + "details": "Benign repeats range from absent [@gnomad:GIPC1] to 32 [@genereviews:NBK535148], while pathogenic alleles range from 73-164 repeats [@pmid:38876750; @genereviews:NBK535148]. Intermediate alleles have undetermined significance but may represent a phenotypic spectrum [@pmid:32413282]. Interruptions documented: CGA [@pmid:35245110]. Interruptions proposed but not confirmed in primary literature: TCG/CCT/TTG [@pmid:38467784].", + "mechanism": "LoF/GoF?", + "mechanism_detail": "RNA mediated toxicity hypothesized [@omim:618940], still unknown [@pmid:36169768].", + "year": "2020 [@pmid:32413282]", + "location_in_gene": "5' UTR", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "CCG" + ], + "pathogenic_motif_reference_orientation": [ + "CCG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CGG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 0, + "benign_max": 32, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 73, + "pathogenic_max": 164, + "motif_len": 3, + "ref_copies": 14.7, + "novel": "ref", + "gard": [ + "16397" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "OCL080" + ], + "medgen": [ + "1718769" + ], + "mondo": [ + "0030134" + ], + "omim": [ + "618940" + ], + "orphanet": [], + "gnomad": [ + "GIPC1" + ], + "stripy": [ + "GIPC1" + ], + "tr_atlas": [ + "TR154638" + ], + "webstr_hg38": [ + "5626440" + ], + "webstr_hg19": [ + "STR_668861" + ], + "locus_tags": [ + "supported_evidence", + "length_affects_onset", + "length_affects_severity" + ], + "disease_tags": [ + "oculopharyngodistal_myopathy" + ], + "references": [ + "pmid:32413282", + "pmid:33374016", + "omim:618940", + "pmid:36169768", + "gnomad:GIPC1", + "genereviews:NBK535148", + "pmid:38876750", + "pmid:35245110", + "pmid:38467784", + "pmid:39349043" + ], + "additional_literature": [ + "pmid:41121761", + "pmid:40645757", + "pmid:40084170", + "pmid:39936620", + "pmid:39492694", + "pmid:39418922", + "pmid:39013564", + "pmid:38871700", + "pmid:37923380", + "pmid:37550168", + "pmid:36108428", + "pmid:36055118", + "pmid:35700120", + "pmid:35521937", + "pmid:35314910", + "pmid:35152460", + "pmid:35148830", + "pmid:34927285", + "pmid:33693509", + "pmid:33239111", + "pmid:22521844" + ] + }, + { + "id": "GDPAG_GLS", + "disease_id": "GDPAG", + "gene": "GLS", + "chrom": "chr2", + "start_hg38": 190880872, + "stop_hg38": 190880920, + "start_hg19": 191745598, + "stop_hg19": 191745646, + "start_t2t": 191369982, + "stop_t2t": 191370024, + "disease": "Glutaminase deficiency", + "inheritance": [ + "AR" + ], + "disease_description": "Glutaminase deficiency is characterized by refractory seizures, respiratory failure, brain abnormalities and death in the neonatal period, though milder cases with spastic ataxia-dysarthria have also been reported. This condition is caused by mutations in the glutaminase (GLS) gene [@mondo:0600001].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "As of 2019, only 7 cases total of GLS deficiency, including non-repeat. Identified unrelated patients have been Canadian [@pmid:30970188], Kurdish (Turkey) [@pmid:35913761], and US-American (Northern European/Native American descent [@pmid:35913761].", + "age_onset": "Early childhood (2-4) [@pmid:30970188; @pmid:35913761].", + "age_onset_min": 2, + "age_onset_max": 4, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "Pathogenic range from 3 unrelated probands; benign range inferred from mutation data [@genereviews:NBK535148]. Disease cases can be caused by homozygosity or compund heterozygotes [@omim:618412].", + "mechanism": "LoF", + "mechanism_detail": "Change in histone modification decreases transcription [@omim:618412].", + "year": "2019 [@pmid:30970188]", + "location_in_gene": "5' UTR", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GCA" + ], + "pathogenic_motif_reference_orientation": [ + "GCA" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "AGC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 5, + "benign_max": 38, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 680, + "pathogenic_max": 1500, + "motif_len": 3, + "ref_copies": 16, + "novel": "ref", + "gard": [], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "SPS235" + ], + "medgen": [ + "987241" + ], + "mondo": [ + "0600001" + ], + "omim": [ + "618412" + ], + "orphanet": [ + "557056" + ], + "gnomad": [ + "GLS" + ], + "stripy": [ + "GLS" + ], + "tr_atlas": [ + "TR24838" + ], + "webstr_hg38": [ + "333878", + "5494902" + ], + "webstr_hg19": [ + "STR_803303" + ], + "locus_tags": [ + "supported_evidence" + ], + "disease_tags": [], + "references": [ + "pmid:30970188", + "pmid:35913761", + "omim:618412", + "genereviews:NBK535148", + "mondo:0600001" + ], + "additional_literature": [ + "pmid:40488180", + "pmid:40417743", + "pmid:39699045", + "pmid:39651202", + "pmid:38877099", + "pmid:38871700", + "pmid:38260514", + "pmid:34285061", + "pmid:34013182", + "pmid:33691262", + "pmid:33413375", + "pmid:14510958", + "pmid:7729621" + ] + }, + { + "id": "HFG_HOXA13-I", + "disease_id": "HFG-I", + "gene": "HOXA13", + "chrom": "chr7", + "start_hg38": 27199924, + "stop_hg38": 27199966, + "start_hg19": 27239543, + "stop_hg19": 27239585, + "start_t2t": 27335912, + "stop_t2t": 27335954, + "disease": "Hand-foot-genital syndrome 1", + "inheritance": [ + "AD" + ], + "disease_description": "Hand-foot-genital syndrome (HFGS) is a very rare multiple congenital abnormality syndrome characterized by distal limb malformations and urogenital defects [@mondo:0007698].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Extremely rare, published cases generally European ancestry or unknown [@pmid:15385446; @pmid:17935235; @genereviews:NBK1423].", + "age_onset": "0 (birth)", + "age_onset_min": 0, + "age_onset_max": 0, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "Anticipation does not occur, and expansions appear fully penetrant [@genereviews:NBK1423].", + "mechanism": "LoF", + "mechanism_detail": "Polyalanine expansions leading to haploinsufficiency [@genereviews:NBK1423]", + "year": "2004 [@pmid:15385446]", + "location_in_gene": "Coding Exon 1", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "NGC" + ], + "pathogenic_motif_reference_orientation": [ + "NGC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CNG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 14, + "benign_max": 14, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 22, + "pathogenic_max": 22, + "motif_len": 3, + "ref_copies": 14, + "novel": "ref", + "gard": [ + "2594" + ], + "genereviews": [ + "NBK1423" + ], + "malacard": [ + "HND004" + ], + "medgen": [ + "331103" + ], + "mondo": [ + "0007698" + ], + "omim": [ + "140000" + ], + "orphanet": [ + "2438" + ], + "gnomad": [ + "HOXA13_1" + ], + "stripy": [ + "HOXA13_1" + ], + "tr_atlas": [ + "TR74138" + ], + "webstr_hg38": [ + "5679832" + ], + "webstr_hg19": [ + "STR_1311037" + ], + "locus_tags": [ + "limited_evidence" + ], + "disease_tags": [ + "hand_foot_genital_syndrome" + ], + "references": [ + "genereviews:NBK1423", + "pmid:15385446", + "pmid:17935235", + "mondo:0007698" + ], + "additional_literature": [ + "pmid:32386547", + "pmid:23532960", + "pmid:19591980", + "pmid:12414828", + "pmid:11543619" + ] + }, + { + "id": "HFG_HOXA13-II", + "disease_id": "HFG-II", + "gene": "HOXA13", + "chrom": "chr7", + "start_hg38": 27199825, + "stop_hg38": 27199861, + "start_hg19": 27239444, + "stop_hg19": 27239480, + "start_t2t": 27335813, + "stop_t2t": 27335849, + "disease": "Hand-foot-genital syndrome 2", + "inheritance": [ + "AD" + ], + "disease_description": "Hand-foot-genital syndrome (HFGS) is a very rare multiple congenital abnormality syndrome characterized by distal limb malformations and urogenital defects [@mondo:0007698].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Extremely rare, published cases generally European ancestry or unknown [@pmid:15385446; @pmid:17935235; @genereviews:NBK1423].", + "age_onset": "0 (birth)", + "age_onset_min": 0, + "age_onset_max": 0, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "Anticipation does not occur, and expansions appear fully penetrant [@genereviews:NBK1423].", + "mechanism": "LoF", + "mechanism_detail": "Polyalanine expansions leading to haploinsufficiency [@genereviews:NBK1423]", + "year": "2003 [@pmid:12676922]", + "location_in_gene": "Coding Exon 1", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "NGC" + ], + "pathogenic_motif_reference_orientation": [ + "NGC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CNG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 12, + "benign_max": 12, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 18, + "pathogenic_max": 18, + "motif_len": 3, + "ref_copies": 12, + "novel": "ref", + "gard": [ + "2594" + ], + "genereviews": [ + "NBK1423" + ], + "malacard": [ + "HND004" + ], + "medgen": [ + "331103" + ], + "mondo": [ + "0007698" + ], + "omim": [ + "140000" + ], + "orphanet": [ + "2438" + ], + "gnomad": [ + "HOXA13_2" + ], + "stripy": [ + "HOXA13_2" + ], + "tr_atlas": [ + "TR74137" + ], + "webstr_hg38": [ + "5679831" + ], + "webstr_hg19": [ + "STR_1311036" + ], + "locus_tags": [ + "limited_evidence" + ], + "disease_tags": [ + "hand_foot_genital_syndrome" + ], + "references": [ + "genereviews:NBK1423", + "pmid:15385446", + "pmid:17935235", + "pmid:12676922", + "mondo:0007698" + ], + "additional_literature": [ + "pmid:32386547", + "pmid:23532960", + "pmid:19591980", + "pmid:12414828", + "pmid:11543619" + ] + }, { - "motif": "CTA", - "count": 10, - "type": "flank_repeat" + "id": "HFG_HOXA13-III", + "disease_id": "HFG-III", + "gene": "HOXA13", + "chrom": "chr7", + "start_hg38": 27199678, + "stop_hg38": 27199732, + "start_hg19": 27239297, + "stop_hg19": 27239351, + "start_t2t": 27335684, + "stop_t2t": 27335720, + "disease": "Hand-foot-genital syndrome 3", + "inheritance": [ + "AD" + ], + "disease_description": "Hand-foot-genital syndrome (HFGS) is a very rare multiple congenital abnormality syndrome characterized by distal limb malformations and urogenital defects [@mondo:0007698].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Extremely rare, published cases generally European ancestry or unknown [@pmid:15385446; @pmid:17935235; @genereviews:NBK1423].", + "age_onset": "0 (birth)", + "age_onset_min": 0, + "age_onset_max": 0, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "Anticipation does not occur, and expansions appear fully penetrant; it is unknown if contractions also lead to phenotypic variation [@genereviews:NBK1423].", + "mechanism": "LoF", + "mechanism_detail": "Polyalanine expansions leading to haploinsufficiency [@genereviews:NBK1423]", + "year": "2000 [@pmid:10839976]", + "location_in_gene": "Coding Exon 1", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "NGC" + ], + "pathogenic_motif_reference_orientation": [ + "NGC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CNG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 8, + "benign_max": 18, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 22, + "pathogenic_max": 32, + "motif_len": 3, + "ref_copies": 18, + "novel": "ref", + "gard": [ + "2594" + ], + "genereviews": [ + "NBK1423" + ], + "malacard": [ + "HND004" + ], + "medgen": [ + "331103" + ], + "mondo": [ + "0007698" + ], + "omim": [ + "140000" + ], + "orphanet": [ + "2438" + ], + "gnomad": [ + "HOXA13_3" + ], + "stripy": [ + "HOXA13_3" + ], + "tr_atlas": [ + "TR74136" + ], + "webstr_hg38": [ + "1365344" + ], + "webstr_hg19": [ + "STR_1311035" + ], + "locus_tags": [ + "limited_evidence" + ], + "disease_tags": [ + "hand_foot_genital_syndrome" + ], + "references": [ + "genereviews:NBK1423", + "pmid:15385446", + "pmid:17935235", + "pmid:10839976", + "mondo:0007698" + ], + "additional_literature": [ + "pmid:32386547", + "pmid:23532960", + "pmid:19591980", + "pmid:12414828", + "pmid:11543619" + ] }, { - "motif": "CTG", - "count": null, - "type": "pathogenic_repeat" - }], - "benign_min": 15, - "benign_max": 50, - "intermediate_min": 50, - "intermediate_max": 70, - "pathogenic_min": 71, - "pathogenic_max": 1300, - "motif_len": 3, - "ref_copies": 15.3, - "novel": "ref", - "gard": ["4956"], - "genereviews": ["NBK1268"], - "malacard": ["SPN304"], - "medgen": ["332457"], - "mondo": ["0012116"], - "omim": ["608768"], - "orphanet": ["98760"], - "gnomad": ["ATXN8OS"], - "stripy": ["ATXN8OS"], - "tr_atlas": ["TR125263", "TR125264"], - "webstr_hg38": ["5356762"], - "webstr_hg19": ["Expansion_SCA8/ATXN8"], - "locus_tags": ["supported_evidence", "somatic_instability", "anticipation", "maternal_expansion", "motif_affects_onset", "motif_affects_penetrance"], - "disease_tags": ["spinocerebellar_ataxia"], - "references": ["genereviews:NBK1268", "doi:10.1101/gr.279634.124", "omim:608768", "pmid:16804541", "pmid:20373340", "pmid:28451643", "pmid:34632710", "pmid:29100084", "pmid:10192387", "mondo:0012116"], - "additional_literature": ["pmid:41353794", "pmid:41082794", "pmid:41079917", "pmid:41074692", "pmid:41001200", "pmid:40906330", "pmid:40890648", "pmid:40844737", "pmid:40765612", "pmid:40488180", "pmid:40007153", "pmid:38961870", "pmid:38227102", "pmid:38165578", "pmid:38152578", "pmid:37906407", "pmid:37848721", "pmid:37146135", "pmid:37003406", "pmid:36703300", "pmid:36530930", "pmid:34622207", "pmid:34600502", "pmid:34284285", "pmid:33526774", "pmid:33502644", "pmid:31471687", "pmid:30109267", "pmid:29316893", "pmid:29111027", "pmid:28782341", "pmid:28229454", "pmid:27896316", "pmid:26374734", "pmid:26077168", "pmid:25466696", "pmid:23711133", "pmid:23026538", "pmid:22581592", "pmid:22520093", "pmid:22297462", "pmid:22053702", "pmid:21173221", "pmid:20403608", "pmid:19259763", "pmid:19229559", "pmid:18684474", "pmid:18418692", "pmid:17961920", "pmid:17005861", "pmid:16184604", "pmid:16054804", "pmid:15553088", "pmid:15148151", "pmid:15080863", "pmid:14972680", "pmid:14966163", "pmid:14960773", "pmid:14756671", "pmid:12838526", "pmid:12764052", "pmid:12545428", "pmid:12505613", "pmid:12470185", "pmid:12431257", "pmid:12372061", "pmid:12140678", "pmid:12042281", "pmid:11939898", "pmid:11839840", "pmid:11807410", "pmid:11708995", "pmid:11591855", "pmid:11448300", "pmid:11160961", "pmid:11121196", "pmid:11102643", "pmid:11030410", "pmid:10976642", "pmid:10958651", "pmid:10785256", "pmid:10712198", "pmid:10700168", "pmid:10690991"] -}, -{ - "id": "SCA31_BEAN1", - "disease_id": "SCA31", - "gene": "BEAN1", - "chrom": "chr16", - "start_hg38": 66490396, - "stop_hg38": 66490466, - "start_hg19": 66524299, - "stop_hg19": 66524369, - "start_t2t": 72284666, - "stop_t2t": 72284761, - "disease": "Spinocerebellar ataxia type 31", - "inheritance": ["AD"], - "disease_description": "Spinocerebellar ataxia type 31 (SCA31) is a very rare subtype of autosomal dominant cerebellar ataxia type III (ADCA type III) characterized by the late-onset of cerebral ataxia, dysarthria and horizontal gaze nystagmus, and that is occasionally accompanied by pyramidal signs, tremor, decreased vibration sense and hearing difficulties [@mondo:0007296].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Has been found in Japanese populations [@omim:117210] and then once respectively in a Korean and a Chinese family [@pmid:36563608].", - "age_onset": "Typical: 56-62 [@pmid:36563608]; Range: 8-83 [@pmid:23331413].", - "age_onset_min": 8.0, - "age_onset_max": 83.0, - "typ_age_onset_min": 56.0, - "typ_age_onset_max": 62.0, - "details": "This locus is a novel STR-containing insertion, not present in reference genome; the pathogenic threshold (110-760) is based on the pure repeat of the pathogenic motif within the insertion [@pmid:19878914].", - "mechanism": "GoF", - "mechanism_detail": "RNA toxicity and gain of function leading to neurodegeneration [@pmid:36371266]. Role in heterochromatin or chromosomal structure theorized [@omim:117210].", - "year": "2009 [@pmid:19878914]", - "location_in_gene": "Intron 4/4", - "gene_strand": "+", - "reference_motif_reference_orientation": ["AATAA"], - "pathogenic_motif_reference_orientation": ["TGGAA", "TAGAA"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": ["AAAAA", "AAAAC", "AAATG", "AGAAA", "ATAAG", "TAAAC", "TAACA", "TACAA", "TCAAA", "TGCAA"], - "pathogenic_motif_gene_orientation": ["AATGG", "AATAG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": ["AAAAA", "AAAAC", "AAATG", "AAAAG", "AAGAT", "AAACT", "AACAT", "AATAC", "AAATC", "AATGC"], - "locus_structure": [], - "benign_min": null, - "benign_max": null, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 110, - "pathogenic_max": 760, - "motif_len": 5, - "ref_copies": 14.4, - "novel": "novel", - "gard": ["9975"], - "genereviews": ["NBK535148"], - "malacard": ["SPN103"], - "medgen": ["348439"], - "mondo": ["0007296"], - "omim": ["117210"], - "orphanet": ["217012"], - "gnomad": ["BEAN1"], - "stripy": ["BEAN1"], - "tr_atlas": ["TR141992"], - "webstr_hg38": ["812447", "5971756"], - "webstr_hg19": ["STR_539736"], - "locus_tags": ["supported_evidence", "anticipation", "motif_affects_onset", "motif_affects_penetrance"], - "disease_tags": ["spinocerebellar_ataxia"], - "references": ["pmid:36563608", "pmid:23331413", "pmid:36371266", "omim:117210", "pmid:19878914", "mondo:0007296"], - "additional_literature": ["pmid:41426430", "pmid:40765612", "pmid:40488180", "pmid:38961870", "pmid:38152578", "pmid:37848721", "pmid:36970617", "pmid:36092952", "pmid:35084690", "pmid:33785066", "pmid:33431896", "pmid:32066831", "pmid:31737797", "pmid:29111027", "pmid:28343865", "pmid:24215022", "pmid:23607545"] -}, -{ - "id": "FTDALS1_C9orf72", - "disease_id": "FTDALS1", - "gene": "C9orf72", - "chrom": "chr9", - "start_hg38": 27573484, - "stop_hg38": 27573546, - "start_hg19": 27573482, - "stop_hg19": 27573544, - "start_t2t": 27584063, - "stop_t2t": 27584155, - "disease": "Frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS)", - "inheritance": ["AD"], - "disease_description": "Pure frontotemporal dementia, pure amyotrophic lateral sclerosis or combination of the two [@pmid:39349043]. Nominal associations with risk of Parkinson's have also been reported [@pmid:41074692].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "The expansion of a hexanucleotide repeat GGGGCC in C9orf72 is the most common known cause of ALS accounting for ~ 40% familial cases and ~ 7% sporadic cases in the European population; overall ALS incidence is 1-2/100,000 person-years, point prevalence is 3-5/100,000 (Europe/US); lifetime risk is 1 in 300 [@pmid:31315673]. Related individuals to patients with C9orf72-ALS appear at an increased risk of disease regardless of carrier status [@pmid:38149039; @pmid:39315390]. C9orf72-FTD is estimated to be 0.04-134:100,000 [@genereviews:NBK268647], and by our estimates 0.65-1.56/100,000 for C9orf72-ALS. The expansion has been found across ethnicities/ancestries, with population-dependent prevalence, highest in those with northern European ancestry [@genereviews:NBK268647].", - "age_onset": "Typical: 50-64; Range: 20-91 [@genereviews:NBK268647].", - "age_onset_min": 20.0, - "age_onset_max": 91.0, - "typ_age_onset_min": 50.0, - "typ_age_onset_max": 64.0, - "details": "FTD and ALS form a clinical spectrum [@pmid:37388914; @pmid:22406228]. The clinical ranges of the C9orf72 locus remain ambiguous [@stripy:C9ORF72]: most healthy controls have alleles up to 24 repeats [@pmid:28319737] yet 24-30 repeats are associated with ALS [@pmid:31315673] and while 60 repeats is frequently used as a threshold for uncertain alleles, the exact threshold of pathogenicity remains unclear [@genereviews:NBK268647; @pmid:38099605]. Repeats of 80 motifs and lower appear to have delayed onset for any phenotype [@pmid:28319737]. >250 repeats are associated with a full FTD/ALS disease state [@pmid:31048495], but pathogenic alleles can range from 30 to more than 4000 repeats [@pmid:38099605; @pmid:39709476]. Penetrance appears to also be age-dependent, with environmental factors and specific phenotypes associated with sex and age at onset [@pmid:28522837]. Methylation appears to increase with expansion length and age [@pmid:39709476].", - "mechanism": "Ambiguous", - "mechanism_detail": "The HRE forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA/DNA hybrids (R-loops). The structural polymorphism causes a repeat length-dependent accumulation of transcripts aborted in the HRE region [@omim:105500]. Addiitonal mechanisms theorized include protein loss of function and RNA gain of function [@pmid:37847372]. Multiple cell types in the prefrontal cortex, including oligodendrocytes, microglia, astrocytes, and neurons, appear impacted during pathogenesis [@pmid:39999167].", - "year": "2011 [@pmid:21944778]", - "location_in_gene": "Intron 1 or 5' UTR depending on transcript", - "gene_strand": "-", - "reference_motif_reference_orientation": ["GGCCCC"], - "pathogenic_motif_reference_orientation": ["GGCCCC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CCGGGG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 2, - "benign_max": 23, - "intermediate_min": 24, - "intermediate_max": 60, - "pathogenic_min": 251, - "pathogenic_max": 4088, - "motif_len": 6, - "ref_copies": 10.8, - "novel": "ref", - "gard": ["18396"], - "genereviews": ["NBK268647"], - "malacard": ["FRN044"], - "medgen": ["1830423"], - "mondo": ["0007105"], - "omim": ["105500"], - "orphanet": ["275872"], - "gnomad": ["C9ORF72"], - "stripy": ["C9ORF72"], - "tr_atlas": ["TR92417"], - "webstr_hg38": ["5877863", "1502453"], - "webstr_hg19": ["STR_1475506"], - "locus_tags": ["supported_evidence", "length_affects_phenotype", "length_affects_onset"], - "disease_tags": ["phenotypic_spectrum"], - "references": ["genereviews:NBK268647", "omim:105500", "pmid:37847372", "pmid:39999167", "pmid:37388914", "pmid:22406228", "stripy:C9ORF72", "pmid:28319737", "pmid:31315673", "pmid:38099605", "pmid:31048495", "pmid:39709476", "pmid:28522837", "pmid:38149039", "pmid:39315390", "pmid:21944778", "pmid:39349043", "pmid:41074692"], - "additional_literature": ["pmid:41440030", "pmid:41437053", "pmid:41426430", "pmid:41423553", "pmid:41394713", "pmid:41394638", "pmid:41379346", "pmid:41366786", "pmid:41359433", "pmid:41358323", "pmid:41294820", "pmid:41283823", "pmid:41278665", "pmid:41271630", "pmid:41269363", "pmid:41256634", "pmid:41240362", "pmid:41216140", "pmid:41196070", 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"pmid:24667415", "pmid:24650794", "pmid:24612676", "pmid:24598541", "pmid:24573903", "pmid:24559645", "pmid:24549040", "pmid:24530272", "pmid:24445987", "pmid:24442578", "pmid:24439166", "pmid:24417314", "pmid:24387986", "pmid:24387985", "pmid:24385136", "pmid:24378086", "pmid:24363131", "pmid:24355526", "pmid:24329881", "pmid:24319645", "pmid:24309270", "pmid:24286341", "pmid:24269022", "pmid:24269018", "pmid:24252571", "pmid:24252525", "pmid:24248382", "pmid:24212388", "pmid:24179835", "pmid:24170096", "pmid:24169076", "pmid:24166615", "pmid:24154603", "pmid:24139042", "pmid:24129584", "pmid:24126854", "pmid:24121957", "pmid:24107864", "pmid:24096617", "pmid:24080172", "pmid:24077574", "pmid:24068985", "pmid:24057670", "pmid:24053774", "pmid:24052799", "pmid:24027057", "pmid:24011653", "pmid:23998997", "pmid:23987827", "pmid:23973441", "pmid:23962495", "pmid:23922030", "pmid:23894576", "pmid:23884045", "pmid:23870417", "pmid:23869403", "pmid:23845100", "pmid:23836460", "pmid:23836290", "pmid:23818065", "pmid:23771489", "pmid:23731538", "pmid:23720273", "pmid:23695224", "pmid:23686809", "pmid:23597494", "pmid:23588498", "pmid:23588422", "pmid:23587638", "pmid:23566336", "pmid:23553481", "pmid:23551834", "pmid:23548882", "pmid:23473366", "pmid:23437264", "pmid:23435409", "pmid:23434116", "pmid:23423380", "pmid:23421625", "pmid:23415312", "pmid:23413259", "pmid:23383383", "pmid:23381195", "pmid:23358603", "pmid:23352322", "pmid:23338750", "pmid:23338682", "pmid:23329412", "pmid:23284068", "pmid:23273600", "pmid:23261768", "pmid:23254636", "pmid:23216213", "pmid:23199140", "pmid:23151261", "pmid:23141412", "pmid:23117491", "pmid:23116878", "pmid:23111906", "pmid:23107433", "pmid:23088937", "pmid:23085936", "pmid:23084342", "pmid:23063644", "pmid:23053136", "pmid:23053135", "pmid:23036583", "pmid:23035801", "pmid:23016833", "pmid:23012445", "pmid:23006986", "pmid:22993125", "pmid:22985429", "pmid:22964911", "pmid:22936364", "pmid:22918453", "pmid:22898310", "pmid:22892647", "pmid:22878164", "pmid:22875087", "pmid:22875086", "pmid:22843265", "pmid:22840558", "pmid:22818528", "pmid:22815561", "pmid:22766732", "pmid:22766072", "pmid:22742426", "pmid:22739338", "pmid:22727276", "pmid:22721568", "pmid:22720079", "pmid:22708871", "pmid:22702520", "pmid:22692064", "pmid:22673113", "pmid:22650353", "pmid:22645277", "pmid:22637471", "pmid:22637429", "pmid:22571983", "pmid:22564974", "pmid:22550220", "pmid:22507827", "pmid:22502998", "pmid:22499346", "pmid:22483864", "pmid:22459598", "pmid:22426854", "pmid:22418734", "pmid:22410647", "pmid:22406229", "pmid:22399793", "pmid:22366794", "pmid:22366793", "pmid:22366792", "pmid:22366791", "pmid:22343411", "pmid:22305801", "pmid:22300876", "pmid:22300873", "pmid:22228244", "pmid:22216764", "pmid:22181065", "pmid:22154785", "pmid:22101323", "pmid:22083254", "pmid:21944779"] -}, -{ - "id": "SCA6_CACNA1A", - "disease_id": "SCA6", - "gene": "CACNA1A", - "chrom": "chr19", - "start_hg38": 13207858, - "stop_hg38": 13207898, - "start_hg19": 13318672, - "stop_hg19": 13318712, - "start_t2t": 13333136, - "stop_t2t": 13333176, - "disease": "Spinocerebellar ataxia type 6", - "inheritance": ["AD"], - "disease_description": "Spinocerebellar ataxia type 6 (SCA6) is the most common subtype of autosomal dominant cerebellar ataxia type III (ADCA type III) characterized by late-onset and slowly progressive gait ataxia and other cerebellar signs such as impaired muscle coordination and nystagmus [@mondo:0008457]. Ao, et al. has proposed that this expansion may have effects on chronotype, differing by sex and menopausal status, as well as depresssion severity [@pmid:41358280].", - "hpo_terms": null, - "prevalence": "2.65/100000", - "prevalence_details": "13-15% of global SCA prevalence, estimated to be 0.02-31/100,000 [@genereviews:NBK1140; @pmid:29100084]: resultant estimate is 0.3-5/100,000. Found across ethnicities/ancestries, with population-dependent prevalence [@genereviews:NBK1140].", - "age_onset": "Typical: 43-52 [@genereviews:NBK1140]; Range: 16 [@pmid:23331413] - 73 [@genereviews:NBK1140].", - "age_onset_min": 16.0, - "age_onset_max": 73.0, - "typ_age_onset_min": 43.0, - "typ_age_onset_max": 52.0, - "details": "The intermediate range (19-20 motifs) [@doi:10.1212/NXG.0000000000200245; @genereviews:NBK1140] can be associated with a premutation, reduced penetrance, atypical phenotype, or a disease state when homozygous [@genereviews:NBK1140]. When the longer allele is > 22 motifs, the short allele does not play a role in pathogenicity/age of onset, but expansions of 21-22 motifs have age of onset influenced by the smaller allele [@doi:10.1212/NXG.0000000000200245]. For individuals with a longest allele of 19-20, the presence of a second allele of 19-20 likely increases the risk of developing SCA6 [@doi:10.1212/NXG.0000000000200245].", - "mechanism": "GoF/LoF", - "mechanism_detail": "Polyglutamine expansions associated increased expression of altered product leading to impaired gene binding and transcription factor function as well as cellular toxicity [@genereviews:NBK1140].", - "year": "1997 [@pmid:8988170]", - "location_in_gene": "Coding, Last Exon: 47 or 48", - "gene_strand": "-", - "reference_motif_reference_orientation": ["CTG"], - "pathogenic_motif_reference_orientation": ["CTG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["AGC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 4, - "benign_max": 18, - "intermediate_min": 19, - "intermediate_max": 20, - "pathogenic_min": 21, - "pathogenic_max": 33, - "motif_len": 3, - "ref_copies": 13.3, - "novel": "ref", - "gard": ["10351"], - "genereviews": ["NBK1140"], - "malacard": ["SPN309"], - "medgen": ["148458"], - "mondo": ["0008457"], - "omim": ["183086"], - "orphanet": ["98758"], - "gnomad": ["CACNA1A"], - "stripy": ["CACNA1A"], - "tr_atlas": ["TR154515"], - "webstr_hg38": ["5624835"], - "webstr_hg19": ["Expansion_SCA6/CACNA1A"], - "locus_tags": ["supported_evidence", "length_affects_phenotype", "length_affects_penetrance", "length_affects_onset"], - "disease_tags": ["spinocerebellar_ataxia"], - "references": ["genereviews:NBK1140", "pmid:23331413", "doi:10.1212/NXG.0000000000200245", "pmid:29100084", "pmid:8988170", "mondo:0008457", "pmid:41358280"], - "additional_literature": ["pmid:41358280", "pmid:41082794", "pmid:41009775", "pmid:40906330", "pmid:40900235", "pmid:40879304", "pmid:40746751", "pmid:40488180", "pmid:40189664", "pmid:39812846", "pmid:39571249", "pmid:39152783", "pmid:39048885", "pmid:38961870", "pmid:38227102", "pmid:38165578", "pmid:38152578", "pmid:37848721", "pmid:37307504", "pmid:37301203", "pmid:36618024", "pmid:36599645", "pmid:36530930", "pmid:35962273", "pmid:35188716", "pmid:35182509", "pmid:35052497", "pmid:34647648", "pmid:34600502", "pmid:34565721", "pmid:34371182", "pmid:34159894", "pmid:33502644", "pmid:33121221", "pmid:32888184", "pmid:32822634", "pmid:31522753", "pmid:30891880", "pmid:30591349", "pmid:30342765", "pmid:30314815", "pmid:30120431", "pmid:30078120", "pmid:29959555", "pmid:29553382", "pmid:29367260", "pmid:29316893", "pmid:29249939", "pmid:29111027", "pmid:29057148", "pmid:28946818", "pmid:28782341", "pmid:28585930", "pmid:28444220", "pmid:28131213", "pmid:27979829", "pmid:27896316", "pmid:27848087", "pmid:27806289", "pmid:27412786", "pmid:27400454", "pmid:27333979", "pmid:26730403", "pmid:26377379", "pmid:26374734", "pmid:26354989", "pmid:26077168", "pmid:26054379", "pmid:25634432", "pmid:25624155", "pmid:25466696", "pmid:24780882", "pmid:24534762", "pmid:24486772", "pmid:24209901", "pmid:23423669", "pmid:23407676", "pmid:23368522", "pmid:23026538", "pmid:22520093", "pmid:26859398", "pmid:26676458", "pmid:21832228", "pmid:21550405", "pmid:20069235", "pmid:19631275", "pmid:19429075", "pmid:19259763", "pmid:19224313", "pmid:18949263", "pmid:18759344", "pmid:18687887", "pmid:18685131", "pmid:18684474", "pmid:18506570", "pmid:18418678", "pmid:18285829", "pmid:18074367", "pmid:17961920", "pmid:17682009", "pmid:17516099", "pmid:17420317", "pmid:16396623", "pmid:16389595", "pmid:16310805", "pmid:16000334", "pmid:15875905", "pmid:15747371", "pmid:15553088", "pmid:15148151", "pmid:15080863", "pmid:15026782", "pmid:14967767", "pmid:14966163", "pmid:14756671", "pmid:14534930", "pmid:12810491", "pmid:12764052", "pmid:12676347", "pmid:12614315", "pmid:12545428", "pmid:11939898", "pmid:11889231", "pmid:11839840", "pmid:11804332", "pmid:11717352", "pmid:11708993", "pmid:11448300", "pmid:11355155", "pmid:11341481", "pmid:11311290", "pmid:11176970", "pmid:11160961", "pmid:10369884", "pmid:11081813", "pmid:11030410", "pmid:10985694", "pmid:10964945", "pmid:10945665", "pmid:10942107", "pmid:10894992", "pmid:10785256", "pmid:10768629", "pmid:10766906", "pmid:10690991", "pmid:10674974", "pmid:10601803", "pmid:10453742", "pmid:10442462", "pmid:10369863", "pmid:10369828", "pmid:10366652", "pmid:10225349", "pmid:9973298", "pmid:9915947", "pmid:9879686", "pmid:9855520", "pmid:9779664", "pmid:9758625", "pmid:9741473", "pmid:9696528", "pmid:9674805", "pmid:9613852", "pmid:9600677", "pmid:9559993", "pmid:9507387", "pmid:9436730", "pmid:9385362", "pmid:9371901", "pmid:9371900", "pmid:9403486", "pmid:9403480", "pmid:9345107", "pmid:9339681", "pmid:9302278", "pmid:9311738", "pmid:9259275", "pmid:9259274", "pmid:10464657", "pmid:9043864"] -}, -{ - "id": "JBS_CBL", - "disease_id": "JBS", - "gene": "CBL", - "chrom": "chr11", - "start_hg38": 119206289, - "stop_hg38": 119206323, - "start_hg19": 119076999, - "stop_hg19": 119077033, - "start_t2t": 119226662, - "stop_t2t": 119226696, - "disease": "Jacobsen syndrome (FRAX11B fragile site)", - "inheritance": ["AD"], - "disease_description": "A multiple congenital anomaly/intellectual disability contiguous gene syndrome caused by partial deletion of the long arm of chromosome 11 [@mondo:0007838].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "1/100,000 births; female/male ratio 2:1 [@pmid:19267933]. Found across ancestries/ethnicities [@omim:147791].", - "age_onset": "Condition at birth.", - "age_onset_min": 0.0, - "age_onset_max": 0.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "70% of individuals have 11 repeats [@pmid:7603564], but pathogenic expansion can span hundreds of motifs [@pmid:10767345]. The CGG repeat expansion can lead to a fragile site and subsequent deletion of 11q (shown in 2 cases) but total causality is unclear; intermediate alleles are associated with a premutation [@pmid:19267933].", - "mechanism": "Hypermethylation", - "mechanism_detail": "DNA hypermethylation/11q deletion in sporadic cases [@pmid:38467784].", - "year": "1995 [@pmid:7603564]", - "location_in_gene": "5' UTR", - "gene_strand": "+", - "reference_motif_reference_orientation": ["CGG"], - "pathogenic_motif_reference_orientation": ["CGG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CGG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 5, - "benign_max": 79, - "intermediate_min": 80, - "intermediate_max": 100, - "pathogenic_min": 101, - "pathogenic_max": 300, - "motif_len": 3, - "ref_copies": 11.3, - "novel": "ref", - "gard": ["307"], - "genereviews": [], - "malacard": ["JCB001"], - "medgen": ["162878"], - "mondo": ["0007838"], - "omim": ["147791"], - "orphanet": ["2308"], - "gnomad": ["CBL"], - "stripy": ["CBL"], - "tr_atlas": ["TR112816"], - "webstr_hg38": ["6166081", "430025"], - "webstr_hg19": ["STR_266122"], - "locus_tags": ["supported_evidence"], - "disease_tags": [], - "references": ["pmid:38467784", "pmid:7603564", "pmid:10767345", "pmid:19267933", "omim:147791", "mondo:0007838"], - "additional_literature": ["pmid:37422244", "pmid:22131879", "pmid:22084433", "pmid:16474167"] -}, -{ - "id": "DM2_CNBP", - "disease_id": "DM2", - "gene": "CNBP", - "chrom": "chr3", - "start_hg38": 129172576, - "stop_hg38": 129172656, - "start_hg19": 128891419, - "stop_hg19": 128891499, - "start_t2t": 131917482, - "stop_t2t": 131917557, - "disease": "Myotonic dystrophy type 2", - "inheritance": ["AD"], - "disease_description": "Myotonic dystrophy type 2 (MD2), also known as proximal myotonic myopathy, is a very rare genetic multi-system disorder of late childhood or adult-onset characterized by mild myotonia, muscle weakness, and rarely cardiac conduction disorders [@mondo:0011266].", - "hpo_terms": null, - "prevalence": "2.29/100000", - "prevalence_details": "2.29/100,000 [@pmid:35483324]; population specific prevalence [@genereviews:NBK1466]. Most cases have European ancestry, but disease has been reported worldwide [@genereviews:NBK1466].", - "age_onset": "Typical: 28-56 [@pmid:29086017]; Range: 0-73 [@pmid:31159885].", - "age_onset_min": 0.0, - "age_onset_max": 73.0, - "typ_age_onset_min": 28.0, - "typ_age_onset_max": 56.0, - "details": "Detailed overview of disease locus through 2024 by Rimoldi et al [@pmid:39643839]. ≤30 uninterrupted CCTG repeats or 11-26 CCTG repeats with GCTC/TCTG interruptions are considered benign; 27-29 repeats with interruptions have currently unknown significance, ~30-~54 repeats are considered premutations, ~55-74 repeats are premutations with possible reduced penetrance, and >74 repeat alleles are considered pathogenic [@genereviews:NBK1466]. Penetrance is age-dependent and approaches 100%. Locus structure is (TG)n(TCTG)n(CCTG)n. CCTG expansion causes DM2 but the other repeat units are also variable. Interruptions include GCTG/TCTG/GGCT [@pmid:35245110]. The effect of the (TCTG)n repeat remains to be determined, but it is potentially common in the repeat structure of this locus [@pmid:39703464].", - "mechanism": "GoF", - "mechanism_detail": "Aberrant splicing, RAN translation [@pmid:22140091; @pmid:38467784].", - "year": "2001 [@pmid:11486088]", - "location_in_gene": "Intron 1", - "gene_strand": "-", - "reference_motif_reference_orientation": ["CAGG"], - "pathogenic_motif_reference_orientation": ["CAGG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": ["CAGA"], - "pathogenic_motif_gene_orientation": ["CCTG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": ["CTGT"], - "locus_structure": [ + "id": "SD5_HOXD13", + "disease_id": "SD5", + "gene": "HOXD13", + "chrom": "chr2", + "start_hg38": 176093058, + "stop_hg38": 176093103, + "start_hg19": 176957786, + "stop_hg19": 176957831, + "start_t2t": 176581179, + "stop_t2t": 176581224, + "disease": "Syndactyly", + "inheritance": [ + "AD" + ], + "disease_description": "Synpolydactyly (SPD), or syndactyly type II, is defined as a connection between the middle and ring fingers and fourth and fifth toes, variably associated with postaxial polydactyly in the same digits. Minor local anomalies and various metacarpal or metatarsal abnormalities may be present [@omim:186000].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Syndactyly is found across dozens of unrelated families worldwide [@pmid:24038517]. However, syndactyly-5 specific to STR expansion has been found in 3 individuals [@genereviews:NBK535148].", + "age_onset": "0 (birth)", + "age_onset_min": 0, + "age_onset_max": 0, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "Benign alleles are highly conserved to be 15 repeats, with disease observed in individuals with 22-23 repeats [@pmid:8614804; @pmid:22406499] as well as in individuals with 8-11 repeats [@genereviews:NBK535148].", + "mechanism": "GoF", + "mechanism_detail": "Polyalanine expansion leading to GoF [@pmid:38467784]", + "year": "1996 [@pmid:8614804]", + "location_in_gene": "Coding Exon 1", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GCN" + ], + "pathogenic_motif_reference_orientation": [ + "GCN" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CNG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 15, + "benign_max": 15, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 22, + "pathogenic_max": 23, + "motif_len": 3, + "ref_copies": 14, + "novel": "ref", + "gard": [ + "17358" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "SYN084" + ], + "medgen": [ + "1809573" + ], + "mondo": [ + "0008513" + ], + "omim": [ + "186000" + ], + "orphanet": [ + "295195" + ], + "gnomad": [ + "HOXD13" + ], + "stripy": [ + "HOXD13" + ], + "tr_atlas": [ + "TR24032" + ], + "webstr_hg38": [ + "5486677" + ], + "webstr_hg19": [ + "STR_796395" + ], + "locus_tags": [ + "supported_evidence", + "contraction" + ], + "disease_tags": [], + "references": [ + "pmid:38467784", + "pmid:8614804", + "pmid:22406499", + "genereviews:NBK535148", + "pmid:24038517", + "omim:186000" + ], + "additional_literature": [ + "pmid:34159400", + "pmid:32652111", + "pmid:32386547", + "pmid:19841179", + "pmid:19546318", + "pmid:17935235", + "pmid:12414828", + "pmid:12116248", + "pmid:11543619" + ] + }, { - "motif": "CAGG", - "count": null, - "type": "pathogenic_repeat" + "id": "HD_HTT", + "disease_id": "HD", + "gene": "HTT", + "chrom": "chr4", + "start_hg38": 3074876, + "stop_hg38": 3074933, + "start_hg19": 3076603, + "stop_hg19": 3076660, + "start_t2t": 3073603, + "stop_t2t": 3073687, + "disease": "Huntington disease", + "inheritance": [ + "AD" + ], + "disease_description": "Huntington disease (HD) is a rare neurodegenerative disorder of the central nervous system characterized by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia [@mondo:0007739].", + "hpo_terms": null, + "prevalence": "1/10000", + "prevalence_details": "6.5-15/100,000 [@pmid:29100084]. 9.71-17:100,000 (European) vs. 0.1-2/100,000 (African), as many as 1 in 400 have reduced penetrance (0.2-2% for 36-38 CAG) HTT alleles [@genereviews:NBK1305]. Found across ethnicities/ancestries, with population-dependent prevalence [@genereviews:NBK1305].", + "age_onset": "Typical: 35-44 [@genereviews:NBK1305]; Range: 1-85 [@pmid:39441074; @pmid:21171977].", + "age_onset_min": 1, + "age_onset_max": 85, + "typ_age_onset_min": 35, + "typ_age_onset_max": 44, + "details": "27-35 motifs are unstable/premutations, while 36-39 motifs are associated with reduced penetrance and mild phenotypes [@pmid:39572770], and alleles over 40 repeats are typically fully penetrant [@genereviews:NBK1305]. >60 motifs associated with onset age <20 years [@genereviews:NBK1305]. Only CAG expansions are considered pathogenic, but interruptions impact pathogenicity (e.g. CAA) [@pmid:35245110]. Only fathers with premutations are considered at risk of transmitting pathogenic alleles [@pmid:19507258]. CAG repeats in the non-HD range (>= 21 repeats) may modulate psychiatric disease risk in an age-dependent manner [@pmid:39572770]", + "mechanism": "GoF/LoF", + "mechanism_detail": "While the primary pathogenic mechanism is gain of function of the protein product, pathogenesis is complex and multifactorial [@pmid:27940602].", + "year": "1993 [@pmid:8458085]", + "location_in_gene": "Coding Exon 1", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "CAG" + ], + "pathogenic_motif_reference_orientation": [ + "CAG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "AGC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [ + { + "motif": "CAG", + "count": null, + "type": "pathogenic_repeat" + }, + { + "motif": "CAACAG", + "count": 1, + "type": "interruption" + }, + { + "motif": "CCG", + "count": 12, + "type": "flank_repeat" + } + ], + "benign_min": 6, + "benign_max": 26, + "intermediate_min": 27, + "intermediate_max": 35, + "pathogenic_min": 36, + "pathogenic_max": 250, + "motif_len": 3, + "ref_copies": 21.3, + "novel": "ref", + "gard": [ + "6677" + ], + "genereviews": [ + "NBK1305" + ], + "malacard": [ + "HNT016" + ], + "medgen": [ + "5654" + ], + "mondo": [ + "0007739" + ], + "omim": [ + "143100" + ], + "orphanet": [ + "399" + ], + "gnomad": [ + "HTT" + ], + "stripy": [ + "HTT" + ], + "tr_atlas": [ + "TR40017", + "TR40018" + ], + "webstr_hg38": [ + "4701738", + "86468", + "86467" + ], + "webstr_hg19": [ + "Expansion_HD/HTT" + ], + "locus_tags": [ + "supported_evidence", + "somatic_instability", + "anticipation", + "paternal_expansion", + "length_affects_onset", + "length_affects_penetrance", + "length_affects_phenotype", + "length_affects_severity", + "motif_affects_instability", + "motif_affects_onset", + "motif_affects_penetrance", + "proposed_modifier" + ], + "disease_tags": [], + "references": [ + "genereviews:NBK1305", + "pmid:39441074", + "pmid:21171977", + "pmid:27940602", + "pmid:39572770", + "pmid:35245110", + "pmid:19507258", + "pmid:29100084", + "pmid:8458085", + "mondo:0007739" + ], + "additional_literature": [ + "pmid:41462929", + "pmid:41427302", + "pmid:41426430", + "pmid:41424860", + "pmid:41418088", + "pmid:41389205", + "pmid:41361856", + "pmid:41358280", + "pmid:41346861", + "pmid:41332649", + "pmid:41279265", + "pmid:41256123", + "pmid:41254939", + "pmid:41240184", + "pmid:41239019", + "pmid:41147028", + "pmid:41139934", + "pmid:41126427", + "pmid:41095675", + "pmid:41095094", + "pmid:41084658", + "pmid:41074680", + "pmid:41030958", + "pmid:41003760", + "pmid:40985165", + "pmid:40945646", + "pmid:40926977", + "pmid:40905034", + "pmid:40898018", + "pmid:40844528", + "pmid:40838126", + "pmid:40801627", + "pmid:40796049", + "pmid:40791503", + "pmid:40777434", + "pmid:40777236", + "pmid:40752726", + "pmid:40748251", + "pmid:40748199", + "pmid:40746751", + 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Largely in individuals of African ancestry [@genereviews:NBK1529], where a possible JPH3 founder mutation has been identified [@pmid:40187026].", + "age_onset": "Typical: 30-52; Range: 12-66 [@genereviews:NBK1529].", + "age_onset_min": 12, + "age_onset_max": 66, + "typ_age_onset_min": 30, + "typ_age_onset_max": 52, + "details": "Intermediate alleles (29-39) may either be premutations or associated with reduced penetrance; the longest pathogenic expansion (40+ motifs) to date is 60 repeats [@genereviews:NBK1529]", + "mechanism": "LoF/GoF", + "mechanism_detail": "Non-mutually exclusive mechanisms include loss of function from RNA sequestration and gain of function from toxic transcripts and increased protein expression [@genereviews:NBK1529]", + "year": "2001 [@pmid:11694876]", + "location_in_gene": "Coding Exon 2", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "CTG" + ], + "pathogenic_motif_reference_orientation": [ + "CTG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CTG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 6, + "benign_max": 28, + "intermediate_min": 29, + "intermediate_max": 39, + "pathogenic_min": 40, + "pathogenic_max": 60, + "motif_len": 3, + "ref_copies": 15.6667, + "novel": "ref", + "gard": [ + "16874" + ], + "genereviews": [ + "NBK1529" + ], + "malacard": [ + "HNT004" + ], + "medgen": [ + "341120" + ], + "mondo": [ + "0011671" + ], + "omim": [ + "606438" + ], + "orphanet": [ + "98934" + ], + "gnomad": [ + "JPH3" + ], + "stripy": [ + "JPH3" + ], + "tr_atlas": [ + "TR143309" + ], + "webstr_hg38": [ + "828516", + "5987878" + ], + "webstr_hg19": [ + "Expansion_HDL2/JPH3" + ], + "locus_tags": [ + "supported_evidence", + "somatic_instability", + "length_affects_phenotype", + "length_affects_onset", + "length_affects_penetrance", + "length_affects_severity" + ], + "disease_tags": [], + "references": [ + "genereviews:NBK1529", + "orphanet:98934", + "pmid:40187026", + "pmid:11694876", + "mondo:0011671" + ], + "additional_literature": [ + "pmid:41074680", + "pmid:40914005", + "pmid:38948793", + "pmid:38725192", + "pmid:38617831", + "pmid:37379724", + "pmid:35926480", + "pmid:33824468", + "pmid:33044188", + "pmid:32675418", + "pmid:32028232", + "pmid:30682531", + "pmid:30615214", + "pmid:29801887", + "pmid:29208631", + "pmid:29066237", + "pmid:27400454", + "pmid:27288455", + "pmid:26079385", + "pmid:24269018", + "pmid:22447335", + "pmid:22367996", + "pmid:22297462", + "pmid:21555070", + "pmid:17516481", + "pmid:16858508", + "pmid:15764008", + "pmid:15468075", + "pmid:14557581", + "pmid:12805114", + "pmid:11906164" + ] }, { - "motif": "CA", - "count": 19, - "type": "flank_repeat" - }], - "benign_min": 11, - "benign_max": 26, - "intermediate_min": 27, - "intermediate_max": 74, - "pathogenic_min": 75, - "pathogenic_max": 11000, - "motif_len": 4, - "ref_copies": 20.8, - "novel": "ref", - "gard": ["9728"], - "genereviews": ["NBK1466"], - "malacard": ["MYT020"], - "medgen": ["419137"], - "mondo": ["0011266"], - "omim": ["602668"], - "orphanet": ["606"], - "gnomad": ["CNBP"], - "stripy": ["CNBP"], - "tr_atlas": ["TR35563", "TR35564", "TR35565"], - "webstr_hg38": ["741073"], - "webstr_hg19": [], - "locus_tags": ["supported_evidence", "somatic_instability", "motif_affects_instability"], - "disease_tags": ["myotonic_dystrophy"], - "references": ["pmid:29086017", "pmid:31159885", "pmid:22140091", "pmid:38467784", "pmid:39643839", "genereviews:NBK1466", "pmid:35245110", "pmid:39703464", "pmid:35483324", "pmid:11486088", "mondo:0011266"], - "additional_literature": ["pmid:41074692", "pmid:40113266", "pmid:39894140", "pmid:39240646", "pmid:39119544", "pmid:38922834", "pmid:37950892", "pmid:37461657", "pmid:37146135", "pmid:36778282", "pmid:36018009", "pmid:35945246", "pmid:35567413", "pmid:34101465", "pmid:34024776", "pmid:33595997", "pmid:31981476", "pmid:31927948", "pmid:30984523", "pmid:30140252", "pmid:30100878", "pmid:29973908", "pmid:29291944", "pmid:28623239", "pmid:28491317", "pmid:28130447", "pmid:27727437", "pmid:27222292", "pmid:26586700", "pmid:25443993", "pmid:25186227", "pmid:24907641", "pmid:23570879", "pmid:22723857", "pmid:22643181", "pmid:22587749", "pmid:22459146", "pmid:22332444", "pmid:22062891", "pmid:21303839", "pmid:21224892", "pmid:21204798", "pmid:20971734", "pmid:20491895", "pmid:20174632", "pmid:19683984", "pmid:19632331", "pmid:19218442", "pmid:18804219", "pmid:18213375", "pmid:16927100", "pmid:16624843", "pmid:16376058", "pmid:15718211", "pmid:15704146", "pmid:15322428", "pmid:15231584", "pmid:15215218", "pmid:15114529", "pmid:15019706", "pmid:14505273", "pmid:12970845", "pmid:12601109"] -}, -{ - "id": "EDM1-PSACH_COMP", - "disease_id": "EDM1, PSACH", - "gene": "COMP", - "chrom": "chr19", - "start_hg38": 18786034, - "stop_hg38": 18786050, - "start_hg19": 18896844, - "stop_hg19": 18896860, - "start_t2t": 18921630, - "stop_t2t": 18921645, - "disease": "Multiple epiphyseal dysplasia, Pseudoachondroplasia", - "inheritance": ["AD"], - "disease_description": "Pseudoachondroplasia is characterized by severe growth deficiency and deformations such as bow legs and hyperlordosis.; Multiple epiphyseal dysplasia type 1 (MED 1) is a form of multiple epiphyseal dysplasia that is characterized by normal or mild short stature, pain in the hips and/or knees, progressive deformity of extremities and early-onset osteoarthrosis. Specific features to MED 1 include a more pronounced involvement of hip joints and gait abnormality and a shorter adult height. MED1 is allelic to pseudoachondroplasia with which it shares clinical and radiological features. The disease follows an autosomal dominant mode of transmission [@mondo:0008322; @mondo:0007561].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Specific contribution of COMP repeats to EDM1 is unknown (~300 COMP mutation variants for both phenotypes); likely 1:90,000 prevalence for COMP-PSACH that is repeat-specific. Found across ancestries/ethnicities [@genereviews:NBK1123; @genereviews:NBK1487].", - "age_onset": "Typical: 0-2 (COMP-PSACH)/ 1-12 (EDM1); Range: 0 (PSACH) - 13 (EDM1). 3-13 specific to trinucleotide expansions (duplications) [@pmid:29530484], several contractions but unknown exact AoO [@genereviews:NBK1123; @genereviews:NBK1487].", - "age_onset_min": 3.0, - "age_onset_max": 13.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "Both expansions to (GTC)6-7 and contractions to (GTC)4 are associated with disease [@genereviews:NBK1487].", - "mechanism": "LoF/GoF?", - "mechanism_detail": "Poly-aspartic acid expansions, domain dependent [@pmid:29530484]; may involve misfolding but still unestablished [@genereviews:NBK1123].", - "year": "1999 [@pmid:9887340]", - "location_in_gene": "Coding Exon 13", - "gene_strand": "-", - "reference_motif_reference_orientation": ["GTC"], - "pathogenic_motif_reference_orientation": ["GTC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["ACG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 5, - "benign_max": 5, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 6, - "pathogenic_max": 7, - "motif_len": 3, - "ref_copies": 5.0, - "novel": "ref", - "gard": ["4540", "2180"], - "genereviews": ["NBK1123", "NBK1487"], - "malacard": ["EPP017", "PSD012"], - "medgen": ["98378", "325376"], - "mondo": ["0008322", "0007561"], - "omim": ["132400", "177170"], - "orphanet": ["750", "93308"], - "gnomad": ["COMP"], - "stripy": ["COMP"], - "tr_atlas": ["TR155017"], - "webstr_hg38": ["1317658"], - "webstr_hg19": ["STR_673389"], - "locus_tags": ["supported_evidence", "contraction"], - "disease_tags": ["phenotypic_spectrum"], - "references": ["pmid:29530484", "genereviews:NBK1123", "genereviews:NBK1487", "pmid:9887340", "mondo:0008322", "mondo:0007561"], - "additional_literature": ["pmid:32097846", "pmid:28924040", "pmid:21644213", "pmid:18353302", "pmid:15014436", "pmid:12483437"] -}, -{ - "id": "EPM1_CSTB", - "disease_id": "EPM1", - "gene": "CSTB", - "chrom": "chr21", - "start_hg38": 43776442, - "stop_hg38": 43776479, - "start_hg19": 45196323, - "stop_hg19": 45196360, - "start_t2t": 42132054, - "stop_t2t": 42132091, - "disease": "Progressive Myoclonic Epilepsy Type 1 (EPM1), a.k.a Unverricht-Lundborg Disease (ULD)", - "inheritance": ["AR"], - "disease_description": "Unverricht-Lundborg disease (ULD) is a rare progressive myoclonic epilepsy disorder characterized by action- and stimulus-sensitive myoclonus, and tonic-clonic seizures with ataxia, but with only a mild cognitive decline over time [@mondo:0009698].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Worldwide prevalence unknown; Finland prevalence 2-4/100,000. Found across ethnicities/ancestries, with population-dependent prevalence; highest in Tunisia, Algeria, Morocco, and Finland [@genereviews:NBK1142].", - "age_onset": "Typical: 6-15 [@genereviews:NBK1142]; Range: 6-18 [@pmid:18325013].", - "age_onset_min": 6.0, - "age_onset_max": 18.0, - "typ_age_onset_min": 6.0, - "typ_age_onset_max": 15.0, - "details": "Affected individuals have an unstable 12-nucleotide (dodecomer) repeat expansion. Alleles containing 2-3 motifs are considered benign, while alleles with 30-125 repeats are fully penetrant [@pmid:18325013]. Alleles in the range 12-17 repeats have been observed, however the individuals carrying them have not undergone clinical evaluation. Alleles in the range 4-11 and 18-29 repeats have not been reported to date.", - "mechanism": "LoF", - "mechanism_detail": "The repeat expanison causes significantly reduced expression of cystatin-B protein [@genereviews:NBK1142].", - "year": "1997 [@pmid:9126745]", - "location_in_gene": "5' UTR", - "gene_strand": "-", - "reference_motif_reference_orientation": ["CGCGGGGCGGGG"], - "pathogenic_motif_reference_orientation": ["CGCGGGGCGGGG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CCCCGCCCCGCG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 2, - "benign_max": 3, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 30, - "pathogenic_max": 125, - "motif_len": 12, - "ref_copies": null, - "novel": null, - "gard": ["3876"], - "genereviews": ["NBK1142"], - "malacard": ["MYC080"], - "medgen": ["155923"], - "mondo": ["0009698"], - "omim": ["254800"], - "orphanet": ["308"], - "gnomad": ["CSTB"], - "stripy": [], - "tr_atlas": ["TR163552"], - "webstr_hg38": ["5547429"], - "webstr_hg19": ["STR_886261"], - "locus_tags": ["supported_evidence", "length_affects_onset", "length_affects_severity"], - "disease_tags": ["ataxia"], - "references": ["genereviews:NBK1142", "pmid:18325013", "pmid:9126745", "mondo:0009698"], - "additional_literature": ["pmid:41268177", "pmid:41147955", "pmid:41074692", "pmid:40442775", "pmid:40340521", "pmid:39156922", "pmid:38135787", "pmid:36398398", "pmid:36359887", "pmid:34474241", "pmid:32920378", "pmid:32875576", "pmid:29352102", "pmid:25752200", "pmid:23883076", "pmid:22581592", "pmid:21757863", "pmid:21075014", "pmid:18358403", "pmid:17003839", "pmid:16379547", "pmid:15483648", "pmid:14517952", "pmid:14510831", "pmid:12215838", "pmid:11790146", "pmid:11697734", "pmid:11571333", "pmid:11524486", "pmid:11240124", "pmid:10927802", "pmid:10721698", "pmid:10660338", "pmid:10515170", "pmid:10441345", "pmid:9529356", "pmid:9090386", "pmid:9054946", "pmid:9012407", "pmid:7885531"] -}, -{ - "id": "SCA37_DAB1", - "disease_id": "SCA37", - "gene": "DAB1", - "chrom": "chr1", - "start_hg38": 57367043, - "stop_hg38": 57367121, - "start_hg19": 57832715, - "stop_hg19": 57832793, - "start_t2t": 57245935, - "stop_t2t": 57245973, - "disease": "Spinocerebellar ataxia type 37", - "inheritance": ["AD"], - "disease_description": "Spinocerebellar ataxia type 37 (SCA37) is a subtype of autosomal dominant cerebellar ataxia type 1 (ADCA type 1), characterized by a cerebellar syndrome along with altered vertical eye movements [@mondo:0014410].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "0.20/100,000 specific to Portugal; not yet found in other geographic regions. Founder effect from Iberian Peninsula [@genereviews:NBK541729].", - "age_onset": "Typical: 33-53; Range: 18-64 [@genereviews:NBK541729].", - "age_onset_min": 18.0, - "age_onset_max": 64.0, - "typ_age_onset_min": 33.0, - "typ_age_onset_max": 53.0, - "details": "Pathogenicity only associated with pathogenic motif >30 repeats, flanked by at least 58 repeats of reference motif on either side; reference repeat (AAAAT) can range from 1 to 400 repeats, although typically less than 30 [@genereviews:NBK541729]. The pathogenic motif is unstable, particularly when transmitted by the father [@genereviews:NBK541729].", - "mechanism": "GoF", - "mechanism_detail": "Toxic gain-of-function mechanism in protein, associated with alternative splicing, an RNA switch, and an upregulation of reelin-DAB1 signalling [@omim:615945; @pmid:30284037].", - "year": "2017 [@pmid:28686858]", - "location_in_gene": "Intron 1 (most isoforms)", - "gene_strand": "-", - "reference_motif_reference_orientation": ["AAAAT"], - "pathogenic_motif_reference_orientation": ["GAAAT"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": ["AAAAA"], - "pathogenic_motif_gene_orientation": ["ATTTC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": ["TTTTT"], - "locus_structure": [ + "id": "OPDM1_LRP12", + "disease_id": "OPDM1", + "gene": "LRP12", + "chrom": "chr8", + "start_hg38": 104588970, + "stop_hg38": 104588999, + "start_hg19": 105601198, + "stop_hg19": 105601227, + "start_t2t": 105716409, + "stop_t2t": 105716441, + "disease": "Oculopharyngodistal myopathy type 1", + "inheritance": [ + "AD" + ], + "disease_description": "Adult-onset ptosis, dysphagia [@pmid:39349043]; External ophthalmoplegia, facial weakness, pharyngeal, and distal limb weakness [@pmid:38876750]; May be slight male predominance [@pmid:34047774].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Population dependent; unknown percentage of LRP12 pathogenic variants. Typically East Asian ancestry [@pmid:38876750]; potentially most frequent cause of OPDM in Japan [@pmid:34047774].", + "age_onset": "Typical: 31-51 [@pmid:34047774]; Range: 7-66 [@pmid:2124290].", + "age_onset_min": 7, + "age_onset_max": 66, + "typ_age_onset_min": 31, + "typ_age_onset_max": 51, + "details": "Benign range (13-45) inferred from cohort data, but pathogenic range isn't yet fully understood [@genereviews:NBK535148]. In a cohort of 65 patients from 59 families, alleles ranged from 85-289 repeats, with an inverse relationship between size and age of onset [@pmid:34047774]. Inherited peripheral neuropathy (IPN) may be associated with shorter expansions [@pmid:39013564]. Interruptions seen: ACG, CCA [@pmid:35245110].", + "mechanism": "GoF?", + "mechanism_detail": "RNA mediated toxicity hypothesized [@omim:164310]; may involve RAN translation [@pmid:38467784]. Somatic mosicism and hypermethylation have also been reported [@pmid:41131788].", + "year": "2019 [@pmid:31332380]", + "location_in_gene": "5' UTR", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "CGC" + ], + "pathogenic_motif_reference_orientation": [ + "CGC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CGG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 13, + "benign_max": 45, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 85, + "pathogenic_max": 289, + "motif_len": 3, + "ref_copies": 11.7, + "novel": "ref", + "gard": [ + "15097" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "OCL076" + ], + "medgen": [ + "1684682" + ], + "mondo": [ + "0020793" + ], + "omim": [ + "164310" + ], + "orphanet": [ + "98897" + ], + "gnomad": [ + "LRP12" + ], + "stripy": [ + "LRP12" + ], + "tr_atlas": [ + "TR88348" + ], + "webstr_hg38": [ + "1082178", + "4874587" + ], + "webstr_hg19": [ + "STR_1441036" + ], + "locus_tags": [ + "supported_evidence", + "somatic_instability", + "anticipation", + "length_affects_onset" + ], + "disease_tags": [ + "oculopharyngodistal_myopathy" + ], + "references": [ + "pmid:34047774", + "pmid:2124290", + "omim:164310", + "pmid:38467784", + "pmid:41131788", + "genereviews:NBK535148", + "pmid:39013564", + "pmid:35245110", + "pmid:38876750", + "pmid:31332380", + "pmid:39349043" + ], + "additional_literature": [ + "pmid:41125376", + "pmid:40645757", + "pmid:40417202", + "pmid:40084170", + "pmid:38726482", + "pmid:37923380", + "pmid:37864208", + "pmid:37339631", + "pmid:36052448", + "pmid:35700120", + "pmid:35314910", + "pmid:35152460", + "pmid:35148830", + "pmid:34927285", + "pmid:33693509", + "pmid:33374016", + "pmid:33239111", + "pmid:32493488", + "pmid:27072820" + ] + }, { - "motif": "AAAAT", - "count": 7, - "type": "internal_repeat" + "id": "FAME3_MARCHF6", + "disease_id": "FAME3", + "gene": "MARCHF6", + "chrom": "chr5", + "start_hg38": 10356343, + "stop_hg38": 10356411, + "start_hg19": 10356455, + "stop_hg19": 10356523, + "start_t2t": 10295525, + "stop_t2t": 10295593, + "disease": "Familial adult myoclonic epilepsy type 3", + "inheritance": [ + "AD" + ], + "disease_description": "Cortical tremor, seizures with generalised motor (tonic-clonic) onset [@pmid:38876750]; Adult-onset cortical tremor with epilepsy [@pmid:39349043].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Overall FAME prevalence is < 1/35,000; MARCHF6-caused much smaller. Most cases have European ancestry [@pmid:38876750].", + "age_onset": "Typical: 24-41 based on one 76 member pedigree [@pmid:19616813]; Range: 10 [@omim:613608] - 50 [@pmid:40788430].", + "age_onset_min": 10, + "age_onset_max": 50, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "Healthy controls do not have pathogenic allele (TTTCA), but do have 9-20 benign motifs (TTTTA) [@genereviews:NBK535148]. Total allele size in probands spanned from 650-1035 repeats; an inverse relationship between allele size and age of onset was noted [@pmid:31664039, @pmid:40788430]. In one study it was proposed that pathogenicity only occurs when TTTCA is expanded [@pmid: 40788430].", + "mechanism": "Unknown", + "mechanism_detail": "Noted as unknown in literature [@omim:613608].", + "year": "2019 [@pmid:31664039]", + "location_in_gene": "Intron 1", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "TTTTA" + ], + "pathogenic_motif_reference_orientation": [ + "TTTCA" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [ + "ATGTT", + "TAGTT", + "TTTTG", + "TTTTT" + ], + "pathogenic_motif_gene_orientation": [ + "ATTTC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [ + "ATGTT", + "AGTTT", + "GTTTT", + "TTTTT" + ], + "locus_structure": [ + { + "motif": "TTTTA", + "count": 12, + "type": "internal_repeat" + }, + { + "motif": "TTTCA", + "count": null, + "type": "pathogenic_repeat" + } + ], + "benign_min": null, + "benign_max": null, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 650, + "pathogenic_max": 1035, + "motif_len": 5, + "ref_copies": 13.6, + "novel": "novel", + "gard": [ + "18084" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "EPL053" + ], + "medgen": [ + "462210" + ], + "mondo": [ + "0013322" + ], + "omim": [ + "613608" + ], + "orphanet": [ + "86814" + ], + "gnomad": [ + "MARCHF6" + ], + "stripy": [ + "MARCHF6" + ], + "tr_atlas": [ + "TR51895" + ], + "webstr_hg38": [ + "5994579" + ], + "webstr_hg19": [ + "STR_1116660" + ], + "locus_tags": [ + "supported_evidence", + "somatic_instability", + "motif_affects_onset", + "motif_affects_penetrance", + "motif_affects_severity" + ], + "disease_tags": [ + "familial_adult_myoclonic_epilepsy" + ], + "references": [ + "pmid:19616813", + "omim:613608", + "pmid:40788430", + "genereviews:NBK535148", + "pmid:31664039", + "pmid: 40788430", + "pmid:38876750", + "pmid:39349043" + ], + "additional_literature": [ + "pmid:41268177", + "pmid:41219789", + "pmid:40417743", + "pmid:40200849", + "pmid:33040085" + ] }, { - "motif": "GAAAT", - "count": null, - "type": "pathogenic_repeat" - }], - "benign_min": 0, - "benign_max": 30, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 31, - "pathogenic_max": 75, - "motif_len": 5, - "ref_copies": 0.0, - "novel": "novel", - "gard": ["12368"], - "genereviews": ["NBK541729"], - "malacard": ["SPN283"], - "medgen": ["855217"], - "mondo": ["0014410"], - "omim": ["615945"], - "orphanet": ["363710"], - "gnomad": ["DAB1"], - "stripy": ["DAB1"], - "tr_atlas": ["TR3445"], - "webstr_hg38": ["1144531"], - "webstr_hg19": ["STR_39393"], - "locus_tags": ["supported_evidence", "maternal_expansion", "paternal_expansion", "motif_affects_onset", "motif_affects_penetrance"], - "disease_tags": ["spinocerebellar_ataxia"], - "references": ["genereviews:NBK541729", "omim:615945", "pmid:30284037", "pmid:28686858", "mondo:0014410"], - "additional_literature": ["pmid:41426430", "pmid:38961870", "pmid:36622139", "pmid:36148898", "pmid:36092952", "pmid:32582864", "pmid:30588707"] -}, -{ - "id": "FRA12A_DIP2B", - "disease_id": "FRA12A", - "gene": "DIP2B", - "chrom": "chr12", - "start_hg38": 50505001, - "stop_hg38": 50505024, - "start_hg19": 50898784, - "stop_hg19": 50898807, - "start_t2t": 50468095, - "stop_t2t": 50468118, - "disease": "Intellectual developmental disorder, FRA12A type", - "inheritance": ["AD"], - "disease_description": "...impaired intellectual development with or without other anomalies has been described in patients with over 40% of cells expressing FRA12A [@omim:136630].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Appears to occur in those of European ancestry/ethnicity [@omim:136630].", - "age_onset": "Typical: 0-1 (small sample size) [@pmid:3742859]. Range: 0-3 [@pmid:4042396].", - "age_onset_min": 0.0, - "age_onset_max": 3.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "Repeat ranges reflect affected and unaffected individuals from a cohort study of 70 controls (6-23 repeats), unaffected carriers representing the intermediate alleles (139-206), and affected individuals (273-306) [@pmid:17236128]. Unmethylated expansions may correspond to movement-related phenotypes (chorea, dystonia, and ataxia) [@pmid:39854091].", - "mechanism": "LoF", - "mechanism_detail": "Hypermethylation leading to decreased expression, although unmethylated expansion leads to increased expression [@omim:136630; @doi:10.1101/2022.09.12.22279739].", - "year": "2007 [@pmid:17236128]", - "location_in_gene": "5' UTR", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GGC"], - "pathogenic_motif_reference_orientation": ["GGC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CGG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 6, - "benign_max": 23, - "intermediate_min": 139, - "intermediate_max": 206, - "pathogenic_min": 273, - "pathogenic_max": 306, - "motif_len": 3, - "ref_copies": 7.0, - "novel": "ref", - "gard": [], - "genereviews": ["NBK535148"], - "malacard": ["INT482"], - "medgen": ["369613"], - "mondo": ["0007634"], - "omim": ["136630"], - "orphanet": [], - "gnomad": ["DIP2B"], - "stripy": ["DIP2B"], - "tr_atlas": ["TR116656"], - "webstr_hg38": ["5075695"], - "webstr_hg19": ["Expansion_FRA12A_MR/DIP2B"], - "locus_tags": ["limited_evidence"], - "disease_tags": [], - "references": ["pmid:3742859", "pmid:4042396", "omim:136630", "doi:10.1101/2022.09.12.22279739", "pmid:17236128", "pmid:39854091"], - "additional_literature": ["pmid:38418263", "pmid:37248219", "pmid:37090938", "pmid:34622207"] -}, -{ - "id": "DMD_DMD", - "disease_id": "DMD", - "gene": "DMD", - "chrom": "chrX", - "start_hg38": 31284557, - "stop_hg38": 31284605, - "start_hg19": 31302674, - "stop_hg19": 31302722, - "start_t2t": 30882677, - "stop_t2t": 30882743, - "disease": "Duchenne muscular dystrophy", - "inheritance": ["XR"], - "disease_description": "Duchenne muscular dystrophy (DMD) is a neuromuscular disease characterized by rapidly progressive muscle weakness and wasting due to degeneration of skeletal, smooth and cardiac muscle [@mondo:0010679].", - "hpo_terms": null, - "prevalence": "4.8/100000", - "prevalence_details": "Believed to be 0 for disease specific to STR expansion. 1/3500-4700 male births (incidence) for overall DMD (one of the most common and severe congenital myopathies) [@genereviews:NBK1119]. 4.8/100,000 prevalence [@pmid:35168641]. DMD repeat locus expansion only identified in one Greek family [@pmid:27417533].", - "age_onset": "Typical: 6-7 (usual disease is 0-3) [@pmid:27417533].", - "age_onset_min": 6.0, - "age_onset_max": 7.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "There is conflicting evidence for the association between this repeat expansion and Duchenne muscular dystrophy. The association was reported in a single family, from which the benign and pathogenic ranges were inferred from affected and unaffected family members [@pmid:27417533]. The population frequency of the proposed pathogenic allele is much higher than expected for a highly penetrant early-onset condition.", - "mechanism": "LoF", - "mechanism_detail": "Functional defect in dystrophin/dystroglycan [@pmid:16969582].", - "year": "2016 [@pmid:27417533]", - "location_in_gene": "Intron 62", - "gene_strand": "-", - "reference_motif_reference_orientation": ["TTC"], - "pathogenic_motif_reference_orientation": ["TTC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["AAG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [ + "id": "MIR7-2_CHNG3", + "disease_id": "CHNG3", + "gene": "MIR7-2", + "chrom": "chr15", + "start_hg38": 88569433, + "stop_hg38": 88569452, + "start_hg19": 89112664, + "stop_hg19": 89112683, + "start_t2t": 86324038, + "stop_t2t": 86324057, + "disease": "Nongoitrous congenital hypothyroidism-3", + "inheritance": [ + "AD" + ], + "disease_description": "Nongoitrous congenital hypothyroidism-3 (CHNG3) is characterized by infantile-onset clinical and subclinical hypothyroidism associated with a small thyroid gland, high circulating TSH, normal free T4 levels, and normal or mildly increased serum thyroglobulin. Untreated patients or patients who discontinue treatment show a characteristic transition to multinodular goiter (MNG) with age [@omim:609893].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Found in 12 families, with ancestry including: Irish, White European, French (Normandie), Ashkenazi, French Canadian, Danish/White European, Welsh, Scottish, Italian, British/White European, Italian/Turkish/Lebanese, German/Palestinian, and South Chinese [@pmid:38714868].", + "age_onset": "0 (birth)", + "age_onset_min": 0, + "age_onset_max": 0, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "Deletion of one repeat (4 to 3 repeats) found in 10 unrelated families with unsolved disease [@pmid:38714869]; a heterozygous T-to-G transversion in the third repeat can also lead to disease [@pmid:38714868].", + "mechanism": "GoF", + "mechanism_detail": "Activates a thyroid-specific enhancer [@pmid:38714868; @pmid:38714869].", + "year": "2024 [@pmid:38714869]", + "location_in_gene": "Non-coding", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "TTTG" + ], + "pathogenic_motif_reference_orientation": [ + "TTTG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "AAAC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 4, + "benign_max": 4, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 3, + "pathogenic_max": 3, + "motif_len": 4, + "ref_copies": null, + "novel": "ref", + "gard": [ + "1487" + ], + "genereviews": [], + "malacard": [ + "HYP355" + ], + "medgen": [ + "424853" + ], + "mondo": [ + "0012360" + ], + "omim": [ + "609893" + ], + "orphanet": [], + "gnomad": [ + "PRE-MIR7-2" + ], + "stripy": [], + "tr_atlas": [ + "TR192005" + ], + "webstr_hg38": [ + "5177365" + ], + "webstr_hg19": [ + "STR_492924" + ], + "locus_tags": [ + "supported_evidence", + "contraction" + ], + "disease_tags": [], + "references": [ + "pmid:38714868", + "pmid:38714869", + "omim:609893" + ], + "additional_literature": [] + }, { - "motif": "TTC", - "count": null, - "type": "pathogenic_repeat" + "id": "ADTKD_MUC1", + "disease_id": "ADTKD", + "gene": "MUC1", + "chrom": "chr1", + "start_hg38": 155188505, + "stop_hg38": 155192239, + "start_hg19": 155160981, + "stop_hg19": 155162030, + "start_t2t": 154328121, + "stop_t2t": 154330802, + "disease": "Autosomal dominant tubulointerstitial kidney disease", + "inheritance": [ + "AD" + ], + "disease_description": "An inherited disorder that causes a gradual loss of kidney function, caused by a mutation in the MUC1 gene that leads to production of an abnormal mucin 1 protein, which deposits in the kidney and leads to slow loss of kidney function [@mondo:0020726].", + "hpo_terms": null, + "prevalence": "2.5/1000000", + "prevalence_details": "Disease is affected 1-4/1,000,000 (likely an underestimate due to unremarkable findings); repeat expansion responsibile for 95% of disease [@genereviews:NBK153723]", + "age_onset": "Age of onset for end-stage renal disease (the only systemic manifestation) ranges from 16 [@pmid:41000883]-70 [@genereviews:NBK153723].", + "age_onset_min": 16, + "age_onset_max": 70, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "Disease is caused by the single base expansion of a heptanucleotide (7) cytosine homopolymer tract (i.e. from (C)7 to (C)8 ) within one copy of a coding VNTR, resulting in a frameshift mutation. This VNTR has a 60 bp motif, varying in length and sequence composition. This motif ranges in copy number from 20-125 (~1.5-5 kb) and is GC-rich (>80%). The specific copy of the VNTR motif involved varies by family but is consistent within a family [@genereviews:NBK535148]. This locus is particularly difficult to genotype [@pmid:23396133; @pmid:39781475]. Gamaarachchi et al. observed 20 unique VNTR haplotypes which ranged in size from 40–83 copies, with no unrelated individuals sharing the same haplotype. Unique haplotypes implied frequent independent origins of the dupC variant [@doi:10.1101/2025.03.31.646505]. NOTE: Disease is caused by a 7 to 8 C homopolymer expansion within the main motif which we represent here as a change in motif.", + "mechanism": "GoF", + "mechanism_detail": "Toxic protein product accumulates in kidneys [@genereviews:NBK153723]", + "year": "2013 [@pmid:23396133]", + "location_in_gene": "Coding Exon 2", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GGCTNNGGGNGCGGTGGAGCCCGGGGCNGGNCTGNTNTCCGGGGCCGAGGTGACANCNTG" + ], + "pathogenic_motif_reference_orientation": [ + "GCCCACGGTGTCACCTCGGCCCCGGACACCAGGCCGGCCCCGGGCTCCACCGCCCCCCCCA" + ], + "benign_motif_reference_orientation": [ + "GCCCACGGTGTCACCTCGGCCCCGGACACCAGGCCGGCCCCGGGCTCCACCGCCCCCCCA" + ], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "ACACCAGGCCGGCCCCGGGCTCCACCGCCCCCCCCAGCCCACGGTGTCACCTCGGCCCCGG" + ], + "benign_motif_gene_orientation": [ + "ACACCAGGCCGGCCCCGGGCTCCACCGCCCCCCCAGCCCACGGTGTCACCTCGGCCCCGG" + ], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": null, + "benign_max": null, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": null, + "pathogenic_max": null, + "motif_len": 1, + "ref_copies": null, + "novel": "ref", + "gard": [ + "7002" + ], + "genereviews": [ + "NBK153723" + ], + "malacard": [ + "TBL032" + ], + "medgen": [ + "358137" + ], + "mondo": [ + "0020726" + ], + "omim": [ + "174000" + ], + "orphanet": [ + "88949" + ], + "gnomad": [], + "stripy": [], + "tr_atlas": [], + "webstr_hg38": [], + "webstr_hg19": [], + "locus_tags": [ + "supported_evidence" + ], + "disease_tags": [], + "references": [ + "pmid:41000883", + "genereviews:NBK153723", + "genereviews:NBK535148", + "pmid:23396133", + "pmid:39781475", + "doi:10.1101/2025.03.31.646505", + "mondo:0020726" + ], + "additional_literature": [ + "pmid:40244446", + "pmid:39848530", + "pmid:39576755", + "pmid:39325540", + "pmid:39314239", + "pmid:38605207", + "pmid:37547453", + "pmid:37456840", + "pmid:37316299", + "pmid:35982790", + "pmid:35497811", + "pmid:34641504", + "pmid:34452200", + "pmid:33672244", + "pmid:33001366", + "pmid:32451462", + "pmid:32293552", + "pmid:31213370", + "pmid:30593830", + "pmid:29520014", + "pmid:29328069", + "pmid:29217307", + "pmid:29156055", + "pmid:29052568", + "pmid:28581490", + "pmid:28407289", + "pmid:27957769", + "pmid:27036738", + "pmid:27367740", + "pmid:27340743", + "pmid:27157321", + "pmid:26943180", + "pmid:26838233", + "pmid:26693201", + "pmid:26692014", + "pmid:26498650", + "pmid:25753030", + "pmid:24718884", + "pmid:24509297", + "pmid:24416403", + "pmid:24246952", + "pmid:24233342", + "pmid:23778023", + "pmid:23770070", + "pmid:23652307", + "pmid:23317217", + "pmid:23259747", + "pmid:22970023", + "pmid:21998660", + "pmid:21385452", + "pmid:20876819", + "pmid:20562098", + "pmid:20470225", + "pmid:21637607", + "pmid:19811637", + "pmid:19625949", + "pmid:19534821", + "pmid:18619437", + "pmid:18094420", + "pmid:18021186", + "pmid:17974963", + "pmid:17694298", + "pmid:17581677", + "pmid:17203187", + "pmid:17050588", + "pmid:16711252", + "pmid:16631167", + "pmid:16302687", + "pmid:16101182", + "pmid:15991935", + "pmid:15944787", + "pmid:15814824", + "pmid:15729696", + "pmid:15604091", + "pmid:15387710", + "pmid:15115750", + "pmid:15041735", + "pmid:14871854", + "pmid:14707484", + "pmid:12747745", + "pmid:12646731", + "pmid:12626424", + "pmid:12090474", + "pmid:11923240", + "pmid:11445551", + "pmid:11391628", + "pmid:11358826", + "pmid:11295060", + "pmid:11169964", + "pmid:10797294", + "pmid:10741704", + "pmid:10653872", + "pmid:10652432", + "pmid:10541345", + "pmid:10430099", + "pmid:10389761", + "pmid:10383817", + "pmid:10235488", + "pmid:10206297", + "pmid:10052816", + "pmid:10024673", + "pmid:10022471", + "pmid:9935162", + "pmid:9823312", + "pmid:9755875", + "pmid:9727561", + "pmid:9690452", + "pmid:9591045", + "pmid:9579805", + "pmid:9575675", + "pmid:9551361", + "pmid:9427605", + "pmid:9419405", + "pmid:8967520", + "pmid:8643693", + "pmid:7594478", + "pmid:8579785", + "pmid:8567787", + "pmid:8519447", + "pmid:7628867", + "pmid:7816840", + "pmid:7946402", + "pmid:7514493", + "pmid:7690213", + "pmid:7685318" + ] }, { - "motif": "T", - "count": 8, - "type": "flank_repeat" - }], - "benign_min": 16, - "benign_max": 33, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 59, - "pathogenic_max": 82, - "motif_len": 3, - "ref_copies": 16.7, - "novel": "ref", - "gard": ["6291"], - "genereviews": ["NBK535148"], - "malacard": ["MSC157"], - "medgen": ["3925"], - "mondo": ["0010679"], - "omim": ["310200"], - "orphanet": ["98896"], - "gnomad": ["DMD"], - "stripy": ["DMD"], - "tr_atlas": ["TR167703"], - "webstr_hg38": [], - "webstr_hg19": ["STR_1545664"], - "locus_tags": ["contradictory_evidence"], - "disease_tags": [], - "references": ["pmid:27417533", "pmid:16969582", "genereviews:NBK1119", "pmid:35168641", "mondo:0010679"], - "additional_literature": ["pmid:41244984", "pmid:41173008", "pmid:39874107", "pmid:39803454", "pmid:39713478", "pmid:39251998", "pmid:38290145", "pmid:37829280", "pmid:37270548", "pmid:37090938", "pmid:36975100", "pmid:36048237", "pmid:35615378", "pmid:35093299", "pmid:34371182", "pmid:34238289", "pmid:33349121", "pmid:30914715", "pmid:30349485", "pmid:29687370", "pmid:27924830", "pmid:27178005", "pmid:27529242", "pmid:27276190", "pmid:24411039", "pmid:25804023", "pmid:24191945", "pmid:23894429", "pmid:23695957", "pmid:23659897", "pmid:23574351", "pmid:23538453", "pmid:21901138", "pmid:21305566", "pmid:22830166", "pmid:19927354", "pmid:19907931", "pmid:19309270", "pmid:19158820", "pmid:19108751", "pmid:18393226", "pmid:18359022", "pmid:17439955", "pmid:16553208", "pmid:16415967", "pmid:12132577", "pmid:11807410", "pmid:11593558", "pmid:11280167", "pmid:11185740", "pmid:10445321", "pmid:9894797", "pmid:8588583", "pmid:7633442", "pmid:7705851"] -}, -{ - "id": "DM1_DMPK", - "disease_id": "DM1", - "gene": "DMPK", - "chrom": "chr19", - "start_hg38": 45770204, - "stop_hg38": 45770266, - "start_hg19": 46273462, - "stop_hg19": 46273524, - "start_t2t": 48597739, - "stop_t2t": 48597756, - "disease": "Myotonic dystrophy type 1", - "inheritance": ["AD"], - "disease_description": "Steinert disease, also known as myotonic dystrophy type 1, is a muscle disease characterized by myotonia and by multiorgan damage that combines various degrees of muscle weakness, arrhythmia and/or cardiac conduction disorders, cataract, endocrine damage, sleep disorders and baldness [@mondo:0008056]. It has also been linked to Autism and related traits, especially in individuals with earlier onset [@pmid:40259070; @pmid:29361396; @pmid:8810716; @pmid:27695335; @pmid:29871899; @pmid:37209486].", - "hpo_terms": null, - "prevalence": "9.27/100000", - "prevalence_details": "5-20/100,000 [@genereviews:NBK1165]. 0.5-18.1/100,000 [@pmid:29100084]; 6.5/100,000 [@pmid:31159885]. 9.27 cases (95% CI: 4.73-15.21) per 100,000, ranging from 0.37 to 36.29 cases per 100,000 [@pmid:35483324]. Found across ethnicities/ancestries, with population-dependent prevalence [@genereviews:NBK1165].", - "age_onset": "Typical: 10-30 [@genereviews:NBK1165]; Range: 0-74 [@pmid:38454488].", - "age_onset_min": 0.0, - "age_onset_max": 74.0, - "typ_age_onset_min": 10.0, - "typ_age_onset_max": 30.0, - "details": "Overview of disease locus through 2024, including largest pathogenic allele of 4,000, described in Rimoldi et al review [@pmid:39643839]. Intermediate alleles (35-49) associated with premutation [@genereviews:NBK1165]. 3%-8% of DM1 expansions contain interrupting variant repeats such as CCG and CGG, associated with later onset and milder phenotype; the variant repeat GCGGCA has also been reported [@pmid:32851192; @doi:10.1016/j.mcp.2024.102005]. In another study, interruptions of the CTG repeat with CCG, GGC, CTC or CAG motifs are estimated to occur in 3-11% of DM1 patients [@pmid:35741732]. Expansions within gene ZNF850 may function as DM1 modifiers [@doi:10.1093/hmg/ddae186].", - "mechanism": "GoF", - "mechanism_detail": "RNA gain-of-function: RNA gelation leading to misregulation of alternative splicing [@pmid:36169768]. Expanded-repeat RNA sequesters the muscleblind-like (MBNL) family of RNA-binding proteins as part of the disruption of pre-mRNA processing, contributing to cardiac phenotypes [@pmid:39932794]. Loss of MBNL proteins has been linked to mis-splicing of Autism spectrum-risk genes such as SCN2A, ANK2, and SHANK2, possibly leading to Autism-related traits [@pmid:40259070]", - "year": "1992 [@pmid:1310900]", - "location_in_gene": "3' UTR", - "gene_strand": "-", - "reference_motif_reference_orientation": ["CAG"], - "pathogenic_motif_reference_orientation": ["CAG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CTG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 5, - "benign_max": 34, - "intermediate_min": 35, - "intermediate_max": 49, - "pathogenic_min": 50, - "pathogenic_max": 4000, - "motif_len": 3, - "ref_copies": 20.7, - "novel": "ref", - "gard": ["8310"], - "genereviews": ["NBK1165"], - "malacard": ["MYT021"], - "medgen": ["886881"], - "mondo": ["0008056"], - "omim": ["160900"], - "orphanet": ["273"], - "gnomad": ["DMPK"], - "stripy": ["DMPK"], - "tr_atlas": ["TR156684"], - "webstr_hg38": ["5650727"], - "webstr_hg19": ["Expansion_DM1/DMPK"], - "locus_tags": ["supported_evidence", "somatic_instability", "anticipation", "maternal_expansion", "length_affects_onset", "length_affects_phenotype", "length_affects_severity", "motif_affects_instability", "motif_affects_onset", "motif_affects_phenotype", "motif_affects_severity"], - "disease_tags": ["myotonic_dystrophy"], - "references": ["genereviews:NBK1165", "pmid:38454488", "pmid:36169768", "pmid:39932794", "pmid:40259070", "pmid:39643839", "pmid:32851192", "doi:10.1016/j.mcp.2024.102005", "pmid:35741732", "doi:10.1093/hmg/ddae186", "pmid:29100084", "pmid:31159885", "pmid:35483324", "pmid:1310900", "mondo:0008056", "pmid:29361396", "pmid:8810716", "pmid:27695335", "pmid:29871899", "pmid:37209486"], - "additional_literature": ["pmid:41379996", "pmid:41260620", "pmid:41250834", "pmid:41226829", "pmid:41212113", "pmid:41161721", "pmid:41074692", "pmid:40903903", "pmid:40896579", "pmid:40879030", "pmid:40712995", "pmid:40606545", "pmid:40599975", "pmid:40417743", "pmid:40296143", "pmid:40113266", "pmid:40092662", "pmid:40004498", "pmid:39710066", "pmid:39679849", "pmid:39492694", "pmid:39433769", "pmid:39415708", "pmid:39391712", "pmid:39383229", "pmid:39278936", "pmid:39267217", "pmid:39273681", "pmid:39232665", "pmid:39180495", "pmid:39126705", "pmid:38709060", "pmid:38704930", "pmid:38490135", "pmid:38314057", "pmid:37829280", "pmid:37744174", "pmid:37645891", "pmid:37638448", "pmid:37521782", "pmid:37397246", "pmid:37373276", "pmid:37352653", "pmid:37200862", "pmid:37146135", "pmid:37143315", "pmid:36892629", "pmid:36778282", "pmid:36701310", "pmid:36627397", "pmid:36352383", "pmid:36230978", "pmid:36222125", "pmid:36099027", "pmid:36084803", "pmid:36011377", "pmid:35770133", "pmid:35767654", "pmid:35567413", "pmid:35328504", "pmid:35243403", "pmid:35182509", "pmid:34976437", "pmid:34915310", "pmid:34513303", "pmid:34472530", "pmid:34432028", "pmid:34386887", "pmid:34372915", "pmid:34371182", "pmid:34262431", "pmid:34114350", "pmid:34025359", "pmid:33682722", "pmid:33624941", "pmid:33575482", "pmid:33526774", "pmid:33497365", "pmid:33363709", "pmid:33362853", "pmid:33235377", "pmid:32929188", "pmid:32823742", "pmid:32717741", "pmid:32656337", "pmid:32607474", "pmid:32350131", "pmid:32203199", "pmid:32109384", "pmid:32063450", "pmid:31996899", "pmid:31873063", "pmid:31759551", "pmid:31649961", "pmid:31624084", "pmid:31570586", "pmid:31395669", "pmid:31334355", "pmid:31316546", "pmid:31253581", "pmid:31227653", "pmid:31220271", "pmid:31164682", "pmid:31027145", "pmid:30891637", "pmid:30700578", "pmid:30615214", "pmid:30546383", "pmid:30425655", "pmid:30304901", "pmid:30216892", "pmid:30140252", "pmid:29967337", "pmid:29947794", "pmid:29592894", "pmid:29551391", "pmid:29381654", "pmid:29334465", "pmid:29274549", "pmid:29246312", "pmid:29114849", "pmid:28942489", "pmid:28886202", "pmid:28810563", "pmid:28782311", "pmid:28623239", "pmid:28435090", "pmid:28363916", "pmid:28211918", "pmid:28129118", "pmid:28102759", "pmid:27854230", "pmid:27727437", "pmid:27358583", "pmid:27245480", "pmid:27222292", "pmid:26708183", "pmid:26640575", "pmid:26586700", "pmid:26498872", "pmid:26190529", "pmid:25958258", "pmid:25712547", "pmid:25655594", "pmid:25606394", "pmid:25307018", "pmid:25303993", "pmid:25168381", "pmid:24824895", "pmid:24795756", "pmid:24781112", "pmid:24715907", "pmid:24705798", "pmid:24455202", "pmid:24269018", "pmid:24196578", "pmid:24092878", "pmid:23811192", "pmid:23570879", "pmid:23308382", "pmid:26317000", "pmid:23263591", "pmid:23209425", "pmid:23183533", "pmid:23161457", "pmid:23159592", "pmid:23139243", "pmid:22643181", "pmid:22595968", "pmid:22459146", "pmid:22427994", "pmid:22078098", "pmid:22062891", "pmid:21971425", "pmid:21949239", "pmid:21511730", "pmid:21303839", "pmid:21245981", "pmid:21204798", "pmid:21103235", "pmid:20801043", "pmid:20635151", "pmid:20603324", "pmid:20346670", "pmid:20228473", "pmid:20179953", "pmid:20171614", "pmid:20074967", "pmid:19946639", "pmid:19715468", "pmid:19632331", "pmid:19516957", "pmid:19470458", "pmid:18798829", "pmid:18729234", "pmid:18611984", "pmid:18563724", "pmid:18561181", "pmid:18559347", "pmid:18299519", "pmid:18228241", "pmid:18213375", "pmid:17987120", "pmid:17950578", "pmid:17877752", "pmid:17728322", "pmid:17487865", "pmid:17158949", "pmid:17150182", "pmid:17145685", "pmid:17114933", "pmid:16978612", "pmid:16927100", "pmid:16716318", "pmid:16624843", "pmid:16401743", "pmid:16376058", "pmid:16193250", "pmid:16027111", "pmid:15972723", "pmid:15961406", "pmid:15750273", "pmid:15684391", "pmid:15576360", "pmid:15489504", "pmid:15462191", "pmid:15459182", "pmid:15336691", "pmid:15215218", "pmid:15114529", "pmid:15019706", "pmid:14734627", "pmid:14597103", "pmid:12970845", "pmid:12630069", "pmid:12614928", "pmid:12427866", "pmid:11978764", "pmid:11809728", "pmid:11793472", "pmid:11726559", "pmid:11686919", "pmid:11592825", "pmid:11590133", "pmid:11555624", "pmid:11526199", "pmid:11260612", "pmid:11124939", "pmid:11013451", "pmid:11001736", "pmid:10970838", "pmid:10958655", "pmid:10951446", "pmid:10909850", "pmid:10802668", "pmid:10802667", "pmid:10767343", "pmid:10699184", "pmid:10668800", "pmid:10480373", "pmid:10454725", "pmid:10435210", "pmid:10332037", "pmid:10332033", "pmid:9950368", "pmid:9887331", "pmid:9858828", "pmid:9668171", "pmid:9537423", "pmid:9402536", "pmid:9401353", "pmid:9371827", "pmid:9294109", "pmid:9241283", "pmid:9241282", "pmid:9207101", "pmid:8948631", "pmid:8923304", "pmid:8673131", "pmid:8659513", "pmid:8784809", "pmid:8595416", "pmid:7626046", "pmid:7590731", "pmid:7726160", "pmid:7896884", "pmid:8288237"] -}, -{ - "id": "RCPS_EIF4A3", - "disease_id": "RCPS", - "gene": "EIF4A3", - "chrom": "chr17", - "start_hg38": 80147009, - "stop_hg38": 80147139, - "start_hg19": 78120808, - "stop_hg19": 78120938, - "start_t2t": 81047404, - "stop_t2t": 81047534, - "disease": "Richieri-Costa-Pereira syndrome", - "inheritance": ["AR"], - "disease_description": "Richieri Costa-Pereira syndrome is characterized by short stature, Robin sequence, cleft mandible, pre/postaxial hand anomalies (including hypoplastic thumbs), and clubfoot. It has been described in 14 Brazilian families and in one unrelated French patient. Prominent low set ears and a highly arched palate were also observed. Transmission is autosomal recessive [@mondo:0009998].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "49 cases as of Nov 2023 [@doi:10.1016/j.omsc.2023.100340]. Found in Brazilian families and one unrelated French patient [@mondo:0009998].", - "age_onset": "0 (birth)", - "age_onset_min": 0.0, - "age_onset_max": 0.0, - "typ_age_onset_min": 0.0, - "typ_age_onset_max": 0.0, - "details": "Complex repeat of 18-20 nucleotides expands to cause disease: disease is found in individuals with 14-16 repeats [@pmid:24360810], while controls have typically 3-12 repeats with as low as 1 repeat [@genereviews:NBK535148; @gnomad:EIF4A3]. Significance of intermediate alleles is unknown [@pmid:29112243].", - "mechanism": "LoF", - "mechanism_detail": "LoF from a hypomorphic allele [@pmid:24360810].", - "year": "2014 [@pmid:24360810]; syndrome described in 1992 [@pmid:1632438]", - "location_in_gene": "5' UTR", - "gene_strand": "-", - "reference_motif_reference_orientation": ["CCTCGCTGTGCCGCTGCCGA"], - "pathogenic_motif_reference_orientation": ["CCTCGCTGTGCCGCTGCCGA"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["ACAGCGAGGTCGGCAGCGGC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 1, - "benign_max": 12, - "intermediate_min": 13, - "intermediate_max": 13, - "pathogenic_min": 14, - "pathogenic_max": 16, - "motif_len": 20, - "ref_copies": null, - "novel": "ref", - "gard": ["4718"], - "genereviews": ["NBK535148"], - "malacard": ["RBN014"], - "medgen": ["336581"], - "mondo": ["0009998"], - "omim": ["268305"], - "orphanet": ["3102"], - "gnomad": ["EIF4A3"], - "stripy": [], - "tr_atlas": ["TR148462"], - "webstr_hg38": [], - "webstr_hg19": [], - "locus_tags": ["supported_evidence"], - "disease_tags": [], - "references": ["pmid:24360810", "genereviews:NBK535148", "gnomad:EIF4A3", "pmid:29112243", "doi:10.1016/j.omsc.2023.100340", "mondo:0009998", "pmid:1632438"], - "additional_literature": [] -}, -{ - "id": "SCA27B_FGF14", - "disease_id": "SCA27B", - "gene": "FGF14", - "chrom": "chr13", - "start_hg38": 102161574, - "stop_hg38": 102161726, - "start_hg19": 102813924, - "stop_hg19": 102814076, - "start_t2t": 101377549, - "stop_t2t": 101377792, - "disease": "Spinocerebellar ataxia 27B", - "inheritance": ["AD"], - "disease_description": "Late-onset ataxia, may have episodic onset, downbeat nystagmus, vertigo, neuropathy [@pmid:39349043]. Involvement of the superior cerebellar peduncles is frequent and may aid in diagnostic efforts [@doi:10.1212/NXG.0000000000200253].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Intermediate expansions 1-2% of population, but non-GAA-pure without relation to ataxia [@genereviews:NBK599589]. Found in multiple ethnicities [@pmid:38876750]; diagnosed patients in America, Brazil, Japan, Germany, Spain, Canada, France, Austria, Australia, and Italy [@genereviews:NBK599589; @pmid:38886208; @pmid:37267898].", - "age_onset": "Typical: 42-70; Range: 21-87 [@genereviews:NBK599589; @pmid:39263992].", - "age_onset_min": 21.0, - "age_onset_max": 87.0, - "typ_age_onset_min": 42.0, - "typ_age_onset_max": 70.0, - "details": "Higher repeat size is associated with earlier age of onset [@pmid:39263992]. The 250-300 repeats range is linked to incomplete penetrance and >300 repeats with complete penetrance in some studies and resources [@genereviews:NBK599589; @pmid:37399286; @pmid:39227614]. However, our thresholds are taken from suggestions made by Mohren et al upon evaluation of 169 cases and 802 controls; the authors propose lower thresholds based on pathogenic cases of shorter pure repeats [@pmid:39227614]. Additionally, this study suggests that benign motifs may disrupt the formation of secondary structures in DNA/RNA, leading to reduced pathogenicity. The affect of interruptions on penetrance and onset has been shown in patients, with uninterrupted expansions apparently necessary for disease [@pmid:40007153]. Variation in flanking regions appear to correlate with repeat size [@pmid:39227614; @pmid:38937606]. Intermediate alleles make pose as susceptibility factors or be associated with a phenotypic spectrum (multiple system atrophy) [@pmid:39227614; @pmid:39604554]. Finally, a complex (TTC/TGC) ≥300 repeat expansion has been associated as a risk factor for Parkinson's disease [@pmid:41327893; @pmid:41277530].", - "mechanism": "LoF", - "mechanism_detail": "Reduced transcript 2 [@pmid:36516086].", - "year": "2023 [@pmid:36493768]", - "location_in_gene": "Intron 1", - "gene_strand": "-", - "reference_motif_reference_orientation": ["GAA"], - "pathogenic_motif_reference_orientation": ["GAA"], - "benign_motif_reference_orientation": ["GAAGGA", "GAAGAAGAAGAAGCA"], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CTT"], - "benign_motif_gene_orientation": ["CCTTCT", "CTGCTTCTTCTTCTT"], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 8, - "benign_max": 179, - "intermediate_min": 180, - "intermediate_max": 319, - "pathogenic_min": 320, - "pathogenic_max": 937, - "motif_len": 3, - "ref_copies": 50.3, - "novel": "ref", - "gard": [], - "genereviews": ["NBK599589"], - "malacard": ["SPN469"], - "medgen": ["1824051"], - "mondo": ["0859340"], - "omim": ["620174"], - "orphanet": ["675216"], - "gnomad": ["FGF14"], - "stripy": ["FGF14"], - "tr_atlas": [], - "webstr_hg38": ["1272528"], - "webstr_hg19": [], - "locus_tags": ["supported_evidence", "maternal_expansion", "length_affects_onset", "length_affects_penetrance", "motif_affects_penetrance", "length_affects_phenotype"], - "disease_tags": ["spinocerebellar_ataxia"], - "references": ["genereviews:NBK599589", "pmid:39263992", "pmid:36516086", "pmid:37399286", "pmid:39227614", "pmid:40007153", "pmid:38937606", "pmid:39604554", "pmid:41327893", "pmid:41277530", "pmid:38876750", "pmid:38886208", "pmid:37267898", "pmid:36493768", "pmid:39349043", "doi:10.1212/NXG.0000000000200253"], - "additional_literature": ["pmid:41327893", "pmid:41277530", "pmid:41118032", "pmid:41065930", "pmid:41055766", "pmid:40974444", "pmid:40906330", "pmid:40898875", "pmid:40894141", "pmid:40879304", "pmid:40835733", "pmid:40679574", "pmid:40637932", "pmid:40623333", "pmid:40579842", "pmid:40556471", "pmid:40488180", "pmid:40379261", "pmid:40273470", "pmid:40239008", "pmid:40191983", "pmid:40141365", "pmid:40024931", "pmid:40017559", "pmid:39996128", "pmid:39821862", "pmid:39801711", "pmid:39723156", "pmid:39666057", "pmid:39666053", "pmid:39574782", "pmid:39571249", "pmid:39392764", "pmid:39378335", "pmid:39152783", "pmid:39006414", "pmid:38976084", "pmid:38949032", "pmid:38866925", "pmid:38816190", "pmid:38513302", "pmid:38487929", "pmid:38472396", "pmid:38405699", "pmid:38381176", "pmid:38221848", "pmid:38170134", "pmid:38150853", "pmid:38058854", "pmid:37916889", "pmid:37646005", "pmid:37578187", "pmid:37577458", "pmid:37322040", "pmid:37165652", "pmid:32717741", "pmid:30017992", "pmid:28444220", "pmid:26677414", "pmid:26149656", "pmid:15470364", "pmid:15148151"] -}, -{ - "id": "FXS_FMR1", - "disease_id": "FXS, FXTAS, POF1", - "gene": "FMR1", - "chrom": "chrX", - "start_hg38": 147912049, - "stop_hg38": 147912111, - "start_hg19": 146993567, - "stop_hg19": 146993629, - "start_t2t": 146176677, - "stop_t2t": 146176769, - "disease": "Fragile X syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency FXPOI/POF1", - "inheritance": ["XD"], - "disease_description": "A genetic syndrome caused by mutations in the FMR1 gene which is responsible for the expression of the fragile X mental retardation 1 protein. This protein participates in neural development. This syndrome is manifested with mental, emotional, behavioral, physical, and learning disabilities.; Any primary ovarian failure in which the cause of the disease is a mutation in the FMR1 gene.; Fragile X-associated tremor/ataxia syndrome (FXTAS) is a rare neurodegenerative disorder characterized by adult-onset progressive intention tremor and gait ataxia [@mondo:0010383; @mondo:0010706; @mondo:0010382].", - "hpo_terms": null, - "prevalence": "14/100000", - "prevalence_details": "Incidence of full mutation in males 19/100,000; prevalence 14/100,000 [@genereviews:NBK1384]. Female prevalence 9/100,000 [@pmid:24700618]. Known carrier frequency is approximately 300-500/100,000 but detected was 11/100,000 [@pmid:29100084]. FXS prevalence 1:7000 males, 1:11,000 females; FX premutation carriers 1:290-855 males, 1:148-300 females [@isbn:978-3-031-66932-3]. Found worldwide [@genereviews:NBK1384]. In Thailand, 1 in 600 women carry a premutation, and 1 in 400 carry a 'gray zone' allele [@pmid:39320553].", - "age_onset": "Typical: FXS 1 to 'first several years of life', FXTAS 60-65 [@genereviews:NBK1384]; Range: 0 [@url:https://www.uptodate.com/contents/fragile-x-syndrome-clinical-features-and-diagnosis-in-children-and-adolescents] - 78 [@pmid:17427188]; detailed description of typical symptom onset and diagnosis available from Arnold et al [@isbn:978-3-031-66932-3].", - "age_onset_min": 0.0, - "age_onset_max": 78.0, - "typ_age_onset_min": 1.0, - "typ_age_onset_max": 65.0, - "details": "Intermediate or 'gray zone' occur at 45-54 alleles and may be unstable enough to expand into the premutation range, as well as associate with parkinsonism [@pmid:32463542; @genereviews:NBK1384]. FXTAS/POI occurs at 55-200 repeats, FXS >200, late onset; AGG and CTG interruptions documented [@genereviews:NBK1384; @pmid:29868108].", - "mechanism": "LoF/GoF", - "mechanism_detail": "Loss of function via transcriptional silencing in FXS, RNA gain of function in FXTAS/FXPOI [@pmid:16205714; @pmid:36169768].", - "year": "1992 [@pmid:1605194]; causative gene discovered in 1991 [@pmid:1710175]", - "location_in_gene": "5' UTR", - "gene_strand": "+", - "reference_motif_reference_orientation": ["CGG"], - "pathogenic_motif_reference_orientation": ["CGG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CGG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 5, - "benign_max": 44, - "intermediate_min": 45, - "intermediate_max": 200, - "pathogenic_min": 201, - "pathogenic_max": 2000, - "motif_len": 3, - "ref_copies": 20.6667, - "novel": "ref", - "gard": ["6464", "16806"], - "genereviews": ["NBK1384"], - "malacard": ["FRG001", "FRG008", "PRM405"], - "medgen": ["8912", "1644269", "333403"], - "mondo": ["0010383", "0010706", "0010382"], - "omim": ["300624", "300623"], - "orphanet": ["908", "642691", "93256"], - "gnomad": ["FMR1"], - "stripy": ["FMR1"], - "tr_atlas": ["TR173944"], - "webstr_hg38": ["885222"], - "webstr_hg19": ["Expansion_FXS/FMR1"], - "locus_tags": ["supported_evidence", "somatic_instability", "anticipation", "maternal_expansion", "length_affects_onset", "length_affects_penetrance", "length_affects_phenotype", "length_affects_severity", "motif_affects_instability"], - "disease_tags": ["phenotypic_spectrum", "ataxia"], - "references": ["genereviews:NBK1384", "url:https://www.uptodate.com/contents/fragile-x-syndrome-clinical-features-and-diagnosis-in-children-and-adolescents", "pmid:17427188", "isbn:978-3-031-66932-3", "pmid:16205714", "pmid:36169768", "pmid:32463542", "pmid:29868108", "pmid:24700618", "pmid:29100084", "pmid:39320553", "pmid:1605194", "pmid:1710175", "mondo:0010383", "mondo:0010706", "mondo:0010382"], - "additional_literature": ["pmid:41409170", "pmid:41386846", "pmid:41385812", "pmid:41372183", "pmid:41351347", "pmid:41278766", "pmid:41256123", "pmid:41167304", "pmid:41145158", "pmid:41120736", "pmid:41098569", "pmid:41074692", "pmid:41028987", "pmid:41015363", "pmid:40980401", "pmid:40940631", "pmid:40877251", "pmid:40869951", "pmid:40879637", "pmid:40778130", "pmid:40653294", "pmid:40600017", "pmid:40534679", "pmid:40488180", "pmid:40480633", "pmid:40459253", "pmid:40455869", "pmid:40418066", "pmid:40417743", "pmid:40296143", "pmid:40287634", "pmid:40244008", "pmid:40243429", "pmid:40243408", "pmid:40220918", "pmid:40166285", "pmid:40149430", "pmid:40141467", "pmid:40141297", "pmid:39945490", "pmid:39934227", "pmid:39839505", "pmid:39684429", "pmid:39654947", "pmid:39588919", "pmid:39574643", "pmid:39553953", "pmid:39492694", "pmid:39482338", "pmid:39488698", "pmid:39095619", "pmid:38997701", "pmid:38961870", "pmid:38946987", "pmid:38865241", "pmid:38772058", "pmid:38714961", "pmid:38522837", "pmid:38412259", "pmid:38307002", "pmid:38164622", "pmid:38162443", "pmid:38134876", "pmid:37970883", "pmid:37936174", "pmid:37906407", "pmid:37776526", "pmid:37745859", "pmid:37628570", "pmid:37583466", "pmid:37551886", "pmid:37551173", "pmid:37508562", "pmid:37364131", "pmid:37352983", "pmid:37347418", "pmid:37333274", "pmid:37209683", "pmid:37200782", "pmid:37146135", "pmid:37120588", "pmid:36882476", "pmid:36816716", "pmid:36250920", "pmid:36227727", "pmid:36012355", "pmid:35977823", "pmid:35948990", "pmid:35904811", "pmid:35729184", "pmid:35701103", "pmid:35681093", "pmid:35609145", "pmid:35182509", "pmid:35152460", "pmid:35129870", "pmid:35101584", "pmid:35072235", "pmid:35038595", "pmid:35026985", "pmid:34938155", "pmid:34926684", "pmid:34924936", "pmid:34880790", "pmid:34845661", "pmid:34828275", "pmid:34738199", "pmid:34690787", "pmid:34679478", "pmid:34646309", "pmid:34641814", "pmid:34641644", "pmid:34542254", "pmid:34456771", "pmid:34421690", "pmid:34372915", "pmid:34358321", "pmid:34321326", "pmid:34296199", "pmid:34276797", "pmid:34193467", "pmid:34153466", "pmid:34117786", "pmid:34111553", "pmid:34077515", "pmid:34054431", "pmid:34046842", "pmid:33998336", "pmid:33856019", "pmid:33854084", "pmid:33772546", "pmid:33709078", "pmid:33692361", "pmid:33642901", "pmid:33627639", "pmid:33585555", "pmid:33523882", "pmid:33497798", "pmid:33381520", "pmid:33374331", "pmid:33296661", "pmid:33195422", "pmid:33181255", "pmid:33151065", "pmid:33039683", "pmid:33008014", "pmid:33007370", "pmid:32787884", "pmid:32716213", "pmid:32695777", "pmid:32688058", "pmid:32589669", "pmid:32478017", "pmid:32446918", "pmid:32281281", "pmid:32258228", "pmid:32089525", "pmid:32066985", "pmid:32048109", "pmid:32012997", "pmid:31991700", "pmid:31989181", "pmid:31891607", "pmid:31887710", "pmid:31880363", "pmid:31866572", "pmid:31804632", "pmid:31733943", "pmid:31671347", "pmid:31665086", "pmid:31632248", "pmid:31586346", "pmid:31566610", "pmid:31512951", "pmid:31481131", "pmid:31468394", "pmid:31352801", "pmid:31347257", "pmid:31336350", "pmid:31332380", "pmid:31299981", "pmid:31294106", "pmid:31264835", "pmid:31159589", "pmid:31096929", "pmid:31026518", "pmid:30984240", "pmid:30900173", "pmid:30847793", "pmid:30840878", "pmid:30832215", "pmid:30808398", "pmid:30665341", "pmid:30619448", "pmid:30606610", "pmid:30576349", "pmid:30567555", "pmid:30566867", "pmid:30538724", "pmid:30509972", "pmid:30396881", "pmid:30396281", "pmid:30312299", "pmid:30311737", "pmid:30211570", "pmid:30197656", "pmid:30173918", "pmid:30160796", "pmid:30158855", "pmid:30147707", "pmid:30030199", "pmid:29990673", "pmid:29981579", "pmid:29971092", "pmid:29880767", "pmid:29844802", "pmid:29766042", "pmid:29760651", "pmid:29379561", "pmid:29375310", "pmid:29316893", "pmid:29275276", "pmid:29267266", "pmid:29209628", "pmid:29188551", "pmid:28967713", "pmid:28895261", "pmid:28829283", "pmid:28815939", "pmid:28812997", "pmid:28697590", "pmid:28504725", "pmid:28454580", "pmid:28391068", "pmid:28369393", "pmid:28278294", "pmid:28233916", "pmid:28193118", "pmid:28173181", "pmid:28103472", "pmid:28065649", "pmid:28005950", "pmid:27883256", "pmid:27862088", "pmid:27841182", "pmid:27841172", "pmid:27840045", "pmid:27822316", "pmid:27816231", "pmid:27784894", "pmid:27646161", "pmid:27768763", "pmid:27761921", "pmid:27667322", "pmid:27616423", "pmid:27713816", "pmid:27708271", "pmid:27696642", "pmid:27696273", "pmid:27695335", "pmid:27540028", "pmid:27427765", "pmid:27375073", "pmid:27372099", "pmid:27355815", "pmid:27355445", "pmid:27335370", "pmid:27315125", "pmid:27294193", "pmid:27066582", "pmid:27042357", "pmid:27041225", "pmid:27001315", "pmid:26940792", "pmid:26825750", "pmid:26743003", "pmid:26716517", "pmid:26694146", "pmid:26554012", "pmid:26537920", "pmid:26463479", "pmid:26440889", "pmid:26420841", "pmid:26345686", "pmid:26322075", "pmid:26298472", "pmid:26194536", "pmid:26099177", "pmid:26029703", "pmid:25954027", "pmid:25953684", "pmid:25886163", "pmid:25875842", "pmid:25788698", "pmid:25776194", "pmid:25763861", "pmid:25726753", "pmid:25693964", "pmid:25689687", "pmid:25606365", "pmid:25436181", "pmid:25399540", "pmid:25366135", "pmid:25346430", "pmid:25290064", "pmid:25278957", "pmid:25250047", "pmid:25179629", "pmid:25171808", "pmid:25170346", "pmid:25147555", "pmid:25110527", "pmid:25093044", "pmid:25085749", "pmid:25013385", "pmid:24998620", "pmid:24963073", "pmid:24958193", "pmid:24938362", "pmid:24920338", "pmid:24912415", "pmid:24875778", "pmid:24858908", "pmid:24821701", "pmid:24816393", "pmid:24814676", "pmid:24787137", "pmid:24763282", "pmid:24743386", "pmid:24718368", "pmid:24715853", "pmid:24657592", "pmid:24654675", "pmid:24630283", "pmid:24591415", "pmid:24578575", "pmid:24463622", "pmid:24455203", "pmid:24452737", "pmid:24448548", "pmid:24428240", "pmid:24424424", "pmid:24401315", "pmid:24352881", "pmid:24289922", "pmid:24261641", "pmid:24249225", "pmid:24177047", "pmid:24130133", "pmid:23949867", "pmid:23896050", "pmid:23792063", "pmid:23753897", "pmid:23731704", "pmid:23719910", "pmid:23683082", "pmid:23602499", "pmid:23574351", "pmid:23553633", "pmid:23497562", "pmid:23478018", "pmid:23464607", "pmid:23440729", "pmid:23250915", "pmid:23198693", "pmid:23148490", "pmid:23146966", "pmid:23015788", "pmid:22924671", "pmid:22918986", "pmid:22887750", "pmid:22796595", "pmid:22707411", "pmid:22612820", "pmid:22619118", "pmid:22581803", "pmid:22507827", "pmid:22498846", "pmid:22489017", "pmid:22466801", "pmid:22427040", "pmid:22393900", "pmid:22387066", "pmid:22311273", "pmid:22251309", "pmid:22241100", "pmid:22224633", "pmid:22223546", "pmid:22211843", "pmid:22177572", "pmid:22161987", "pmid:22149120", "pmid:22022567", "pmid:22004265", "pmid:21944929", "pmid:21808616", "pmid:21807882", "pmid:21775729", "pmid:21767618", "pmid:21720528", "pmid:21671049", "pmid:21646280", "pmid:21636656", "pmid:21617890", "pmid:21596781", "pmid:21572337", "pmid:21567456", "pmid:21499798", "pmid:21476992", "pmid:21445959", "pmid:21430544", "pmid:21389081", "pmid:21329465", "pmid:21270637", "pmid:21267007", "pmid:21254876", "pmid:21170301", "pmid:21051337", "pmid:20938029", "pmid:20935171", "pmid:20858229", "pmid:20801083", "pmid:20799337", "pmid:20736975", "pmid:20702130", "pmid:20616364", "pmid:20431035", "pmid:20425835", "pmid:20410144", "pmid:20364100", "pmid:20221430", "pmid:20213777", "pmid:20168238", "pmid:20118148", "pmid:20051238", "pmid:20011099", "pmid:20001115", "pmid:19927162", "pmid:19846466", "pmid:19804849", "pmid:19796183", "pmid:19778484", "pmid:19760650", "pmid:19710035", "pmid:19684044", "pmid:19562332", "pmid:19525339", "pmid:19514725", "pmid:19460939", "pmid:19460937", "pmid:19440516", "pmid:19404994", "pmid:19204162", "pmid:19097038", "pmid:19045956", "pmid:19026394", "pmid:19014369", "pmid:18565783", "pmid:18563710", "pmid:18553360", "pmid:18535897", "pmid:18472227", "pmid:18428348", "pmid:18413472", "pmid:18403614", "pmid:18384775", "pmid:18373410", "pmid:18357616", "pmid:18310361", "pmid:18281036", "pmid:18165971", "pmid:18165276", "pmid:18160412", "pmid:18057320", "pmid:17724287", "pmid:17698009", "pmid:17674408", "pmid:17635840", "pmid:17591512", "pmid:17516099", "pmid:17442505", "pmid:17322660", "pmid:17295053", "pmid:17279084", "pmid:17266074", "pmid:17152065", "pmid:17150213", "pmid:17089161", "pmid:17044853", "pmid:16780889", "pmid:16761284", "pmid:16361284", "pmid:16337617", "pmid:16258159", "pmid:16164596", "pmid:16047092", "pmid:16047089", "pmid:15971024", "pmid:15947063", "pmid:15876460", "pmid:15811008", "pmid:15741991", "pmid:15659577", "pmid:15649335", "pmid:15629215", "pmid:15483045", "pmid:15377638", "pmid:15302914", "pmid:15068386", "pmid:14755444", "pmid:14735162", "pmid:14722156", "pmid:14560307", "pmid:14519687", "pmid:14517952", "pmid:12948442", "pmid:12905066", "pmid:12853612", "pmid:12681986", "pmid:12659659", "pmid:12634803", "pmid:12515381", "pmid:12379314", "pmid:12232854", "pmid:12160728", "pmid:12111644", "pmid:11992571", "pmid:11886710", "pmid:11807410", "pmid:11551101", "pmid:11499669", "pmid:11487573", "pmid:11410685", "pmid:11256870", "pmid:11229516", "pmid:11142761", "pmid:11142752", "pmid:11119302", "pmid:11097353", "pmid:11073538", "pmid:11070156", "pmid:11005143", "pmid:10995510", "pmid:10987654", "pmid:10941804", "pmid:10915764", "pmid:10870330", "pmid:10855793", "pmid:10780779", "pmid:10773084", "pmid:10710419", "pmid:10674158", "pmid:10631132", "pmid:10587583", "pmid:10567518", "pmid:10545610", "pmid:10521303", "pmid:10462618", "pmid:10447261", "pmid:10445321", "pmid:10424820", "pmid:10409756", "pmid:10369109", "pmid:10331601", "pmid:10331600", "pmid:10204857", "pmid:9916838", "pmid:9856500", "pmid:9811938", "pmid:9806479", "pmid:9792200", "pmid:9761677", "pmid:9738717", "pmid:9653650", "pmid:9624140", "pmid:9630071", "pmid:9604772", "pmid:9603608", "pmid:9529778", "pmid:9485421", "pmid:9514250", "pmid:9507388", "pmid:9415473", "pmid:9437788", "pmid:9399905", "pmid:9358013", "pmid:9341861", "pmid:9382110", "pmid:9299309", "pmid:9279752", "pmid:9254854", "pmid:9207038", "pmid:9201980", "pmid:9195158", "pmid:9640603", "pmid:9131013", "pmid:8798682", "pmid:8808600", "pmid:8792815", "pmid:8792813", "pmid:8844091", "pmid:8844089", "pmid:8844077", "pmid:8844068", "pmid:8844065", "pmid:8844064", "pmid:8755928", "pmid:8698331", "pmid:8826482", "pmid:8826479", "pmid:8725793", "pmid:8636996", "pmid:8673086", "pmid:8664297", "pmid:8644711", "pmid:8626781", "pmid:8872026", "pmid:8800930", "pmid:8519769", "pmid:8634688", "pmid:7499428", "pmid:8589687", "pmid:7581460", "pmid:8593539", "pmid:8579216", "pmid:8559749", "pmid:7541938", "pmid:7761473", "pmid:7758107", "pmid:7732383", "pmid:7783163", "pmid:8750357", "pmid:7825564", "pmid:7717734", "pmid:7881407", "pmid:7864047", "pmid:7927336", "pmid:7849707", "pmid:7987398", "pmid:8023854", "pmid:8197163", "pmid:8162055", "pmid:8275089", "pmid:8244331", "pmid:8237919", "pmid:7902319", "pmid:7692601", "pmid:8242066", "pmid:8334699", "pmid:1642231", "pmid:1605199"] -}, -{ - "id": "BPES_FOXL2", - "disease_id": "BPES", - "gene": "FOXL2", - "chrom": "chr3", - "start_hg38": 138946019, - "stop_hg38": 138946062, - "start_hg19": 138664861, - "stop_hg19": 138664904, - "start_t2t": 141687011, - "stop_t2t": 141687054, - "disease": "Blepharophimosis, epicanthus inversus, and ptosis", - "inheritance": ["AD", "AR"], - "disease_description": "Blepharophimosis, Ptosis, and Epicanthus Inversus syndrome (BPES) is an ophthalmic disorder characterized by blepharophimosis, ptosis, epicanthus inversus, and telecanthus, that can appear associated with (type I) or without premature ovarian failure (POF) (type II) [@mondo:0007201].", - "hpo_terms": null, - "prevalence": "0.3/50000", - "prevalence_details": "1 in 50,000 births globally for all BPES, with FOXL2 expansions ~30% of pathogenic variants [@genereviews:NBK1441; @genereviews:NBK535148; @pmid:12529855]. Found worldwide, without differences in prevalence based on sex/ethnicity [@genereviews:NBK1441].", - "age_onset": "0 (birth)", - "age_onset_min": 0.0, - "age_onset_max": 0.0, - "typ_age_onset_min": 0.0, - "typ_age_onset_max": 0.0, - "details": "14 repeats appears highly constrained in humans: homozygous expansions from 14 polyalanines to 19 leads to disease, which can be limited to isolated palpebral defects [@pmid:15591279]. Heterozygous expansions to 24 polyalanines also lead to disease [@pmid:15591279]. Locus start can differ between catalogs, which can affect genotyping.", - "mechanism": "GoF/LoF", - "mechanism_detail": "Polyalanine expansion leads to haploinsufficiency, likely due to decreased protein availibility due to mislocalization following nuclear inclusion [@genereviews:NBK1441; @pmid:15591279]", - "year": "2003 [@pmid:12529855]", - "location_in_gene": "Coding Exon 1", - "gene_strand": "-", - "reference_motif_reference_orientation": ["NGC"], - "pathogenic_motif_reference_orientation": ["NGC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CNG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 14, - "benign_max": 14, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 15, - "pathogenic_max": 24, - "motif_len": 3, - "ref_copies": 14.0, - "novel": "ref", - "gard": ["23"], - "genereviews": ["NBK1441"], - "malacard": ["BLP046"], - "medgen": ["66312"], - "mondo": ["0007201"], - "omim": ["110100"], - "orphanet": ["126"], - "gnomad": ["FOXL2"], - "stripy": ["FOXL2"], - "tr_atlas": ["TR36092"], - "webstr_hg38": [], - "webstr_hg19": [], - "locus_tags": ["supported_evidence"], - "disease_tags": [], - "references": ["genereviews:NBK1441", "pmid:15591279", "genereviews:NBK535148", "pmid:12529855", "mondo:0007201"], - "additional_literature": ["pmid:22926839", "pmid:18158309", "pmid:17089161", "pmid:7633459"] -}, -{ - "id": "FRDA_FXN", - "disease_id": "FRDA", - "gene": "FXN", - "chrom": "chr9", - "start_hg38": 69037286, - "stop_hg38": 69037304, - "start_hg19": 71652202, - "stop_hg19": 71652220, - "start_t2t": 81210834, - "stop_t2t": 81210861, - "disease": "Friedreich ataxia", - "inheritance": ["AR"], - "disease_description": "Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia with associated limb muscle weakness, absent lower limb reflexes, extensor plantar responses, dysarthria, and decreased vibratory sense and proprioception. Onset is usually in the first or second decade, before the end of puberty [@omim:229300].", - "hpo_terms": null, - "prevalence": "1/50000", - "prevalence_details": "1/50,000 [@omim:229300; @pmid:29100084]: Known carrier frequency 1000/100,000; observed 421/100,000. Most common inherited ataxia in Europe, the Middle East, India, and North Africa; not documented in Southeast Asia, in sub-Saharan Africa, or among Native Americans [@genereviews:NBK1281].", - "age_onset": "Typical: 10-15; Range: 2-80 [@genereviews:NBK1281].", - "age_onset_min": 2.0, - "age_onset_max": 80.0, - "typ_age_onset_min": 10.0, - "typ_age_onset_max": 15.0, - "details": "96% of FA patients have biallelic GAA expansions in intron 1 (compared to compound heterozygous with another mutation type), in which the reference allele is conventionally 5-33 repeats [@genereviews:NBK1281]. Intermediate alleles (34-55) are associated with premutations, but may lead to disease as exact pathogenicity/penetrance thresholds have not been demarcated [@genereviews:NBK1281]. The expanded repeats can interrupted either with GAAGAG, GAAGGA, or GAAGAAAA sequences, leading to differential phenotypes [@pmid:11748752]. Allele size is correlated with disease severity and inversely correlated to age of onset, and expansions can reach 1700 repeats [@pmid:8815938].", - "mechanism": "LoF", - "mechanism_detail": "Loss of function via transcriptional silencing [@pmid:16205714; @pmid:36169768].", - "year": "1996 [@pmid:8596916]", - "location_in_gene": "Intron 1", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GAA"], - "pathogenic_motif_reference_orientation": ["GAA"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["AAG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [ + "id": "NME_NAXE", + "disease_id": "NME", + "gene": "NAXE", + "chrom": "chr1", + "start_hg38": 156591765, + "stop_hg38": 156591783, + "start_hg19": 156561557, + "stop_hg19": 156561575, + "start_t2t": 155728131, + "stop_t2t": 155728159, + "disease": "NAXE-related mitochondrial encephalopathy", + "inheritance": [ + "AR" + ], + "disease_description": "Patients with NAXE-related mitochondrial encephalopathy exhibit developmental delay, cognitive regression, altered consciousness, abnormalities in eye movement (including nystagmus), muscle weakness, respiratory failure, seizure, ataxia, and gait disturbance at the age of 1 to 2 years. The disease is characterized by fluctuating symptoms over time, often exacerbated by febrile illness; it is progressive and fatal in the long term [@pmid:39455596].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Single proband found in Japanese cohort [@pmid:39455596].", + "age_onset": "Single repeat expansion case had onset at 13 months, while NAXE-related mitochondrial encephalopathy more generally has predominately infantile onset, extending to 20y or older [@pmid:39455596].", + "age_onset_min": 1, + "age_onset_max": 1, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "Benign range (2-7) alleles established by 484 control alleles and validated with orthogonal databases, while single proband had expansion of ~200 repeats inherited from mother via uniparental disomy [@pmid:39455596]. While the repeat expansion is newly reported, other variants in the NAXE gene have previously been associated with mitochondrial encephalopathy.", + "mechanism": "LoF", + "mechanism_detail": "Reduced NAXE expression from expansion in promoter; hypermethylation was detected at and downstream of the repeat sequence in the proband as well as the maternal copy of the expanded allele, which was not present in the maternal normal range allele nor in the controls [@pmid:39455596]", + "year": "2024 [@pmid:39455596]", + "location_in_gene": "5' UTR", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GGGCC" + ], + "pathogenic_motif_reference_orientation": [ + "GGGCC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CCGGG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 2, + "benign_max": 7, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 200, + "pathogenic_max": 200, + "motif_len": 5, + "ref_copies": null, + "novel": "ref", + "gard": [ + "17991" + ], + "genereviews": [], + "malacard": [ + "ENC069" + ], + "medgen": [ + "934642" + ], + "mondo": [ + "0020781" + ], + "omim": [ + "617186" + ], + "orphanet": [ + "555407" + ], + "gnomad": [ + "NAXE" + ], + "stripy": [], + "tr_atlas": [ + "TR7952" + ], + "webstr_hg38": [ + "1184343", + "6351240" + ], + "webstr_hg19": [], + "locus_tags": [ + "limited_evidence" + ], + "disease_tags": [], + "references": [ + "pmid:39455596" + ], + "additional_literature": [ + "pmid:41091881" + ] + }, { - "motif": "A", - "count": 16, - "type": "flank_repeat" + "id": "ALS1_NIPA1", + "disease_id": "ALS1", + "gene": "NIPA1", + "chrom": "chr15", + "start_hg38": 22786677, + "stop_hg38": 22786703, + "start_hg19": 23086363, + "stop_hg19": 23086389, + "start_t2t": 20458510, + "stop_t2t": 20458536, + "disease": "Amyotrophic lateral sclerosis", + "inheritance": [ + "AD" + ], + "disease_description": "Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life [@omim:105400].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "2.7-7.4/100,000 for all cases of ALS, NIPA1 + C9orf72 is 0.37% of ALS patients; frequency of NIPA1 expansion in controls is 3.74% [@pmid:31286297]. The NIPA1 expansion is associated with disease globally [@pmid:30342764], but likely unassociated in African probands [@pmid:34179866].", + "age_onset": "Typical: 44-60 [@pmid:26777436]; Range: 25 [@pmid:22378146] - 77 [@pmid:26777436].", + "age_onset_min": 25, + "age_onset_max": 77, + "typ_age_onset_min": 44, + "typ_age_onset_max": 60, + "details": "Allelic ranges taken from STRipy based on primary literature [@stripy:NIPA1]. Currently proposed as a modifier for ALS [@pmid:31286297]. Note: the motif for this locus is CGG in hg38 and T2T reference genomes, while in hg19, the motif is the reverse complement CCG because it is on the negative strand.", + "mechanism": null, + "mechanism_detail": null, + "year": "2019 [@pmid:30342764]", + "location_in_gene": "Coding Exon 1/Intron 1 depending on transcript", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GCG" + ], + "pathogenic_motif_reference_orientation": [ + "GCG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CGG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 6, + "benign_max": 10, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 11, + "pathogenic_max": 56, + "motif_len": 3, + "ref_copies": 10.7, + "novel": "ref", + "gard": [ + "5786" + ], + "genereviews": [], + "malacard": [ + "FRN044" + ], + "medgen": [ + "400169" + ], + "mondo": [ + "0007103" + ], + "omim": [ + "105400" + ], + "orphanet": [ + "282", + "803" + ], + "gnomad": [ + "NIPA1" + ], + "stripy": [ + "NIPA1" + ], + "tr_atlas": [ + "TR133649" + ], + "webstr_hg38": [ + "5135087" + ], + "webstr_hg19": [], + "locus_tags": [ + "contradictory_evidence", + "proposed_modifier" + ], + "disease_tags": [], + "references": [ + "pmid:26777436", + "pmid:22378146", + "stripy:NIPA1", + "pmid:31286297", + "pmid:30342764", + "pmid:34179866", + "omim:105400" + ], + "additional_literature": [ + "pmid:41426430", + "pmid:38667292", + "pmid:37043475", + "pmid:35869263", + "pmid:33414559", + "pmid:32954321", + "pmid:24866401", + "pmid:21419568", + "pmid:11839840", + "pmid:10987648", + "pmid:9736780" + ] }, { - "motif": "GAA", - "count": null, - "type": "pathogenic_repeat" - }], - "benign_min": 5, - "benign_max": 33, - "intermediate_min": 34, - "intermediate_max": 55, - "pathogenic_min": 56, - "pathogenic_max": 1700, - "motif_len": 3, - "ref_copies": 6.0, - "novel": "ref", - "gard": ["6468"], - "genereviews": ["NBK1281"], - "malacard": ["FRD001"], - "medgen": ["383962"], - "mondo": ["0100340"], - "omim": ["229300"], - "orphanet": ["95"], - "gnomad": ["FXN"], - "stripy": ["FXN"], - "tr_atlas": ["TR93516"], - "webstr_hg38": ["1509872"], - "webstr_hg19": [], - "locus_tags": ["supported_evidence", "somatic_instability", "maternal_expansion", "length_affects_onset", "length_affects_phenotype", "motif_affects_instability", "motif_affects_onset", "motif_affects_penetrance"], - "disease_tags": ["ataxia"], - "references": ["genereviews:NBK1281", "pmid:16205714", "pmid:36169768", "pmid:11748752", "pmid:8815938", "omim:229300", "pmid:29100084", "pmid:8596916"], - "additional_literature": ["pmid:41432640", "pmid:41426430", "pmid:41318543", "pmid:41301739", "pmid:41278766", "pmid:41176519", "pmid:41137390", "pmid:41074692", "pmid:41014100", "pmid:40994821", "pmid:40970480", "pmid:40898875", "pmid:40880907", "pmid:40507780", "pmid:40488180", "pmid:40419681", "pmid:40404357", "pmid:40296143", "pmid:40141365", "pmid:39812846", "pmid:39810753", "pmid:39574782", "pmid:39571249", "pmid:39519164", "pmid:39496895", "pmid:39324476", "pmid:39235665", "pmid:39219417", "pmid:39062522", "pmid:38936158", "pmid:38495102", "pmid:38484450", "pmid:38396238", "pmid:38367363", "pmid:38352270", "pmid:38141359", "pmid:38063871", "pmid:38014032", "pmid:37891254", "pmid:37585105", "pmid:37006329", "pmid:36928898", "pmid:36800320", "pmid:36780807", "pmid:36777637", "pmid:36638893", "pmid:36635061", "pmid:36618024", "pmid:36511872", "pmid:36369844", "pmid:36133907", "pmid:36036008", "pmid:35850241", "pmid:35708503", "pmid:35595154", "pmid:35301072", "pmid:35182509", "pmid:34920960", "pmid:34849883", "pmid:34786480", "pmid:34747814", "pmid:34687355", "pmid:34643298", "pmid:34600502", "pmid:34408077", "pmid:34372915", "pmid:34299126", "pmid:34214898", "pmid:33820410", "pmid:33629768", "pmid:33624863", "pmid:33599954", "pmid:33592237", "pmid:33529321", "pmid:33354116", "pmid:33151022", "pmid:33028632", "pmid:32746884", "pmid:32744307", "pmid:32717741", "pmid:32608417", "pmid:32586831", "pmid:32582297", "pmid:32481586", "pmid:32385683", "pmid:32291635", "pmid:31911468", "pmid:31904895", "pmid:31877117", "pmid:31673878", "pmid:31650522", "pmid:31446150", "pmid:31279523", "pmid:30874991", "pmid:30828501", "pmid:30761510", "pmid:30635474", "pmid:30596685", "pmid:30590615", "pmid:30552117", "pmid:30519163", "pmid:30464193", "pmid:30425621", "pmid:30358880", "pmid:30237783", "pmid:30159187", "pmid:30097477", "pmid:30076049", "pmid:30065630", "pmid:29666341", "pmid:29529236", "pmid:29261783", "pmid:29125828", "pmid:29070698", "pmid:28904984", "pmid:28812047", "pmid:28716278", "pmid:28451558", "pmid:28282710", "pmid:28109580", "pmid:27518705", "pmid:27668106", "pmid:27648458", "pmid:27644330", "pmid:27522354", "pmid:27425605", "pmid:27386501", "pmid:27228352", "pmid:27206881", "pmid:27142428", "pmid:26906906", "pmid:26896803", "pmid:28392990", "pmid:26704351", "pmid:26414159", "pmid:26401053", "pmid:26393353", "pmid:26379101", "pmid:26339677", "pmid:26338206", "pmid:26301374", "pmid:26149656", "pmid:26099177", "pmid:25845763", "pmid:25831023", "pmid:25814655", "pmid:25758173", "pmid:25685137", "pmid:25681319", "pmid:25616511", "pmid:25207996", "pmid:25198290", "pmid:25112975", "pmid:25022367", "pmid:24971578", "pmid:24962209", "pmid:24858524", "pmid:24819921", "pmid:24816001", "pmid:24787137", "pmid:24714088", "pmid:24691413", "pmid:24667739", "pmid:24665325", "pmid:24613765", "pmid:24586819", "pmid:24455203", "pmid:24371004", "pmid:24327207", "pmid:24209901", "pmid:24023969", "pmid:23996585", "pmid:23943791", "pmid:23925595", "pmid:23922695", "pmid:23879205", "pmid:23838345", "pmid:23775342", "pmid:23691127", "pmid:23640016", "pmid:23625326", "pmid:23474817", "pmid:23418481", "pmid:23382970", "pmid:23280845", "pmid:25499576", "pmid:23269675", "pmid:23242090", "pmid:23071719", "pmid:22798143", "pmid:22787155", "pmid:22764244", "pmid:22752483", "pmid:22691228", "pmid:22447512", "pmid:22414340", "pmid:22409940", "pmid:22289650", "pmid:22262734", "pmid:21830088", "pmid:21776984", "pmid:21745819", "pmid:21652007", "pmid:21486239", "pmid:21397024", "pmid:21181307", "pmid:21127046", "pmid:21051337", "pmid:21040903", "pmid:20675166", "pmid:20559546", "pmid:20506029", "pmid:20373285", "pmid:20098685", "pmid:20090835", "pmid:19956589", "pmid:19876374", "pmid:19733517", "pmid:19485941", "pmid:19370769", "pmid:19259763", "pmid:19043662", "pmid:18820300", "pmid:18697824", "pmid:18597733", "pmid:18045775", "pmid:17703324", "pmid:17498922", "pmid:28182935", "pmid:17262846", "pmid:17235301", "pmid:17024371", "pmid:16989817", "pmid:16919418", "pmid:16857735", "pmid:16764889", "pmid:16644517", "pmid:16120311", "pmid:15376485", "pmid:15340363", "pmid:15233994", "pmid:15201464", "pmid:15180699", "pmid:14978261", "pmid:14962663", "pmid:12516053", "pmid:12112211", "pmid:11939898", "pmid:11843702", "pmid:11809170", "pmid:11428460", "pmid:11340071", "pmid:11325966", "pmid:11240567", "pmid:11071107", "pmid:11054139", "pmid:10982543", "pmid:10982187", "pmid:10969848", "pmid:10896266", "pmid:10732799", "pmid:10681084", "pmid:10556290", "pmid:10230399", "pmid:10102712", "pmid:10077729", "pmid:9811933", "pmid:9779809", "pmid:9737785", "pmid:9667602", "pmid:9577387", "pmid:9443873", "pmid:9486868", "pmid:9448568", "pmid:9416816", "pmid:9409356", "pmid:9326946", "pmid:9339708", "pmid:9339680", "pmid:9270667", "pmid:9270608", "pmid:9241271", "pmid:9177790", "pmid:9153531", "pmid:9153129", "pmid:10464657", "pmid:9331900", "pmid:8751856"] -}, -{ - "id": "OPDM2_GIPC1", - "disease_id": "OPDM2", - "gene": "GIPC1", - "chrom": "chr19", - "start_hg38": 14496041, - "stop_hg38": 14496075, - "start_hg19": 14606853, - "stop_hg19": 14606887, - "start_t2t": 14622655, - "stop_t2t": 14622692, - "disease": "Oculopharyngodistal myopathy type 2", - "inheritance": ["AD"], - "disease_description": "Ptosis, external ophthalmoplegia, facial weakness, and pharyngeal and distal limb weakness [@pmid:38876750]; Slowly progressive distal weakness, ophthalmoplegia, facial and bulbar weakness [@pmid:39349043].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Population dependent; presumed rare. Predominantly found in individuals of East Asian ancestry [@pmid:38876750].", - "age_onset": "Typical: 20-34 [@pmid:32413282]; Range: 14 [@pmid:32413282] - 70 [@pmid:33374016].", - "age_onset_min": 14.0, - "age_onset_max": 70.0, - "typ_age_onset_min": 20.0, - "typ_age_onset_max": 34.0, - "details": "Benign repeats range from absent [@gnomad:GIPC1] to 32 [@genereviews:NBK535148], while pathogenic alleles range from 73-164 repeats [@pmid:38876750; @genereviews:NBK535148]. Intermediate alleles have undetermined significance but may represent a phenotypic spectrum [@pmid:32413282]. Interruptions documented: CGA [@pmid:35245110]. Interruptions proposed but not confirmed in primary literature: TCG/CCT/TTG [@pmid:38467784].", - "mechanism": "LoF/GoF?", - "mechanism_detail": "RNA mediated toxicity hypothesized [@omim:618940], still unknown [@pmid:36169768].", - "year": "2020 [@pmid:32413282]", - "location_in_gene": "5' UTR", - "gene_strand": "-", - "reference_motif_reference_orientation": ["CCG"], - "pathogenic_motif_reference_orientation": ["CCG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CGG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 0, - "benign_max": 32, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 73, - "pathogenic_max": 164, - "motif_len": 3, - "ref_copies": 14.7, - "novel": "ref", - "gard": ["16397"], - "genereviews": ["NBK535148"], - "malacard": ["OCL080"], - "medgen": ["1718769"], - "mondo": ["0030134"], - "omim": ["618940"], - "orphanet": [], - "gnomad": ["GIPC1"], - "stripy": ["GIPC1"], - "tr_atlas": ["TR154638"], - "webstr_hg38": ["5626440"], - "webstr_hg19": ["STR_668861"], - "locus_tags": ["supported_evidence", "length_affects_onset", "length_affects_severity"], - "disease_tags": ["oculopharyngodistal_myopathy"], - "references": ["pmid:32413282", "pmid:33374016", "omim:618940", "pmid:36169768", "gnomad:GIPC1", "genereviews:NBK535148", "pmid:38876750", "pmid:35245110", "pmid:38467784", "pmid:39349043"], - "additional_literature": ["pmid:41121761", "pmid:40645757", "pmid:40084170", "pmid:39936620", "pmid:39492694", "pmid:39418922", "pmid:39013564", "pmid:38871700", "pmid:37923380", "pmid:37550168", "pmid:36108428", "pmid:36055118", "pmid:35700120", "pmid:35521937", "pmid:35314910", "pmid:35152460", "pmid:35148830", "pmid:34927285", "pmid:33693509", "pmid:33239111", "pmid:22521844"] -}, -{ - "id": "GDPAG_GLS", - "disease_id": "GDPAG", - "gene": "GLS", - "chrom": "chr2", - "start_hg38": 190880872, - "stop_hg38": 190880920, - "start_hg19": 191745598, - "stop_hg19": 191745646, - "start_t2t": 191369982, - "stop_t2t": 191370024, - "disease": "Glutaminase deficiency", - "inheritance": ["AR"], - "disease_description": "Glutaminase deficiency is characterized by refractory seizures, respiratory failure, brain abnormalities and death in the neonatal period, though milder cases with spastic ataxia-dysarthria have also been reported. This condition is caused by mutations in the glutaminase (GLS) gene [@mondo:0600001].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "As of 2019, only 7 cases total of GLS deficiency, including non-repeat. Identified unrelated patients have been Canadian [@pmid:30970188], Kurdish (Turkey) [@pmid:35913761], and US-American (Northern European/Native American descent [@pmid:35913761].", - "age_onset": "Early childhood (2-4) [@pmid:30970188; @pmid:35913761].", - "age_onset_min": 2.0, - "age_onset_max": 4.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "Pathogenic range from 3 unrelated probands; benign range inferred from mutation data [@genereviews:NBK535148]. Disease cases can be caused by homozygosity or compund heterozygotes [@omim:618412].", - "mechanism": "LoF", - "mechanism_detail": "Change in histone modification decreases transcription [@omim:618412].", - "year": "2019 [@pmid:30970188]", - "location_in_gene": "5' UTR", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GCA"], - "pathogenic_motif_reference_orientation": ["GCA"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["AGC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 5, - "benign_max": 38, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 680, - "pathogenic_max": 1500, - "motif_len": 3, - "ref_copies": 16.0, - "novel": "ref", - "gard": [], - "genereviews": ["NBK535148"], - "malacard": ["SPS235"], - "medgen": ["987241"], - "mondo": ["0600001"], - "omim": ["618412"], - "orphanet": ["557056"], - "gnomad": ["GLS"], - "stripy": ["GLS"], - "tr_atlas": ["TR24838"], - "webstr_hg38": ["333878", "5494902"], - "webstr_hg19": ["STR_803303"], - "locus_tags": ["supported_evidence"], - "disease_tags": [], - "references": ["pmid:30970188", "pmid:35913761", "omim:618412", "genereviews:NBK535148", "mondo:0600001"], - "additional_literature": ["pmid:40488180", "pmid:40417743", "pmid:39699045", "pmid:39651202", "pmid:38877099", "pmid:38871700", "pmid:38260514", "pmid:34285061", "pmid:34013182", "pmid:33691262", "pmid:33413375", "pmid:14510958", "pmid:7729621"] -}, -{ - "id": "HFG_HOXA13-I", - "disease_id": "HFG-I", - "gene": "HOXA13", - "chrom": "chr7", - "start_hg38": 27199924, - "stop_hg38": 27199966, - "start_hg19": 27239543, - "stop_hg19": 27239585, - "start_t2t": 27335912, - "stop_t2t": 27335954, - "disease": "Hand-foot-genital syndrome 1", - "inheritance": ["AD"], - "disease_description": "Hand-foot-genital syndrome (HFGS) is a very rare multiple congenital abnormality syndrome characterized by distal limb malformations and urogenital defects [@mondo:0007698].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Extremely rare, published cases generally European ancestry or unknown [@pmid:15385446; @pmid:17935235; @genereviews:NBK1423].", - "age_onset": "0 (birth)", - "age_onset_min": 0.0, - "age_onset_max": 0.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "Anticipation does not occur, and expansions appear fully penetrant [@genereviews:NBK1423].", - "mechanism": "LoF", - "mechanism_detail": "Polyalanine expansions leading to haploinsufficiency [@genereviews:NBK1423]", - "year": "2004 [@pmid:15385446]", - "location_in_gene": "Coding Exon 1", - "gene_strand": "-", - "reference_motif_reference_orientation": ["NGC"], - "pathogenic_motif_reference_orientation": ["NGC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CNG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 14, - "benign_max": 14, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 22, - "pathogenic_max": 22, - "motif_len": 3, - "ref_copies": 14.0, - "novel": "ref", - "gard": ["2594"], - "genereviews": ["NBK1423"], - "malacard": ["HND004"], - "medgen": ["331103"], - "mondo": ["0007698"], - "omim": ["140000"], - "orphanet": ["2438"], - "gnomad": ["HOXA13_1"], - "stripy": ["HOXA13_1"], - "tr_atlas": ["TR74138"], - "webstr_hg38": ["5679832"], - "webstr_hg19": ["STR_1311037"], - "locus_tags": ["limited_evidence"], - "disease_tags": ["hand_foot_genital_syndrome"], - "references": ["genereviews:NBK1423", "pmid:15385446", "pmid:17935235", "mondo:0007698"], - "additional_literature": ["pmid:32386547", "pmid:23532960", "pmid:19591980", "pmid:12414828", "pmid:11543619"] -}, -{ - "id": "HFG_HOXA13-II", - "disease_id": "HFG-II", - "gene": "HOXA13", - "chrom": "chr7", - "start_hg38": 27199825, - "stop_hg38": 27199861, - "start_hg19": 27239444, - "stop_hg19": 27239480, - "start_t2t": 27335813, - "stop_t2t": 27335849, - "disease": "Hand-foot-genital syndrome 2", - "inheritance": ["AD"], - "disease_description": "Hand-foot-genital syndrome (HFGS) is a very rare multiple congenital abnormality syndrome characterized by distal limb malformations and urogenital defects [@mondo:0007698].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Extremely rare, published cases generally European ancestry or unknown [@pmid:15385446; @pmid:17935235; @genereviews:NBK1423].", - "age_onset": "0 (birth)", - "age_onset_min": 0.0, - "age_onset_max": 0.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "Anticipation does not occur, and expansions appear fully penetrant [@genereviews:NBK1423].", - "mechanism": "LoF", - "mechanism_detail": "Polyalanine expansions leading to haploinsufficiency [@genereviews:NBK1423]", - "year": "2003 [@pmid:12676922]", - "location_in_gene": "Coding Exon 1", - "gene_strand": "-", - "reference_motif_reference_orientation": ["NGC"], - "pathogenic_motif_reference_orientation": ["NGC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CNG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 12, - "benign_max": 12, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 18, - "pathogenic_max": 18, - "motif_len": 3, - "ref_copies": 12.0, - "novel": "ref", - "gard": ["2594"], - "genereviews": ["NBK1423"], - "malacard": ["HND004"], - "medgen": ["331103"], - "mondo": ["0007698"], - "omim": ["140000"], - "orphanet": ["2438"], - "gnomad": ["HOXA13_2"], - "stripy": ["HOXA13_2"], - "tr_atlas": ["TR74137"], - "webstr_hg38": ["5679831"], - "webstr_hg19": ["STR_1311036"], - "locus_tags": ["limited_evidence"], - "disease_tags": ["hand_foot_genital_syndrome"], - "references": ["genereviews:NBK1423", "pmid:15385446", "pmid:17935235", "pmid:12676922", "mondo:0007698"], - "additional_literature": ["pmid:32386547", "pmid:23532960", "pmid:19591980", "pmid:12414828", "pmid:11543619"] -}, -{ - "id": "HFG_HOXA13-III", - "disease_id": "HFG-III", - "gene": "HOXA13", - "chrom": "chr7", - "start_hg38": 27199678, - "stop_hg38": 27199732, - "start_hg19": 27239297, - "stop_hg19": 27239351, - "start_t2t": 27335684, - "stop_t2t": 27335720, - "disease": "Hand-foot-genital syndrome 3", - "inheritance": ["AD"], - "disease_description": "Hand-foot-genital syndrome (HFGS) is a very rare multiple congenital abnormality syndrome characterized by distal limb malformations and urogenital defects [@mondo:0007698].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Extremely rare, published cases generally European ancestry or unknown [@pmid:15385446; @pmid:17935235; @genereviews:NBK1423].", - "age_onset": "0 (birth)", - "age_onset_min": 0.0, - "age_onset_max": 0.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "Anticipation does not occur, and expansions appear fully penetrant; it is unknown if contractions also lead to phenotypic variation [@genereviews:NBK1423].", - "mechanism": "LoF", - "mechanism_detail": "Polyalanine expansions leading to haploinsufficiency [@genereviews:NBK1423]", - "year": "2000 [@pmid:10839976]", - "location_in_gene": "Coding Exon 1", - "gene_strand": "-", - "reference_motif_reference_orientation": ["NGC"], - "pathogenic_motif_reference_orientation": ["NGC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CNG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 8, - "benign_max": 18, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 22, - "pathogenic_max": 32, - "motif_len": 3, - "ref_copies": 18.0, - "novel": "ref", - "gard": ["2594"], - "genereviews": ["NBK1423"], - "malacard": ["HND004"], - "medgen": ["331103"], - "mondo": ["0007698"], - "omim": ["140000"], - "orphanet": ["2438"], - "gnomad": ["HOXA13_3"], - "stripy": ["HOXA13_3"], - "tr_atlas": ["TR74136"], - "webstr_hg38": ["1365344"], - "webstr_hg19": ["STR_1311035"], - "locus_tags": ["limited_evidence"], - "disease_tags": ["hand_foot_genital_syndrome"], - "references": ["genereviews:NBK1423", "pmid:15385446", "pmid:17935235", "pmid:10839976", "mondo:0007698"], - "additional_literature": ["pmid:32386547", "pmid:23532960", "pmid:19591980", "pmid:12414828", "pmid:11543619"] -}, -{ - "id": "SD5_HOXD13", - "disease_id": "SD5", - "gene": "HOXD13", - "chrom": "chr2", - "start_hg38": 176093058, - "stop_hg38": 176093103, - "start_hg19": 176957786, - "stop_hg19": 176957831, - "start_t2t": 176581179, - "stop_t2t": 176581224, - "disease": "Syndactyly", - "inheritance": ["AD"], - "disease_description": "Synpolydactyly (SPD), or syndactyly type II, is defined as a connection between the middle and ring fingers and fourth and fifth toes, variably associated with postaxial polydactyly in the same digits. Minor local anomalies and various metacarpal or metatarsal abnormalities may be present [@omim:186000].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Syndactyly is found across dozens of unrelated families worldwide [@pmid:24038517]. However, syndactyly-5 specific to STR expansion has been found in 3 individuals [@genereviews:NBK535148].", - "age_onset": "0 (birth)", - "age_onset_min": 0.0, - "age_onset_max": 0.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "Benign alleles are highly conserved to be 15 repeats, with disease observed in individuals with 22-23 repeats [@pmid:8614804; @pmid:22406499] as well as in individuals with 8-11 repeats [@genereviews:NBK535148].", - "mechanism": "GoF", - "mechanism_detail": "Polyalanine expansion leading to GoF [@pmid:38467784]", - "year": "1996 [@pmid:8614804]", - "location_in_gene": "Coding Exon 1", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GCN"], - "pathogenic_motif_reference_orientation": ["GCN"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CNG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 15, - "benign_max": 15, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 22, - "pathogenic_max": 23, - "motif_len": 3, - "ref_copies": 14.0, - "novel": "ref", - "gard": ["17358"], - "genereviews": ["NBK535148"], - "malacard": ["SYN084"], - "medgen": ["1809573"], - "mondo": ["0008513"], - "omim": ["186000"], - "orphanet": ["295195"], - "gnomad": ["HOXD13"], - "stripy": ["HOXD13"], - "tr_atlas": ["TR24032"], - "webstr_hg38": ["5486677"], - "webstr_hg19": ["STR_796395"], - "locus_tags": ["supported_evidence", "contraction"], - "disease_tags": [], - "references": ["pmid:38467784", "pmid:8614804", "pmid:22406499", "genereviews:NBK535148", "pmid:24038517", "omim:186000"], - "additional_literature": ["pmid:34159400", "pmid:32652111", "pmid:32386547", "pmid:19841179", "pmid:19546318", "pmid:17935235", "pmid:12414828", "pmid:12116248", "pmid:11543619"] -}, -{ - "id": "HD_HTT", - "disease_id": "HD", - "gene": "HTT", - "chrom": "chr4", - "start_hg38": 3074876, - "stop_hg38": 3074933, - "start_hg19": 3076603, - "stop_hg19": 3076660, - "start_t2t": 3073603, - "stop_t2t": 3073687, - "disease": "Huntington disease", - "inheritance": ["AD"], - "disease_description": "Huntington disease (HD) is a rare neurodegenerative disorder of the central nervous system characterized by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia [@mondo:0007739].", - "hpo_terms": null, - "prevalence": "1/10000", - "prevalence_details": "6.5-15/100,000 [@pmid:29100084]. 9.71-17:100,000 (European) vs. 0.1-2/100,000 (African), as many as 1 in 400 have reduced penetrance (0.2-2% for 36-38 CAG) HTT alleles [@genereviews:NBK1305]. Found across ethnicities/ancestries, with population-dependent prevalence [@genereviews:NBK1305].", - "age_onset": "Typical: 35-44 [@genereviews:NBK1305]; Range: 1-85 [@pmid:39441074; @pmid:21171977].", - "age_onset_min": 1.0, - "age_onset_max": 85.0, - "typ_age_onset_min": 35.0, - "typ_age_onset_max": 44.0, - "details": "27-35 motifs are unstable/premutations, while 36-39 motifs are associated with reduced penetrance and mild phenotypes [@pmid:39572770], and alleles over 40 repeats are typically fully penetrant [@genereviews:NBK1305]. >60 motifs associated with onset age <20 years [@genereviews:NBK1305]. Only CAG expansions are considered pathogenic, but interruptions impact pathogenicity (e.g. CAA) [@pmid:35245110]. Only fathers with premutations are considered at risk of transmitting pathogenic alleles [@pmid:19507258]. CAG repeats in the non-HD range (>= 21 repeats) may modulate psychiatric disease risk in an age-dependent manner [@pmid:39572770]", - "mechanism": "GoF/LoF", - "mechanism_detail": "While the primary pathogenic mechanism is gain of function of the protein product, pathogenesis is complex and multifactorial [@pmid:27940602].", - "year": "1993 [@pmid:8458085]", - "location_in_gene": "Coding Exon 1", - "gene_strand": "+", - "reference_motif_reference_orientation": ["CAG"], - "pathogenic_motif_reference_orientation": ["CAG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["AGC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [ + "id": "SCA36_NOP56", + "disease_id": "SCA36", + "gene": "NOP56", + "chrom": "chr20", + "start_hg38": 2652732, + "stop_hg38": 2652757, + "start_hg19": 2633378, + "stop_hg19": 2633403, + "start_t2t": 2683189, + "stop_t2t": 2683230, + "disease": "Spinocerebellar ataxia type 36", + "inheritance": [ + "AD" + ], + "disease_description": "Spinocerebellar ataxia type 36 (SCA36) is a subtype of autosomal dominant cerebellar ataxia type 1 (ADCA type 1) characterized by gait and limb ataxia, lower limb spasticity, dysarthria, muscle fasiculations, tongue atrophy and hyperreflexia [@mondo:0013594].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Western Japan: 3.6% of all SCA; Costa da Morte region of Spain: 6.3% of all SCA [@pmid:37332636]; US: 0.7% of large undiagnosed ataxia cohort [@pmid:28761930]. Found across ancestries/ethnicities [@omim:614153].", + "age_onset": "Typical: 40-60 [@pmid:25101480]; Range: 28 [@pmid:37810464] - 67 [@pmid:37332636].", + "age_onset_min": 28, + "age_onset_max": 67, + "typ_age_onset_min": 40, + "typ_age_onset_max": 60, + "details": "Benign alleles range from 3-14 repeats and pathogenic alleles (650+ repeats) appear fully penetrant; the significance of intermediate alleles has yet to be elucidated [@pmid:25101480]. Interruptions documented: GGCTG, GGCCCTG, GGCCG, and GGCCTTG [@pmid:37051597].", + "mechanism": "GoF", + "mechanism_detail": "Toxic protein gain-of-function, RAN translation [@omim:614153].", + "year": "2011 [@pmid:21683323]", + "location_in_gene": "Intron 1", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GGCCTG" + ], + "pathogenic_motif_reference_orientation": [ + "GGCCTG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CCTGGG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [ + { + "motif": "GGCCTG", + "count": null, + "type": "pathogenic_repeat" + }, + { + "motif": "CGCCTG", + "count": 3, + "type": "flank_repeat" + } + ], + "benign_min": 3, + "benign_max": 14, + "intermediate_min": 15, + "intermediate_max": 649, + "pathogenic_min": 650, + "pathogenic_max": 2500, + "motif_len": 6, + "ref_copies": 7.2, + "novel": "ref", + "gard": [ + "12367" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "SPN265" + ], + "medgen": [ + "483339" + ], + "mondo": [ + "0013594" + ], + "omim": [ + "614153" + ], + "orphanet": [ + "276198" + ], + "gnomad": [ + "NOP56" + ], + "stripy": [ + "NOP56" + ], + "tr_atlas": [ + "TR157810", + "TR157811" + ], + "webstr_hg38": [ + "6177296", + "890490" + ], + "webstr_hg19": [ + "STR_833720" + ], + "locus_tags": [ + "supported_evidence", + "somatic_instability", + "length_affects_onset", + "length_affects_severity" + ], + "disease_tags": [ + "spinocerebellar_ataxia" + ], + "references": [ + "pmid:25101480", + "pmid:37810464", + "pmid:37332636", + "omim:614153", + "pmid:37051597", + "pmid:28761930", + "pmid:21683323", + "mondo:0013594" + ], + "additional_literature": [ + "pmid:41337098", + "pmid:41074692", + "pmid:40898875", + "pmid:40765612", + "pmid:40488180", + "pmid:40015643", + "pmid:40004498", + "pmid:38961870", + "pmid:38934198", + "pmid:38811808", + "pmid:38667292", + "pmid:38227102", + "pmid:36599645", + "pmid:36572080", + "pmid:36530930", + "pmid:35599735", + "pmid:35077744", + "pmid:34179866", + "pmid:33705846", + "pmid:32989102", + "pmid:32407596", + "pmid:32375063", + "pmid:32375043", + "pmid:32270466", + "pmid:31737797", + "pmid:30610877", + "pmid:30109267", + "pmid:29316893", + "pmid:29281254", + "pmid:28918022", + "pmid:27123487", + "pmid:26661328", + "pmid:25476002", + "pmid:24985895", + "pmid:24269018", + "pmid:22744658", + "pmid:22492559" + ] + }, { - "motif": "CAG", - "count": null, - "type": "pathogenic_repeat" + "id": "NIID_NOTCH2NLC", + "disease_id": "NIID", + "gene": "NOTCH2NLC", + "chrom": "chr1", + "start_hg38": 149390802, + "stop_hg38": 149390842, + "start_hg19": 145209323, + "stop_hg19": 145209354, + "start_t2t": 148519695, + "stop_t2t": 148519738, + "disease": "Neuronal intranuclear inclusion disease, Alzheimer disease and parkinsonism phenotype, Oculopharyngodistal myopathy (OPDM) type 3, Hereditary essential tremor type 6", + "inheritance": [ + "AD" + ], + "disease_description": "Neuronal intranuclear inclusion disease (NIID) is a very rare multisystem neurodegenerative disorder characterized by the presence of eosinophilic intranuclear inclusions in neuronal and glial cells, and neuronal loss [@mondo:0011327].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": ">400 patients reported in literature [@pmid:37371433]. Found in individuals of East Asian ancestry [@pmid:38876750].", + "age_onset": "Typical: 30-70 [@omim:603472]; Range: 10 [@pmid:37090934] - 78 [@pmid:37305750].", + "age_onset_min": 10, + "age_onset_max": 78, + "typ_age_onset_min": 30, + "typ_age_onset_max": 70, + "details": "Benign alleles are less than 38 repeats, while pathogenic alleles contain 66+ repeats [@genereviews:NBK535148]. Intermediate alleles may be associated with a phenotypic spectrum, and even pathogenic cases can have variable phenotype [@pmid:39055960; @pmid:39496005]: NOTCH2NLC expansions have been linked Alzheimer's disease and Parkinson's disease, leading to a potential role in NIID-related disorders [@pmid:31178126]. Age of onset inversely related to allele size [@pmid:38377026]. Motif variation in controls: (AGG)(CGG)n(AGG)0-3(CGG)0-2. GGA and AGC interruptions may influence phenotype [@pmid:34718964]. Interruptions documented: GGA, GGG [@pmid:35245110]; ACCGAGAAGATGCCCGCCCTGC interruption proposed but not confirmed [@pmid:38467784]. Detection may be challenging due to parology between genes: C253572.1, NOTCH2, NOTCH2NL, NBPF14, NBPF19.", + "mechanism": "GoF", + "mechanism_detail": "Polyglycine expansion; may relate to methylation or RNA pathogenicity [@omim:603472; @pmid:36169768; @pmid:38467784]. The polyglycine-containing protein sequesters a key subunit of transcription factor NF-κB in nuclear inclusions, leading to impaired autophagy [@doi:10.1186/s12964-025-02079-1].", + "year": "2019 [@pmid:31332380]", + "location_in_gene": "5' UTR", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GGC" + ], + "pathogenic_motif_reference_orientation": [ + "GGC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CGG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 7, + "benign_max": 37, + "intermediate_min": 38, + "intermediate_max": 65, + "pathogenic_min": 66, + "pathogenic_max": 517, + "motif_len": 3, + "ref_copies": 13.3, + "novel": "ref", + "gard": [ + "3971" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "NRN008" + ], + "medgen": [ + "355075" + ], + "mondo": [ + "0011327" + ], + "omim": [ + "603472", + "619473", + "618866" + ], + "orphanet": [ + "2289" + ], + "gnomad": [ + "NOTCH2NLC" + ], + "stripy": [ + "NOTCH2NLC" + ], + "tr_atlas": [ + "TR7525" + ], + "webstr_hg38": [], + "webstr_hg19": [], + "locus_tags": [ + "supported_evidence", + "somatic_instability", + "paternal_expansion", + "length_affects_onset", + "length_affects_phenotype", + "motif_affects_onset", + "motif_affects_phenotype" + ], + "disease_tags": [ + "phenotypic_spectrum" + ], + "references": [ + "omim:603472", + "pmid:37090934", + "pmid:37305750", + "pmid:36169768", + "pmid:38467784", + "doi:10.1186/s12964-025-02079-1", + "genereviews:NBK535148", + "pmid:39055960", + "pmid:39496005", + "pmid:31178126", + "pmid:38377026", + "pmid:34718964", + "pmid:35245110", + "pmid:37371433", + "pmid:38876750", + "pmid:31332380", + "mondo:0011327" + ], + "additional_literature": [ + "pmid:41235412", + "pmid:41154122", + "pmid:41074692", + "pmid:40934004", + "pmid:40879637", + "pmid:40765612", + "pmid:40708231", + "pmid:40645757", + "pmid:40635536", + "pmid:40609325", + "pmid:40517194", + "pmid:40515658", + "pmid:40514451", + "pmid:40267536", + "pmid:40084170", + "pmid:39936620", + "pmid:39920690", + "pmid:39609868", + "pmid:39529621", + "pmid:39505310", + "pmid:39492694", + "pmid:39418922", + "pmid:39167540", + "pmid:39078482", + "pmid:38779172", + "pmid:38709391", + "pmid:38667292", + "pmid:38579412", + "pmid:38477063", + "pmid:38288273", + "pmid:38145851", + "pmid:37975799", + "pmid:37923380", + "pmid:37864208", + "pmid:37823700", + "pmid:37644522", + "pmid:37365282", + "pmid:37271829", + "pmid:37237429", + "pmid:37184590", + "pmid:37131242", + "pmid:37001413", + "pmid:36948577", + "pmid:36942588", + "pmid:36825461", + "pmid:36823368", + "pmid:36809423", + "pmid:36715780", + "pmid:36672065", + "pmid:36621630", + "pmid:36588885", + "pmid:36570826", + "pmid:36545534", + "pmid:36483830", + "pmid:36458450", + "pmid:36417528", + "pmid:36263606", + "pmid:36216675", + "pmid:36207023", + "pmid:36191230", + "pmid:36172483", + "pmid:36150977", + "pmid:36086903", + "pmid:36061987", + "pmid:36041634", + "pmid:36033605", + "pmid:35974122", + "pmid:35866887", + "pmid:35857137", + "pmid:35838850", + "pmid:35788208", + "pmid:35772299", + "pmid:35700120", + "pmid:35419641", + "pmid:35411397", + "pmid:35402653", + "pmid:35366689", + "pmid:35314910", + "pmid:35297556", + "pmid:35180462", + "pmid:35152460", + "pmid:35148830", + "pmid:35147270", + "pmid:34927285", + "pmid:34797461", + "pmid:34774111", + "pmid:34750918", + "pmid:34694469", + "pmid:34675106", + "pmid:34641814", + "pmid:34392981", + "pmid:34306035", + "pmid:34243731", + "pmid:34054431", + "pmid:34017298", + "pmid:33943039", + "pmid:33887199", + "pmid:33871559", + "pmid:33871549", + "pmid:33766934", + "pmid:33693509", + "pmid:33679585", + "pmid:33626493", + "pmid:33625684", + "pmid:33388663", + "pmid:33377220", + "pmid:33377207", + "pmid:33239111", + "pmid:33201994", + "pmid:33201988", + "pmid:33146692", + "pmid:33146671", + "pmid:33026126", + "pmid:33016348", + "pmid:32989102", + "pmid:32931575", + "pmid:32852534", + "pmid:32827029", + "pmid:32817896", + "pmid:32777174", + "pmid:32768149", + "pmid:32602554", + "pmid:32535679", + "pmid:32516806", + "pmid:32495371", + "pmid:32449905", + "pmid:32268889", + "pmid:32250060", + "pmid:32081467", + "pmid:32039647", + "pmid:31886491", + "pmid:31819945", + "pmid:31433517", + "pmid:31413119", + "pmid:31332381" + ] }, { - "motif": "CAACAG", - "count": 1, - "type": "interruption" + "id": "OPML1_NUTM2B-AS1", + "disease_id": "OPML1", + "gene": "NUTM2B-AS1", + "chrom": "chr10", + "start_hg38": 79826383, + "stop_hg38": 79826404, + "start_hg19": 81586139, + "stop_hg19": 81586160, + "start_t2t": 80695718, + "stop_t2t": 80695748, + "disease": "Oculopharyngeal myopathy with leukoencephalopathy 1", + "inheritance": [ + "AD" + ], + "disease_description": "Oculopharyngodistal myopathy and white matter abnormalities [@pmid:38876750]; Ptosis, ophthalmoplegia, dysphagia, dysarthria [@pmid:39349043].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Rare, found in individuals of East Asian ancestry [@pmid:38876750].", + "age_onset": "15-40 (only characterized in one family) [@pmid:31332380].", + "age_onset_min": 15, + "age_onset_max": 40, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "Benign range (3-16 repeats) established in 1000 controls, studied alongside pathogenic probands of up to 700 repeats [@pmid:31332380]. Pathogenicity occurs at repeats as short as 161 motifs [@pmid:38159879; @pmid:37923380], while intermediate alleles may correlate to milder phenotypes [@pmid:38159879]. Alt transcript in opposite direction: LOC642361.", + "mechanism": "GoF?", + "mechanism_detail": "RNA mediated toxicity hypothesized, overall mechanism unknown [@omim:618637; @pmid:36169768].", + "year": "2019 [@pmid:31332380]", + "location_in_gene": "Exon 1 of lncRNA (noncoding)", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GGC" + ], + "pathogenic_motif_reference_orientation": [ + "GGC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CGG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 3, + "benign_max": 16, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 161, + "pathogenic_max": 700, + "motif_len": 3, + "ref_copies": 7, + "novel": "ref", + "gard": [], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "OCL077" + ], + "medgen": [ + "1684701" + ], + "mondo": [ + "0032843" + ], + "omim": [ + "618637" + ], + "orphanet": [], + "gnomad": [ + "NUTM2B-AS1" + ], + "stripy": [ + "NUTM2B-AS1" + ], + "tr_atlas": [ + "TR102881" + ], + "webstr_hg38": [], + "webstr_hg19": [ + "STR_173942" + ], + "locus_tags": [ + "supported_evidence", + "length_affects_severity", + "length_affects_phenotype" + ], + "disease_tags": [], + "references": [ + "pmid:31332380", + "omim:618637", + "pmid:36169768", + "pmid:38159879", + "pmid:37923380", + "pmid:38876750", + "pmid:39349043" + ], + "additional_literature": [ + "pmid:40645757", + "pmid:39308795", + "pmid:35152460" + ] }, { - "motif": "CCG", - "count": 12, - "type": "flank_repeat" - }], - "benign_min": 6, - "benign_max": 26, - "intermediate_min": 27, - "intermediate_max": 35, - "pathogenic_min": 36, - "pathogenic_max": 250, - "motif_len": 3, - "ref_copies": 21.3, - "novel": "ref", - "gard": ["6677"], - "genereviews": ["NBK1305"], - "malacard": ["HNT016"], - "medgen": ["5654"], - "mondo": ["0007739"], - "omim": 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"pmid:8735227", "pmid:8643525", "pmid:8678115", "pmid:8606810", "pmid:8714530", "pmid:8614526", "pmid:8985734", "pmid:8954302", "pmid:8840396", "pmid:8766138", "pmid:8572659", "pmid:8557266", "pmid:7477379", "pmid:8804464", "pmid:7576661", "pmid:7568002", "pmid:8544189", "pmid:8541834", "pmid:7668287", "pmid:7668260", "pmid:7639626", "pmid:7484060", "pmid:7480359", "pmid:7774020", "pmid:7675777", "pmid:7898693", "pmid:7868117", "pmid:7634532", "pmid:7757069", "pmid:9173995", "pmid:7881406", "pmid:7969980", "pmid:7959696", "pmid:7853373", "pmid:7915776", "pmid:7815437", "pmid:8208412", "pmid:8178825", "pmid:8064815", "pmid:7909529", "pmid:8162059", "pmid:8162055", "pmid:8162053", "pmid:8044653", "pmid:7888133", "pmid:7865169", "pmid:8133511", "pmid:8133510", "pmid:8133508", "pmid:8133495", "pmid:8111374", "pmid:8087617", "pmid:8105214", "pmid:8268906", "pmid:8252042", "pmid:8242074", "pmid:8401589", "pmid:8401588", "pmid:8401587", "pmid:2521771", "pmid:2971929", "pmid:3131233"] -}, -{ - "id": "HDL2_JPH3", - "disease_id": "HDL2", - "gene": "JPH3", - "chrom": "chr16", - "start_hg38": 87604282, - "stop_hg38": 87604329, - "start_hg19": 87637888, - "stop_hg19": 87637935, - "start_t2t": 93675723, - "stop_t2t": 93675776, - "disease": "Huntington disease-like 2", - "inheritance": ["AD"], - "disease_description": "Huntington disease-like 2 (HDL2) is a severe neurodegenerative disorder considered part of the neuroacanthocytosis syndromes characterized by a triad of movement, psychiatric, and cognitive abnormalities [@mondo:0011671].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "<1/1,000,000 [@orphanet:98934]. Largely in individuals of African ancestry [@genereviews:NBK1529], where a possible JPH3 founder mutation has been identified [@pmid:40187026].", - "age_onset": "Typical: 30-52; Range: 12-66 [@genereviews:NBK1529].", - "age_onset_min": 12.0, - "age_onset_max": 66.0, - "typ_age_onset_min": 30.0, - "typ_age_onset_max": 52.0, - "details": "Intermediate alleles (29-39) may either be premutations or associated with reduced penetrance; the longest pathogenic expansion (40+ motifs) to date is 60 repeats [@genereviews:NBK1529]", - "mechanism": "LoF/GoF", - "mechanism_detail": "Non-mutually exclusive mechanisms include loss of function from RNA sequestration and gain of function from toxic transcripts and increased protein expression [@genereviews:NBK1529]", - "year": "2001 [@pmid:11694876]", - "location_in_gene": "Coding Exon 2", - "gene_strand": "+", - "reference_motif_reference_orientation": ["CTG"], - "pathogenic_motif_reference_orientation": ["CTG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CTG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 6, - "benign_max": 28, - "intermediate_min": 29, - "intermediate_max": 39, - "pathogenic_min": 40, - "pathogenic_max": 60, - "motif_len": 3, - "ref_copies": 15.6667, - "novel": "ref", - "gard": ["16874"], - "genereviews": ["NBK1529"], - "malacard": ["HNT004"], - "medgen": ["341120"], - "mondo": ["0011671"], - "omim": ["606438"], - "orphanet": ["98934"], - "gnomad": ["JPH3"], - "stripy": ["JPH3"], - "tr_atlas": ["TR143309"], - "webstr_hg38": ["828516", "5987878"], - "webstr_hg19": ["Expansion_HDL2/JPH3"], - "locus_tags": ["supported_evidence", "somatic_instability", "length_affects_phenotype", "length_affects_onset", "length_affects_penetrance", "length_affects_severity"], - "disease_tags": [], - "references": ["genereviews:NBK1529", "orphanet:98934", "pmid:40187026", "pmid:11694876", "mondo:0011671"], - "additional_literature": ["pmid:41074680", "pmid:40914005", "pmid:38948793", "pmid:38725192", "pmid:38617831", "pmid:37379724", "pmid:35926480", "pmid:33824468", "pmid:33044188", "pmid:32675418", "pmid:32028232", "pmid:30682531", "pmid:30615214", "pmid:29801887", "pmid:29208631", "pmid:29066237", "pmid:27400454", "pmid:27288455", "pmid:26079385", "pmid:24269018", "pmid:22447335", "pmid:22367996", "pmid:22297462", "pmid:21555070", "pmid:17516481", "pmid:16858508", "pmid:15764008", "pmid:15468075", "pmid:14557581", "pmid:12805114", "pmid:11906164"] -}, -{ - "id": "OPDM1_LRP12", - "disease_id": "OPDM1", - "gene": "LRP12", - "chrom": "chr8", - "start_hg38": 104588970, - "stop_hg38": 104588999, - "start_hg19": 105601198, - "stop_hg19": 105601227, - "start_t2t": 105716409, - "stop_t2t": 105716441, - "disease": "Oculopharyngodistal myopathy type 1", - "inheritance": ["AD"], - "disease_description": "Adult-onset ptosis, dysphagia [@pmid:39349043]; External ophthalmoplegia, facial weakness, pharyngeal, and distal limb weakness [@pmid:38876750]; May be slight male predominance [@pmid:34047774].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Population dependent; unknown percentage of LRP12 pathogenic variants. Typically East Asian ancestry [@pmid:38876750]; potentially most frequent cause of OPDM in Japan [@pmid:34047774].", - "age_onset": "Typical: 31-51 [@pmid:34047774]; Range: 7-66 [@pmid:2124290].", - "age_onset_min": 7.0, - "age_onset_max": 66.0, - "typ_age_onset_min": 31.0, - "typ_age_onset_max": 51.0, - "details": "Benign range (13-45) inferred from cohort data, but pathogenic range isn't yet fully understood [@genereviews:NBK535148]. In a cohort of 65 patients from 59 families, alleles ranged from 85-289 repeats, with an inverse relationship between size and age of onset [@pmid:34047774]. Inherited peripheral neuropathy (IPN) may be associated with shorter expansions [@pmid:39013564]. Interruptions seen: ACG, CCA [@pmid:35245110].", - "mechanism": "GoF?", - "mechanism_detail": "RNA mediated toxicity hypothesized [@omim:164310]; may involve RAN translation [@pmid:38467784]. Somatic mosicism and hypermethylation have also been reported [@pmid:41131788].", - "year": "2019 [@pmid:31332380]", - "location_in_gene": "5' UTR", - "gene_strand": "-", - "reference_motif_reference_orientation": ["CGC"], - "pathogenic_motif_reference_orientation": ["CGC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CGG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 13, - "benign_max": 45, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 85, - "pathogenic_max": 289, - "motif_len": 3, - "ref_copies": 11.7, - "novel": "ref", - "gard": ["15097"], - "genereviews": ["NBK535148"], - "malacard": ["OCL076"], - "medgen": ["1684682"], - "mondo": ["0020793"], - "omim": ["164310"], - "orphanet": ["98897"], - "gnomad": ["LRP12"], - "stripy": ["LRP12"], - "tr_atlas": ["TR88348"], - "webstr_hg38": ["1082178", "4874587"], - "webstr_hg19": ["STR_1441036"], - "locus_tags": ["supported_evidence", "somatic_instability", "anticipation", "length_affects_onset"], - "disease_tags": ["oculopharyngodistal_myopathy"], - "references": ["pmid:34047774", "pmid:2124290", "omim:164310", "pmid:38467784", "pmid:41131788", "genereviews:NBK535148", "pmid:39013564", "pmid:35245110", "pmid:38876750", "pmid:31332380", "pmid:39349043"], - "additional_literature": ["pmid:41125376", "pmid:40645757", "pmid:40417202", "pmid:40084170", "pmid:38726482", "pmid:37923380", "pmid:37864208", "pmid:37339631", "pmid:36052448", "pmid:35700120", "pmid:35314910", "pmid:35152460", "pmid:35148830", "pmid:34927285", "pmid:33693509", "pmid:33374016", "pmid:33239111", "pmid:32493488", "pmid:27072820"] -}, -{ - "id": "FAME3_MARCHF6", - "disease_id": "FAME3", - "gene": "MARCHF6", - "chrom": "chr5", - "start_hg38": 10356343, - "stop_hg38": 10356411, - "start_hg19": 10356455, - "stop_hg19": 10356523, - "start_t2t": 10295525, - "stop_t2t": 10295593, - "disease": "Familial adult myoclonic epilepsy type 3", - "inheritance": ["AD"], - "disease_description": "Cortical tremor, seizures with generalised motor (tonic-clonic) onset [@pmid:38876750]; Adult-onset cortical tremor with epilepsy [@pmid:39349043].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Overall FAME prevalence is < 1/35,000; MARCHF6-caused much smaller. Most cases have European ancestry [@pmid:38876750].", - "age_onset": "Typical: 24-41 based on one 76 member pedigree [@pmid:19616813]; Range: 10 [@omim:613608] - 50 [@pmid:40788430].", - "age_onset_min": 10.0, - "age_onset_max": 50.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "Healthy controls do not have pathogenic allele (TTTCA), but do have 9-20 benign motifs (TTTTA) [@genereviews:NBK535148]. Total allele size in probands spanned from 650-1035 repeats; an inverse relationship between allele size and age of onset was noted [@pmid:31664039, @pmid:40788430]. In one study it was proposed that pathogenicity only occurs when TTTCA is expanded [@pmid: 40788430].", - "mechanism": "Unknown", - "mechanism_detail": "Noted as unknown in literature [@omim:613608].", - "year": "2019 [@pmid:31664039]", - "location_in_gene": "Intron 1", - "gene_strand": "+", - "reference_motif_reference_orientation": ["TTTTA"], - "pathogenic_motif_reference_orientation": ["TTTCA"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": ["ATGTT", "TAGTT", "TTTTG", "TTTTT"], - "pathogenic_motif_gene_orientation": ["ATTTC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": ["ATGTT", "AGTTT", "GTTTT", "TTTTT"], - "locus_structure": [ + "id": "OPMD_PABPN1", + "disease_id": "OPMD", + "gene": "PABPN1", + "chrom": "chr14", + "start_hg38": 23321472, + "stop_hg38": 23321503, + "start_hg19": 23790681, + "stop_hg19": 23790712, + "start_t2t": 17522488, + "stop_t2t": 17522519, + "disease": "Oculopharyngeal muscular dystrophy", + "inheritance": [ + "AD", + "AR" + ], + "disease_description": "Ptosis and dysphagia [@pmid:39349043]; facial weakness, ptosis [@pmid:38876750].", + "hpo_terms": null, + "prevalence": "1/100000", + "prevalence_details": "1/100,000 (population specific) [@pmid:29100084]. Frequency of (GCN)11 alleles is 1-2% of North America/Europe/Japan [@genereviews:NBK1126]. Disease is found worldwide, in more than 30 countries [@genereviews:NBK1126].", + "age_onset": "Typical: 40-59 [@pmid:37519616]; Range: 20-79 [@pmid:35112761].", + "age_onset_min": 20, + "age_onset_max": 79, + "typ_age_onset_min": 40, + "typ_age_onset_max": 59, + "details": "Disease is caused by a GCN polyalanine expansion in the first exon of PABPN1. Most known patients have (GCG)+, but GCN (any polyalanine) may be pathogenic [@genereviews:NBK1126]. This locus acts in a dominant manner for allele sizes ≥ 12 GCN motifs (90% of cases) and in a recessive manner for 11 GCN motifs, i.e. the genotype (GCN)11(GCN)11 (10% of cases). Additionally, disease is known to be more severe in cases of two expanded alleles. Age of onset is inverse to allele size, while penetrance and severity increase with allele size [@genereviews:NBK1126]. Mild, late-onset disease can occur in individuals with a (GCN)10(GCN)11 genotype, suggesting variable penetrance [@pmid:28011929]. The definition of this locus differs in the literature with prior work counting exact GCG motifs for a benign size of (GCG)6 [@pmid:9462747], while later resources count GCNs (any alanine codon), widening the region by 4 motifs to a benign size of (GCN)10 [@genereviews:NBK1126; @pmid:39349043]. STRchive is using the GCN definition.", + "mechanism": "GoF/LoF", + "mechanism_detail": "Polyalanine expansions leading to cellular toxicity (loss of function) as well as abnormal aggregation and inefficient protein degradation, which may impact mRNA processing [@genereviews:NBK1126].", + "year": "1998 [@pmid:9462747]", + "location_in_gene": "Coding Exon 1", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GCN" + ], + "pathogenic_motif_reference_orientation": [ + "GCN" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CNG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 10, + "benign_max": 10, + "intermediate_min": 11, + "intermediate_max": 11, + "pathogenic_min": 12, + "pathogenic_max": 18, + "motif_len": 3, + "ref_copies": 7, + "novel": "ref", + "gard": [ + "7245" + ], + "genereviews": [ + "NBK1126" + ], + "malacard": [ + "OCL088" + ], + "medgen": [ + "1054618" + ], + "mondo": [ + "0958176" + ], + "omim": [ + "164300" + ], + "orphanet": [ + "270" + ], + "gnomad": [ + "PABPN1" + ], + "stripy": [ + "PABPN1" + ], + "tr_atlas": [ + "TR128439" + ], + "webstr_hg38": [ + "1442709", + "5271481" + ], + "webstr_hg19": [ + "Expansion_OPMD/PAPBN1" + ], + "locus_tags": [ + "supported_evidence", + "length_affects_onset", + "length_affects_severity" + ], + "disease_tags": [], + "references": [ + "pmid:37519616", + "pmid:35112761", + "genereviews:NBK1126", + "pmid:28011929", + "pmid:9462747", + "pmid:39349043", + "pmid:29100084", + "pmid:38876750" + ], + "additional_literature": [ + "pmid:40594369", + "pmid:40552959", + "pmid:40220918", + "pmid:39113268", + "pmid:38165364", + "pmid:37698929", + "pmid:37559347", + "pmid:36790141", + "pmid:35859342", + "pmid:34927285", + "pmid:34225694", + "pmid:34047774", + "pmid:31294444", + "pmid:30455479", + "pmid:28361972", + "pmid:27980005", + "pmid:26428746", + "pmid:23793615", + "pmid:23399899", + "pmid:22519734", + "pmid:21742497", + "pmid:21647273", + "pmid:21602480", + "pmid:21316245", + "pmid:19641605", + "pmid:19101703", + "pmid:18481858", + "pmid:18367172", + "pmid:18343218", + "pmid:17138075", + "pmid:16648376", + "pmid:16642034", + "pmid:16481821", + "pmid:16378590", + "pmid:16239242", + "pmid:15811916", + "pmid:15755680", + "pmid:15725589", + "pmid:15645184", + "pmid:14627730", + "pmid:12673802", + "pmid:11712939", + "pmid:11304042", + "pmid:11222452", + "pmid:11150975", + "pmid:11087766", + "pmid:11003790", + "pmid:10734263", + "pmid:10680791", + "pmid:9084936" + ] + }, { - "motif": "TTTTA", - "count": 12, - "type": "internal_repeat" + "id": "CCHS_PHOX2B", + "disease_id": "CCHS", + "gene": "PHOX2B", + "chrom": "chr4", + "start_hg38": 41745972, + "stop_hg38": 41746032, + "start_hg19": 41747989, + "stop_hg19": 41748049, + "start_t2t": 41719745, + "stop_t2t": 41719805, + "disease": "Congenital central hypoventilation syndrome", + "inheritance": [ + "AD" + ], + "disease_description": "A rare disease due to a severely impaired central autonomic control of breathing and dysfunction of the autonomous nervous system. The incidence is estimated to be at 1 of 200 000 livebirths. A heterozygous mutation of PHOX-2B gene is found in 90% of the patients. Association with a Hirschsprung's disease is observed in 16% of the cases (adapted from Mondo) [@mondo:0800026].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Incidence is 1:148000-200000 births (Estimated, may include mild/undiagnosed or be overestimated globally) [@genereviews:NBK1427]. Rare, but reported worldwide [@pmid:15121777].", + "age_onset": "Typical: 0-2 [@genereviews:NBK1427; @pmid:15121777]; Range: 0-36 [@pmid:16873766].", + "age_onset_min": 0, + "age_onset_max": 36, + "typ_age_onset_min": 0, + "typ_age_onset_max": 2, + "details": "Alleles of 24 repeats (and sometimes 25 repeats) correspond to delayed disease onset and/or milder phenotype; alleles above benign range (9-20 repeats) and below the pathogenic range (26-33 repeats) have uncertain significance [@genereviews:NBK1427].", + "mechanism": "LoF/GoF", + "mechanism_detail": "Polyalanine expansion leading to loss or gain of function, dependent on altered protein product [@pmid:38467784; @genereviews:NBK1427]. Correlation between length and reduced transcriptional activity [@pmid:15888479].", + "year": "2003 [@pmid:12640453]", + "location_in_gene": "Coding Exon 3", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "GCN" + ], + "pathogenic_motif_reference_orientation": [ + "GCN" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CNG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 9, + "benign_max": 20, + "intermediate_min": 21, + "intermediate_max": 25, + "pathogenic_min": 26, + "pathogenic_max": 33, + "motif_len": 3, + "ref_copies": 15.7, + "novel": "ref", + "gard": [ + "8535" + ], + "genereviews": [ + "NBK1427" + ], + "malacard": [ + "CNT119" + ], + "medgen": [ + "1794285" + ], + "mondo": [ + "0800026" + ], + "omim": [ + "209880" + ], + "orphanet": [ + "661" + ], + "gnomad": [ + "PHOX2B" + ], + "stripy": [ + "PHOX2B" + ], + "tr_atlas": [ + "TR42548" + ], + "webstr_hg38": [ + "4725362" + ], + "webstr_hg19": [ + "Expansion_CCHS/PHOX2B" + ], + "locus_tags": [ + "supported_evidence", + "length_affects_onset", + "length_affects_severity" + ], + "disease_tags": [], + "references": [ + "genereviews:NBK1427", + "pmid:15121777", + "pmid:16873766", + "pmid:38467784", + "pmid:15888479", + "pmid:12640453", + "mondo:0800026" + ], + "additional_literature": [ + "pmid:41420984", + "pmid:41188450", + "pmid:38467313", + "pmid:38454954", + "pmid:38431667", + "pmid:38001308", + "pmid:36394266", + "pmid:35421844", + "pmid:34626313", + "pmid:34012823", + "pmid:33958749", + "pmid:33855005", + "pmid:33047879", + "pmid:32822965", + "pmid:31950261", + "pmid:30786110", + "pmid:30672101", + "pmid:30227298", + "pmid:29058474", + "pmid:28992836", + "pmid:27485184", + "pmid:27129232", + "pmid:26378991", + "pmid:26375764", + "pmid:26063465", + "pmid:26011159", + "pmid:25975378", + "pmid:25085640", + "pmid:24442913", + "pmid:24135798", + "pmid:23460545", + "pmid:23460419", + "pmid:23103552", + "pmid:23045564", + "pmid:22922260", + "pmid:22829249", + "pmid:22821709", + "pmid:22437207", + "pmid:22278185", + "pmid:22125732", + "pmid:21373876", + "pmid:20236122", + "pmid:19881470", + "pmid:19608868", + "pmid:18798833", + "pmid:18157832", + "pmid:17928950", + "pmid:17909190", + "pmid:17045833", + "pmid:16888290", + "pmid:16258163", + "pmid:16249188" + ] }, { - "motif": "TTTCA", - "count": null, - "type": "pathogenic_repeat" - }], - "benign_min": null, - "benign_max": null, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 650, - "pathogenic_max": 1035, - "motif_len": 5, - "ref_copies": 13.6, - "novel": "novel", - "gard": ["18084"], - "genereviews": ["NBK535148"], - "malacard": ["EPL053"], - "medgen": ["462210"], - "mondo": ["0013322"], - "omim": ["613608"], - "orphanet": ["86814"], - "gnomad": ["MARCHF6"], - "stripy": ["MARCHF6"], - "tr_atlas": ["TR51895"], - "webstr_hg38": ["5994579"], - "webstr_hg19": ["STR_1116660"], - "locus_tags": ["supported_evidence", "somatic_instability", "motif_affects_onset", "motif_affects_penetrance", "motif_affects_severity"], - "disease_tags": ["familial_adult_myoclonic_epilepsy"], - "references": ["pmid:19616813", "omim:613608", "pmid:40788430", "genereviews:NBK535148", "pmid:31664039", "pmid: 40788430", "pmid:38876750", "pmid:39349043"], - "additional_literature": ["pmid:41268177", "pmid:41219789", "pmid:40417743", "pmid:40200849", "pmid:33040085"] -}, -{ - "id": "MIR7-2_CHNG3", - "disease_id": "CHNG3", - "gene": "MIR7-2", - "chrom": "chr15", - "start_hg38": 88569433, - "stop_hg38": 88569452, - "start_hg19": 89112664, - "stop_hg19": 89112683, - "start_t2t": 86324038, - "stop_t2t": 86324057, - "disease": "Nongoitrous congenital hypothyroidism-3", - "inheritance": ["AD"], - "disease_description": "Nongoitrous congenital hypothyroidism-3 (CHNG3) is characterized by infantile-onset clinical and subclinical hypothyroidism associated with a small thyroid gland, high circulating TSH, normal free T4 levels, and normal or mildly increased serum thyroglobulin. Untreated patients or patients who discontinue treatment show a characteristic transition to multinodular goiter (MNG) with age [@omim:609893].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Found in 12 families, with ancestry including: Irish, White European, French (Normandie), Ashkenazi, French Canadian, Danish/White European, Welsh, Scottish, Italian, British/White European, Italian/Turkish/Lebanese, German/Palestinian, and South Chinese [@pmid:38714868].", - "age_onset": "0 (birth)", - "age_onset_min": 0.0, - "age_onset_max": 0.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "Deletion of one repeat (4 to 3 repeats) found in 10 unrelated families with unsolved disease [@pmid:38714869]; a heterozygous T-to-G transversion in the third repeat can also lead to disease [@pmid:38714868].", - "mechanism": "GoF", - "mechanism_detail": "Activates a thyroid-specific enhancer [@pmid:38714868; @pmid:38714869].", - "year": "2024 [@pmid:38714869]", - "location_in_gene": "Non-coding", - "gene_strand": "-", - "reference_motif_reference_orientation": ["TTTG"], - "pathogenic_motif_reference_orientation": ["TTTG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["AAAC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 4, - "benign_max": 4, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 3, - "pathogenic_max": 3, - "motif_len": 4, - "ref_copies": null, - "novel": "ref", - "gard": ["1487"], - "genereviews": [], - "malacard": ["HYP355"], - "medgen": ["424853"], - "mondo": ["0012360"], - "omim": ["609893"], - "orphanet": [], - "gnomad": ["PRE-MIR7-2"], - "stripy": [], - "tr_atlas": ["TR192005"], - "webstr_hg38": ["5177365"], - "webstr_hg19": ["STR_492924"], - "locus_tags": ["supported_evidence", "contraction"], - "disease_tags": [], - "references": ["pmid:38714868", "pmid:38714869", "omim:609893"], - "additional_literature": [] -}, -{ - "id": "ADTKD_MUC1", - "disease_id": "ADTKD", - "gene": "MUC1", - "chrom": "chr1", - "start_hg38": 155188505, - "stop_hg38": 155192239, - "start_hg19": 155160981, - "stop_hg19": 155162030, - "start_t2t": 154328121, - "stop_t2t": 154330802, - "disease": "Autosomal dominant tubulointerstitial kidney disease", - "inheritance": ["AD"], - "disease_description": "An inherited disorder that causes a gradual loss of kidney function, caused by a mutation in the MUC1 gene that leads to production of an abnormal mucin 1 protein, which deposits in the kidney and leads to slow loss of kidney function [@mondo:0020726].", - "hpo_terms": null, - "prevalence": "2.5/1000000", - "prevalence_details": "Disease is affected 1-4/1,000,000 (likely an underestimate due to unremarkable findings); repeat expansion responsibile for 95% of disease [@genereviews:NBK153723]", - "age_onset": "Age of onset for end-stage renal disease (the only systemic manifestation) ranges from 16 [@pmid:41000883]-70 [@genereviews:NBK153723].", - "age_onset_min": 16.0, - "age_onset_max": 70.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "Disease is caused by the single base expansion of a heptanucleotide (7) cytosine homopolymer tract (i.e. from (C)7 to (C)8 ) within one copy of a coding VNTR, resulting in a frameshift mutation. This VNTR has a 60 bp motif, varying in length and sequence composition. This motif ranges in copy number from 20-125 (~1.5-5 kb) and is GC-rich (>80%). The specific copy of the VNTR motif involved varies by family but is consistent within a family [@genereviews:NBK535148]. This locus is particularly difficult to genotype [@pmid:23396133; @pmid:39781475]. Gamaarachchi et al. observed 20 unique VNTR haplotypes which ranged in size from 40–83 copies, with no unrelated individuals sharing the same haplotype. Unique haplotypes implied frequent independent origins of the dupC variant [@doi:10.1101/2025.03.31.646505]. NOTE: Disease is caused by a 7 to 8 C homopolymer expansion within the main motif which we represent here as a change in motif.", - "mechanism": "GoF", - "mechanism_detail": "Toxic protein product accumulates in kidneys [@genereviews:NBK153723]", - "year": "2013 [@pmid:23396133]", - "location_in_gene": "Coding Exon 2", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GGCTNNGGGNGCGGTGGAGCCCGGGGCNGGNCTGNTNTCCGGGGCCGAGGTGACANCNTG"], - "pathogenic_motif_reference_orientation": ["GCCCACGGTGTCACCTCGGCCCCGGACACCAGGCCGGCCCCGGGCTCCACCGCCCCCCCCA"], - "benign_motif_reference_orientation": ["GCCCACGGTGTCACCTCGGCCCCGGACACCAGGCCGGCCCCGGGCTCCACCGCCCCCCCA"], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["ACACCAGGCCGGCCCCGGGCTCCACCGCCCCCCCCAGCCCACGGTGTCACCTCGGCCCCGG"], - "benign_motif_gene_orientation": ["ACACCAGGCCGGCCCCGGGCTCCACCGCCCCCCCAGCCCACGGTGTCACCTCGGCCCCGG"], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": null, - "benign_max": null, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": null, - "pathogenic_max": null, - "motif_len": 1, - "ref_copies": null, - "novel": "ref", - "gard": ["7002"], - "genereviews": ["NBK153723"], - "malacard": ["TBL032"], - "medgen": ["358137"], - "mondo": ["0020726"], - "omim": ["174000"], - "orphanet": ["88949"], - "gnomad": [], - "stripy": [], - "tr_atlas": [], - "webstr_hg38": [], - "webstr_hg19": [], - "locus_tags": ["supported_evidence"], - "disease_tags": [], - "references": ["pmid:41000883", "genereviews:NBK153723", "genereviews:NBK535148", "pmid:23396133", "pmid:39781475", "doi:10.1101/2025.03.31.646505", "mondo:0020726"], - "additional_literature": ["pmid:40244446", "pmid:39848530", "pmid:39576755", "pmid:39325540", "pmid:39314239", "pmid:38605207", "pmid:37547453", "pmid:37456840", "pmid:37316299", "pmid:35982790", "pmid:35497811", "pmid:34641504", "pmid:34452200", "pmid:33672244", "pmid:33001366", "pmid:32451462", "pmid:32293552", "pmid:31213370", "pmid:30593830", "pmid:29520014", "pmid:29328069", "pmid:29217307", "pmid:29156055", "pmid:29052568", "pmid:28581490", "pmid:28407289", "pmid:27957769", "pmid:27036738", "pmid:27367740", "pmid:27340743", "pmid:27157321", "pmid:26943180", "pmid:26838233", "pmid:26693201", "pmid:26692014", "pmid:26498650", "pmid:25753030", "pmid:24718884", "pmid:24509297", "pmid:24416403", "pmid:24246952", "pmid:24233342", "pmid:23778023", "pmid:23770070", "pmid:23652307", "pmid:23317217", "pmid:23259747", "pmid:22970023", "pmid:21998660", "pmid:21385452", "pmid:20876819", "pmid:20562098", "pmid:20470225", "pmid:21637607", "pmid:19811637", "pmid:19625949", "pmid:19534821", "pmid:18619437", "pmid:18094420", "pmid:18021186", "pmid:17974963", "pmid:17694298", "pmid:17581677", "pmid:17203187", "pmid:17050588", "pmid:16711252", "pmid:16631167", "pmid:16302687", "pmid:16101182", "pmid:15991935", "pmid:15944787", "pmid:15814824", "pmid:15729696", "pmid:15604091", "pmid:15387710", "pmid:15115750", "pmid:15041735", "pmid:14871854", "pmid:14707484", "pmid:12747745", "pmid:12646731", "pmid:12626424", "pmid:12090474", "pmid:11923240", "pmid:11445551", "pmid:11391628", "pmid:11358826", "pmid:11295060", "pmid:11169964", "pmid:10797294", "pmid:10741704", "pmid:10653872", "pmid:10652432", "pmid:10541345", "pmid:10430099", "pmid:10389761", "pmid:10383817", "pmid:10235488", "pmid:10206297", "pmid:10052816", "pmid:10024673", "pmid:10022471", "pmid:9935162", "pmid:9823312", "pmid:9755875", "pmid:9727561", "pmid:9690452", "pmid:9591045", "pmid:9579805", "pmid:9575675", "pmid:9551361", "pmid:9427605", "pmid:9419405", "pmid:8967520", "pmid:8643693", "pmid:7594478", "pmid:8579785", "pmid:8567787", "pmid:8519447", "pmid:7628867", "pmid:7816840", "pmid:7946402", "pmid:7514493", "pmid:7690213", "pmid:7685318"] -}, -{ - "id": "NME_NAXE", - "disease_id": "NME", - "gene": "NAXE", - "chrom": "chr1", - "start_hg38": 156591765, - "stop_hg38": 156591783, - "start_hg19": 156561557, - "stop_hg19": 156561575, - "start_t2t": 155728131, - "stop_t2t": 155728159, - "disease": "NAXE-related mitochondrial encephalopathy", - "inheritance": ["AR"], - "disease_description": "Patients with NAXE-related mitochondrial encephalopathy exhibit developmental delay, cognitive regression, altered consciousness, abnormalities in eye movement (including nystagmus), muscle weakness, respiratory failure, seizure, ataxia, and gait disturbance at the age of 1 to 2 years. The disease is characterized by fluctuating symptoms over time, often exacerbated by febrile illness; it is progressive and fatal in the long term [@pmid:39455596].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Single proband found in Japanese cohort [@pmid:39455596].", - "age_onset": "Single repeat expansion case had onset at 13 months, while NAXE-related mitochondrial encephalopathy more generally has predominately infantile onset, extending to 20y or older [@pmid:39455596].", - "age_onset_min": 1.0, - "age_onset_max": 1.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "Benign range (2-7) alleles established by 484 control alleles and validated with orthogonal databases, while single proband had expansion of ~200 repeats inherited from mother via uniparental disomy [@pmid:39455596]. While the repeat expansion is newly reported, other variants in the NAXE gene have previously been associated with mitochondrial encephalopathy.", - "mechanism": "LoF", - "mechanism_detail": "Reduced NAXE expression from expansion in promoter; hypermethylation was detected at and downstream of the repeat sequence in the proband as well as the maternal copy of the expanded allele, which was not present in the maternal normal range allele nor in the controls [@pmid:39455596]", - "year": "2024 [@pmid:39455596]", - "location_in_gene": "5' UTR", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GGGCC"], - "pathogenic_motif_reference_orientation": ["GGGCC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CCGGG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 2, - "benign_max": 7, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 200, - "pathogenic_max": 200, - "motif_len": 5, - "ref_copies": null, - "novel": "ref", - "gard": ["17991"], - "genereviews": [], - "malacard": ["ENC069"], - "medgen": ["934642"], - "mondo": ["0020781"], - "omim": ["617186"], - "orphanet": ["555407"], - "gnomad": ["NAXE"], - "stripy": [], - "tr_atlas": ["TR7952"], - "webstr_hg38": ["1184343", "6351240"], - "webstr_hg19": [], - "locus_tags": ["limited_evidence"], - "disease_tags": [], - "references": ["pmid:39455596"], - "additional_literature": ["pmid:41091881"] -}, -{ - "id": "ALS1_NIPA1", - "disease_id": "ALS1", - "gene": "NIPA1", - "chrom": "chr15", - "start_hg38": 22786677, - "stop_hg38": 22786703, - "start_hg19": 23086363, - "stop_hg19": 23086389, - "start_t2t": 20458510, - "stop_t2t": 20458536, - "disease": "Amyotrophic lateral sclerosis", - "inheritance": ["AD"], - "disease_description": "Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life [@omim:105400].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "2.7-7.4/100,000 for all cases of ALS, NIPA1 + C9orf72 is 0.37% of ALS patients; frequency of NIPA1 expansion in controls is 3.74% [@pmid:31286297]. The NIPA1 expansion is associated with disease globally [@pmid:30342764], but likely unassociated in African probands [@pmid:34179866].", - "age_onset": "Typical: 44-60 [@pmid:26777436]; Range: 25 [@pmid:22378146] - 77 [@pmid:26777436].", - "age_onset_min": 25.0, - "age_onset_max": 77.0, - "typ_age_onset_min": 44.0, - "typ_age_onset_max": 60.0, - "details": "Allelic ranges taken from STRipy based on primary literature [@stripy:NIPA1]. Currently proposed as a modifier for ALS [@pmid:31286297]. Note: the motif for this locus is CGG in hg38 and T2T reference genomes, while in hg19, the motif is the reverse complement CCG because it is on the negative strand.", - "mechanism": null, - "mechanism_detail": null, - "year": "2019 [@pmid:30342764]", - "location_in_gene": "Coding Exon 1/Intron 1 depending on transcript", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GCG"], - "pathogenic_motif_reference_orientation": ["GCG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CGG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 6, - "benign_max": 10, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 11, - "pathogenic_max": 56, - "motif_len": 3, - "ref_copies": 10.7, - "novel": "ref", - "gard": ["5786"], - "genereviews": [], - "malacard": ["FRN044"], - "medgen": ["400169"], - "mondo": ["0007103"], - "omim": ["105400"], - "orphanet": ["282", "803"], - "gnomad": ["NIPA1"], - "stripy": ["NIPA1"], - "tr_atlas": ["TR133649"], - "webstr_hg38": ["5135087"], - "webstr_hg19": [], - "locus_tags": ["contradictory_evidence", "proposed_modifier"], - "disease_tags": [], - "references": ["pmid:26777436", "pmid:22378146", "stripy:NIPA1", "pmid:31286297", "pmid:30342764", "pmid:34179866", "omim:105400"], - "additional_literature": ["pmid:41426430", "pmid:38667292", "pmid:37043475", "pmid:35869263", "pmid:33414559", "pmid:32954321", "pmid:24866401", "pmid:21419568", "pmid:11839840", "pmid:10987648", "pmid:9736780"] -}, -{ - "id": "SCA36_NOP56", - "disease_id": "SCA36", - "gene": "NOP56", - "chrom": "chr20", - "start_hg38": 2652732, - "stop_hg38": 2652757, - "start_hg19": 2633378, - "stop_hg19": 2633403, - "start_t2t": 2683189, - "stop_t2t": 2683230, - "disease": "Spinocerebellar ataxia type 36", - "inheritance": ["AD"], - "disease_description": "Spinocerebellar ataxia type 36 (SCA36) is a subtype of autosomal dominant cerebellar ataxia type 1 (ADCA type 1) characterized by gait and limb ataxia, lower limb spasticity, dysarthria, muscle fasiculations, tongue atrophy and hyperreflexia [@mondo:0013594].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Western Japan: 3.6% of all SCA; Costa da Morte region of Spain: 6.3% of all SCA [@pmid:37332636]; US: 0.7% of large undiagnosed ataxia cohort [@pmid:28761930]. Found across ancestries/ethnicities [@omim:614153].", - "age_onset": "Typical: 40-60 [@pmid:25101480]; Range: 28 [@pmid:37810464] - 67 [@pmid:37332636].", - "age_onset_min": 28.0, - "age_onset_max": 67.0, - "typ_age_onset_min": 40.0, - "typ_age_onset_max": 60.0, - "details": "Benign alleles range from 3-14 repeats and pathogenic alleles (650+ repeats) appear fully penetrant; the significance of intermediate alleles has yet to be elucidated [@pmid:25101480]. Interruptions documented: GGCTG, GGCCCTG, GGCCG, and GGCCTTG [@pmid:37051597].", - "mechanism": "GoF", - "mechanism_detail": "Toxic protein gain-of-function, RAN translation [@omim:614153].", - "year": "2011 [@pmid:21683323]", - "location_in_gene": "Intron 1", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GGCCTG"], - "pathogenic_motif_reference_orientation": ["GGCCTG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CCTGGG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [ + "id": "MRUPAV_PLIN4", + "disease_id": "MRUPAV", + "gene": "PLIN4", + "chrom": "chr19", + "start_hg38": 4510727, + "stop_hg38": 4513659, + "start_hg19": 4510739, + "stop_hg19": 4513671, + "start_t2t": 4494212, + "stop_t2t": 4497342, + "disease": "Myopathy with Rimmed Ubiquitin-Positive Autophagic Vacuolation, PLIN4-Related Myopathy", + "inheritance": [ + "AD" + ], + "disease_description": "Autosomal dominant myopathy with rimmed ubiquitin-positive autophagic vacuolation (MRUPAV) is characterized by adult onset of slowly progressive skeletal muscle weakness variably affecting the distal or proximal lower limbs. Some patients may also have upper limb involvement or neck muscle weakness, but respiratory and bulbar involvement only rarely occurs. EMG studies show a myopathic process, and myotonia may also be observed [@omim:601846]. An early characterisation of the disease was reported in Blasi, et al. [@pmid:15236412].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Studied in patients of chinese ancestry and two families of spanish ancestry [@pmid:36151849; @pmid:40693562].", + "age_onset": "22-66 [@pmid:36151849; @pmid:37145156; @pmid:35499779; @pmid:40693562].", + "age_onset_min": 22, + "age_onset_max": 66, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "This is an expanded variable number tandem repeat (VNTR) in the PLIN4 gene, located in exon 3. This repeat consists of a 99 bp motif which encodes 33 amino-acids within the perilipin-4 protein [@pmid:32451610]. Expansions of this 99 bp motif leads to insertion of multiple imperfect 33–amino acid repeats. These repetitive sequences are thought to contribute to abnormal protein aggregation and dysregulated autophagy seen in affected muscle tissue [@omim:601846].", + "mechanism": "GoF", + "mechanism_detail": "The present disease is characterized by dominantly inherited progressively increasing mobilization of aggrephagy at sites of progressive accumulation of a mutated protein, suggesting that the mutation is leading to aggregation, likely through misfolding, exceeding aggrephagic capacity. [@pmid:32451610]", + "year": "2020 [@pmid:32451610]", + "location_in_gene": "Coding Exon 3", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "TGGTGTCCACGCCGGTCTGGATGGTTCCTTTGGCCACATTCATGGCACCAGTCACCCCACTACAGACGGTGTCCTTGGTACCTGTTAGGACAGTCTTAC" + ], + "pathogenic_motif_reference_orientation": [ + "TGGTGTCCACGCCGGTCTGGATGGTTCCTTTGGCCACATTCATGGCACCAGTCACCCCACTACAGACGGTGTCCTTGGTACCTGTTAGGACAGTCTTAC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "AAAGGAACCATCCAGACCGGCGTGGACACCAGTAAGACTGTCCTAACAGGTACCAAGGACACCGTCTGTAGTGGGGTGACTGGTGCCATGAATGTGGCC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 29, + "benign_max": 31, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 37, + "pathogenic_max": 50, + "motif_len": 99, + "ref_copies": 31, + "novel": "ref", + "gard": [], + "genereviews": [], + "malacard": [], + "medgen": [ + "355637" + ], + "mondo": [ + "0011155" + ], + "omim": [ + "601846" + ], + "orphanet": [ + "696063" + ], + "gnomad": [], + "stripy": [], + "tr_atlas": [], + "webstr_hg38": [], + "webstr_hg19": [], + "locus_tags": [ + "supported_evidence", + "anticipation", + "length_affects_onset" + ], + "disease_tags": [], + "references": [ + "pmid:36151849", + "pmid:37145156", + "pmid:35499779", + "pmid:40693562", + "pmid:32451610", + "omim:601846", + "pmid:15236412" + ], + "additional_literature": [ + "pmid:39492694" + ] + }, { - "motif": "GGCCTG", - "count": null, - "type": "pathogenic_repeat" + "id": "CPEO_POLG", + "disease_id": "CPEO", + "gene": "POLG", + "chrom": "chr15", + "start_hg38": 89333588, + "stop_hg38": 89333629, + "start_hg19": 89876819, + "stop_hg19": 89876860, + "start_t2t": 87088411, + "stop_t2t": 87088452, + "disease": "Progressive external ophthalmoplegia, Parkinson's disease", + "inheritance": [], + "disease_description": "sensory ataxic neuropathy, dysarthria, and ophtalmoparesis [@pmid:38876750].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Disease association unclear but largely studied in European cohorts/patients [@omim:258450; @omim:157640].", + "age_onset": "Typical: 57 [@pmid:20399836] - 59 [@pmid:20826197]; Range: 23-87 [@pmid:20399836].", + "age_onset_min": 23, + "age_onset_max": 87, + "typ_age_onset_min": 57, + "typ_age_onset_max": 59, + "details": "There is conflicting evidence for the association between this repeat expansion and Parkinson's risk [@pmid:20399836; @pmid:10196696; @pmid:22963882], as well as overall disease significance. May be predisposing factor in earlier age of onset in FRDA patients [@pmid:19043662].", + "mechanism": null, + "mechanism_detail": null, + "year": null, + "location_in_gene": "Coding Exon 2", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "GCT" + ], + "pathogenic_motif_reference_orientation": [ + "GCT" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "AGC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [ + { + "motif": "GCT", + "count": 2, + "type": "flank_repeat" + }, + { + "motif": "GTT", + "count": 1, + "type": "flank_repeat" + }, + { + "motif": "GCT", + "count": null, + "type": "pathogenic_repeat" + } + ], + "benign_min": 10, + "benign_max": 10, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": null, + "pathogenic_max": null, + "motif_len": 3, + "ref_copies": 13.7, + "novel": "ref", + "gard": [ + "15215", + "13174" + ], + "genereviews": [], + "malacard": [ + "PRG130", + "PRK002" + ], + "medgen": [ + "897191", + "371919" + ], + "mondo": [ + "0009783", + "0024528" + ], + "omim": [ + "258450", + "157640" + ], + "orphanet": [ + "520820" + ], + "gnomad": [], + "stripy": [], + "tr_atlas": [ + "TR137533" + ], + "webstr_hg38": [ + "5177947" + ], + "webstr_hg19": [ + "STR_493430" + ], + "locus_tags": [ + "contradictory_evidence", + "proposed_modifier" + ], + "disease_tags": [], + "references": [ + "pmid:20399836", + "pmid:20826197", + "pmid:10196696", + "pmid:22963882", + "pmid:19043662", + "omim:258450", + "omim:157640", + "pmid:38876750" + ], + "additional_literature": [ + "pmid:41009775", + "pmid:40844737", + "pmid:39812846", + "pmid:34600502", + "pmid:29029963", + "pmid:28444220", + "pmid:25767537", + "pmid:24491464", + "pmid:23912752", + "pmid:23493802", + "pmid:20803511", + "pmid:15694274", + "pmid:12036482" + ] }, { - "motif": "CGCCTG", - "count": 3, - "type": "flank_repeat" - }], - "benign_min": 3, - "benign_max": 14, - "intermediate_min": 15, - "intermediate_max": 649, - "pathogenic_min": 650, - "pathogenic_max": 2500, - "motif_len": 6, - "ref_copies": 7.2, - "novel": "ref", - "gard": ["12367"], - "genereviews": ["NBK535148"], - "malacard": ["SPN265"], - "medgen": ["483339"], - "mondo": ["0013594"], - "omim": ["614153"], - "orphanet": ["276198"], - "gnomad": ["NOP56"], - "stripy": ["NOP56"], - "tr_atlas": ["TR157810", "TR157811"], - "webstr_hg38": ["6177296", "890490"], - "webstr_hg19": ["STR_833720"], - "locus_tags": ["supported_evidence", "somatic_instability", "length_affects_onset", "length_affects_severity"], - "disease_tags": ["spinocerebellar_ataxia"], - "references": ["pmid:25101480", "pmid:37810464", "pmid:37332636", "omim:614153", "pmid:37051597", "pmid:28761930", "pmid:21683323", "mondo:0013594"], - "additional_literature": ["pmid:41337098", "pmid:41074692", "pmid:40898875", "pmid:40765612", "pmid:40488180", "pmid:40015643", "pmid:40004498", "pmid:38961870", "pmid:38934198", "pmid:38811808", "pmid:38667292", "pmid:38227102", "pmid:36599645", "pmid:36572080", "pmid:36530930", "pmid:35599735", "pmid:35077744", "pmid:34179866", "pmid:33705846", "pmid:32989102", "pmid:32407596", "pmid:32375063", "pmid:32375043", "pmid:32270466", "pmid:31737797", "pmid:30610877", "pmid:30109267", "pmid:29316893", "pmid:29281254", "pmid:28918022", "pmid:27123487", "pmid:26661328", "pmid:25476002", "pmid:24985895", "pmid:24269018", "pmid:22744658", "pmid:22492559"] -}, -{ - "id": "NIID_NOTCH2NLC", - "disease_id": "NIID", - "gene": "NOTCH2NLC", - "chrom": "chr1", - "start_hg38": 149390802, - "stop_hg38": 149390842, - "start_hg19": 145209323, - "stop_hg19": 145209354, - "start_t2t": 148519695, - "stop_t2t": 148519738, - "disease": "Neuronal intranuclear inclusion disease, Alzheimer disease and parkinsonism phenotype, Oculopharyngodistal myopathy (OPDM) type 3", - "inheritance": ["AD"], - "disease_description": "Neuronal intranuclear inclusion disease (NIID) is a very rare multisystem neurodegenerative disorder characterized by the presence of eosinophilic intranuclear inclusions in neuronal and glial cells, and neuronal loss [@mondo:0011327].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": ">400 patients reported in literature [@pmid:37371433]. Found in individuals of East Asian ancestry [@pmid:38876750].", - "age_onset": "Typical: 30-70 [@omim:603472]; Range: 10 [@pmid:37090934] - 78 [@pmid:37305750].", - "age_onset_min": 10.0, - "age_onset_max": 78.0, - "typ_age_onset_min": 30.0, - "typ_age_onset_max": 70.0, - "details": "Benign alleles are less than 38 repeats, while pathogenic alleles contain 66+ repeats [@genereviews:NBK535148]. Intermediate alleles may be associated with a phenotypic spectrum, and even pathogenic cases can have variable phenotype [@pmid:39055960; @pmid:39496005]: NOTCH2NLC expansions have been linked Alzheimer's disease and Parkinson's disease, leading to a potential role in NIID-related disorders [@pmid:31178126]. Age of onset inversely related to allele size [@pmid:38377026]. Motif variation in controls: (AGG)(CGG)n(AGG)0-3(CGG)0-2. GGA and AGC interruptions may influence phenotype [@pmid:34718964]. Interruptions documented: GGA, GGG [@pmid:35245110]; ACCGAGAAGATGCCCGCCCTGC interruption proposed but not confirmed [@pmid:38467784]. Detection may be challenging due to parology between genes: C253572.1, NOTCH2, NOTCH2NL, NBPF14, NBPF19.", - "mechanism": "GoF", - "mechanism_detail": "Polyglycine expansion; may relate to methylation or RNA pathogenicity [@omim:603472; @pmid:36169768; @pmid:38467784]. The polyglycine-containing protein sequesters a key subunit of transcription factor NF-κB in nuclear inclusions, leading to impaired autophagy [@doi:10.1186/s12964-025-02079-1].", - "year": "2019 [@pmid:31332380]", - "location_in_gene": "5' UTR", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GGC"], - "pathogenic_motif_reference_orientation": ["GGC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CGG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 7, - "benign_max": 37, - "intermediate_min": 38, - "intermediate_max": 65, - "pathogenic_min": 66, - "pathogenic_max": 517, - "motif_len": 3, - "ref_copies": 13.3, - "novel": "ref", - "gard": ["3971"], - "genereviews": ["NBK535148"], - "malacard": ["NRN008"], - "medgen": ["355075"], - "mondo": ["0011327"], - "omim": ["603472", "619473"], - "orphanet": ["2289"], - "gnomad": ["NOTCH2NLC"], - "stripy": ["NOTCH2NLC"], - "tr_atlas": ["TR7525"], - "webstr_hg38": [], - "webstr_hg19": [], - "locus_tags": ["supported_evidence", "somatic_instability", "paternal_expansion", "length_affects_onset", "length_affects_phenotype", "motif_affects_onset", "motif_affects_phenotype"], - "disease_tags": ["phenotypic_spectrum"], - "references": ["omim:603472", "pmid:37090934", "pmid:37305750", "pmid:36169768", "pmid:38467784", "doi:10.1186/s12964-025-02079-1", "genereviews:NBK535148", "pmid:39055960", "pmid:39496005", "pmid:31178126", "pmid:38377026", "pmid:34718964", "pmid:35245110", "pmid:37371433", "pmid:38876750", "pmid:31332380", "mondo:0011327"], - "additional_literature": ["pmid:41235412", "pmid:41154122", "pmid:41074692", "pmid:40934004", "pmid:40879637", "pmid:40765612", "pmid:40708231", "pmid:40645757", "pmid:40635536", "pmid:40609325", "pmid:40517194", "pmid:40515658", "pmid:40514451", "pmid:40267536", "pmid:40084170", "pmid:39936620", "pmid:39920690", "pmid:39609868", "pmid:39529621", "pmid:39505310", "pmid:39492694", "pmid:39418922", "pmid:39167540", "pmid:39078482", "pmid:38779172", "pmid:38709391", "pmid:38667292", "pmid:38579412", "pmid:38477063", "pmid:38288273", "pmid:38145851", "pmid:37975799", "pmid:37923380", "pmid:37864208", "pmid:37823700", "pmid:37644522", "pmid:37365282", "pmid:37271829", "pmid:37237429", "pmid:37184590", "pmid:37131242", "pmid:37001413", "pmid:36948577", "pmid:36942588", "pmid:36825461", "pmid:36823368", "pmid:36809423", "pmid:36715780", "pmid:36672065", "pmid:36621630", "pmid:36588885", "pmid:36570826", "pmid:36545534", "pmid:36483830", "pmid:36458450", "pmid:36417528", "pmid:36263606", "pmid:36216675", "pmid:36207023", "pmid:36191230", "pmid:36172483", "pmid:36150977", "pmid:36086903", "pmid:36061987", "pmid:36041634", "pmid:36033605", "pmid:35974122", "pmid:35866887", "pmid:35857137", "pmid:35838850", "pmid:35788208", "pmid:35772299", "pmid:35700120", "pmid:35419641", "pmid:35411397", "pmid:35402653", "pmid:35366689", "pmid:35314910", "pmid:35297556", "pmid:35180462", "pmid:35152460", "pmid:35148830", "pmid:35147270", "pmid:34927285", "pmid:34797461", "pmid:34774111", "pmid:34750918", "pmid:34694469", "pmid:34675106", "pmid:34641814", "pmid:34392981", "pmid:34306035", "pmid:34243731", "pmid:34054431", "pmid:34017298", "pmid:33943039", "pmid:33887199", "pmid:33871559", "pmid:33871549", "pmid:33766934", "pmid:33693509", "pmid:33679585", "pmid:33626493", "pmid:33625684", "pmid:33388663", "pmid:33377220", "pmid:33377207", "pmid:33239111", "pmid:33201994", "pmid:33201988", "pmid:33146692", "pmid:33146671", "pmid:33026126", "pmid:33016348", "pmid:32989102", "pmid:32931575", "pmid:32852534", "pmid:32827029", "pmid:32817896", "pmid:32777174", "pmid:32768149", "pmid:32602554", "pmid:32535679", "pmid:32516806", "pmid:32495371", "pmid:32449905", "pmid:32268889", "pmid:32250060", "pmid:32081467", "pmid:32039647", "pmid:31886491", "pmid:31819945", "pmid:31433517", "pmid:31413119", "pmid:31332381"] -}, -{ - "id": "OPML1_NUTM2B-AS1", - "disease_id": "OPML1", - "gene": "NUTM2B-AS1", - "chrom": "chr10", - "start_hg38": 79826383, - "stop_hg38": 79826404, - "start_hg19": 81586139, - "stop_hg19": 81586160, - "start_t2t": 80695718, - "stop_t2t": 80695748, - "disease": "Oculopharyngeal myopathy with leukoencephalopathy 1", - "inheritance": ["AD"], - "disease_description": "Oculopharyngodistal myopathy and white matter abnormalities [@pmid:38876750]; Ptosis, ophthalmoplegia, dysphagia, dysarthria [@pmid:39349043].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Rare, found in individuals of East Asian ancestry [@pmid:38876750].", - "age_onset": "15-40 (only characterized in one family) [@pmid:31332380].", - "age_onset_min": 15.0, - "age_onset_max": 40.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "Benign range (3-16 repeats) established in 1000 controls, studied alongside pathogenic probands of up to 700 repeats [@pmid:31332380]. Pathogenicity occurs at repeats as short as 161 motifs [@pmid:38159879; @pmid:37923380], while intermediate alleles may correlate to milder phenotypes [@pmid:38159879]. Alt transcript in opposite direction: LOC642361.", - "mechanism": "GoF?", - "mechanism_detail": "RNA mediated toxicity hypothesized, overall mechanism unknown [@omim:618637; @pmid:36169768].", - "year": "2019 [@pmid:31332380]", - "location_in_gene": "Exon 1 of lncRNA (noncoding)", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GGC"], - "pathogenic_motif_reference_orientation": ["GGC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CGG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 3, - "benign_max": 16, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 161, - "pathogenic_max": 700, - "motif_len": 3, - "ref_copies": 7.0, - "novel": "ref", - "gard": [], - "genereviews": ["NBK535148"], - "malacard": ["OCL077"], - "medgen": ["1684701"], - "mondo": ["0032843"], - "omim": ["618637"], - "orphanet": [], - "gnomad": ["NUTM2B-AS1"], - "stripy": ["NUTM2B-AS1"], - "tr_atlas": ["TR102881"], - "webstr_hg38": [], - "webstr_hg19": ["STR_173942"], - "locus_tags": ["supported_evidence", "length_affects_severity", "length_affects_phenotype"], - "disease_tags": [], - "references": ["pmid:31332380", "omim:618637", "pmid:36169768", "pmid:38159879", "pmid:37923380", "pmid:38876750", "pmid:39349043"], - "additional_literature": ["pmid:40645757", "pmid:39308795", "pmid:35152460"] -}, -{ - "id": "OPMD_PABPN1", - "disease_id": "OPMD", - "gene": "PABPN1", - "chrom": "chr14", - "start_hg38": 23321472, - "stop_hg38": 23321503, - "start_hg19": 23790681, - "stop_hg19": 23790712, - "start_t2t": 17522488, - "stop_t2t": 17522519, - "disease": "Oculopharyngeal muscular dystrophy", - "inheritance": ["AD", "AR"], - "disease_description": "Ptosis and dysphagia [@pmid:39349043]; facial weakness, ptosis [@pmid:38876750].", - "hpo_terms": null, - "prevalence": "1/100000", - "prevalence_details": "1/100,000 (population specific) [@pmid:29100084]. Frequency of (GCN)11 alleles is 1-2% of North America/Europe/Japan [@genereviews:NBK1126]. Disease is found worldwide, in more than 30 countries [@genereviews:NBK1126].", - "age_onset": "Typical: 40-59 [@pmid:37519616]; Range: 20-79 [@pmid:35112761].", - "age_onset_min": 20.0, - "age_onset_max": 79.0, - "typ_age_onset_min": 40.0, - "typ_age_onset_max": 59.0, - "details": "Disease is caused by a GCN polyalanine expansion in the first exon of PABPN1. Most known patients have (GCG)+, but GCN (any polyalanine) may be pathogenic [@genereviews:NBK1126]. This locus acts in a dominant manner for allele sizes ≥ 12 GCN motifs (90% of cases) and in a recessive manner for 11 GCN motifs, i.e. the genotype (GCN)11(GCN)11 (10% of cases). Additionally, disease is known to be more severe in cases of two expanded alleles. Age of onset is inverse to allele size, while penetrance and severity increase with allele size [@genereviews:NBK1126]. Mild, late-onset disease can occur in individuals with a (GCN)10(GCN)11 genotype, suggesting variable penetrance [@pmid:28011929]. The definition of this locus differs in the literature with prior work counting exact GCG motifs for a benign size of (GCG)6 [@pmid:9462747], while later resources count GCNs (any alanine codon), widening the region by 4 motifs to a benign size of (GCN)10 [@genereviews:NBK1126; @pmid:39349043]. STRchive is using the GCN definition.", - "mechanism": "GoF/LoF", - "mechanism_detail": "Polyalanine expansions leading to cellular toxicity (loss of function) as well as abnormal aggregation and inefficient protein degradation, which may impact mRNA processing [@genereviews:NBK1126].", - "year": "1998 [@pmid:9462747]", - "location_in_gene": "Coding Exon 1", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GCN"], - "pathogenic_motif_reference_orientation": ["GCN"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CNG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 10, - "benign_max": 10, - "intermediate_min": 11, - "intermediate_max": 11, - "pathogenic_min": 12, - "pathogenic_max": 18, - "motif_len": 3, - "ref_copies": 7.0, - "novel": "ref", - "gard": ["7245"], - "genereviews": ["NBK1126"], - "malacard": ["OCL088"], - "medgen": ["1054618"], - "mondo": ["0958176"], - "omim": ["164300"], - "orphanet": ["270"], - "gnomad": ["PABPN1"], - "stripy": ["PABPN1"], - "tr_atlas": ["TR128439"], - "webstr_hg38": ["1442709", "5271481"], - "webstr_hg19": ["Expansion_OPMD/PAPBN1"], - "locus_tags": ["supported_evidence", "length_affects_onset", "length_affects_severity"], - "disease_tags": [], - "references": ["pmid:37519616", "pmid:35112761", "genereviews:NBK1126", "pmid:28011929", "pmid:9462747", "pmid:39349043", "pmid:29100084", "pmid:38876750"], - "additional_literature": ["pmid:40594369", "pmid:40552959", "pmid:40220918", "pmid:39113268", "pmid:38165364", "pmid:37698929", "pmid:37559347", "pmid:36790141", "pmid:35859342", "pmid:34927285", "pmid:34225694", "pmid:34047774", "pmid:31294444", "pmid:30455479", "pmid:28361972", "pmid:27980005", "pmid:26428746", "pmid:23793615", "pmid:23399899", "pmid:22519734", "pmid:21742497", "pmid:21647273", "pmid:21602480", "pmid:21316245", "pmid:19641605", "pmid:19101703", "pmid:18481858", "pmid:18367172", "pmid:18343218", "pmid:17138075", "pmid:16648376", "pmid:16642034", "pmid:16481821", "pmid:16378590", "pmid:16239242", "pmid:15811916", "pmid:15755680", "pmid:15725589", "pmid:15645184", "pmid:14627730", "pmid:12673802", "pmid:11712939", "pmid:11304042", "pmid:11222452", "pmid:11150975", "pmid:11087766", "pmid:11003790", "pmid:10734263", "pmid:10680791", "pmid:9084936"] -}, -{ - "id": "CCHS_PHOX2B", - "disease_id": "CCHS", - "gene": "PHOX2B", - "chrom": "chr4", - "start_hg38": 41745972, - "stop_hg38": 41746032, - "start_hg19": 41747989, - "stop_hg19": 41748049, - "start_t2t": 41719745, - "stop_t2t": 41719805, - "disease": "Congenital central hypoventilation syndrome", - "inheritance": ["AD"], - "disease_description": "A rare disease due to a severely impaired central autonomic control of breathing and dysfunction of the autonomous nervous system. The incidence is estimated to be at 1 of 200 000 livebirths. A heterozygous mutation of PHOX-2B gene is found in 90% of the patients. Association with a Hirschsprung's disease is observed in 16% of the cases (adapted from Mondo) [@mondo:0800026].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Incidence is 1:148000-200000 births (Estimated, may include mild/undiagnosed or be overestimated globally) [@genereviews:NBK1427]. Rare, but reported worldwide [@pmid:15121777].", - "age_onset": "Typical: 0-2 [@genereviews:NBK1427; @pmid:15121777]; Range: 0-36 [@pmid:16873766].", - "age_onset_min": 0.0, - "age_onset_max": 36.0, - "typ_age_onset_min": 0.0, - "typ_age_onset_max": 2.0, - "details": "Alleles of 24 repeats (and sometimes 25 repeats) correspond to delayed disease onset and/or milder phenotype; alleles above benign range (9-20 repeats) and below the pathogenic range (26-33 repeats) have uncertain significance [@genereviews:NBK1427].", - "mechanism": "LoF/GoF", - "mechanism_detail": "Polyalanine expansion leading to loss or gain of function, dependent on altered protein product [@pmid:38467784; @genereviews:NBK1427]. Correlation between length and reduced transcriptional activity [@pmid:15888479].", - "year": "2003 [@pmid:12640453]", - "location_in_gene": "Coding Exon 3", - "gene_strand": "-", - "reference_motif_reference_orientation": ["GCN"], - "pathogenic_motif_reference_orientation": ["GCN"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CNG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 9, - "benign_max": 20, - "intermediate_min": 21, - "intermediate_max": 25, - "pathogenic_min": 26, - "pathogenic_max": 33, - "motif_len": 3, - "ref_copies": 15.7, - "novel": "ref", - "gard": ["8535"], - "genereviews": ["NBK1427"], - "malacard": ["CNT119"], - "medgen": ["1794285"], - "mondo": ["0800026"], - "omim": ["209880"], - "orphanet": ["661"], - "gnomad": ["PHOX2B"], - "stripy": ["PHOX2B"], - "tr_atlas": ["TR42548"], - "webstr_hg38": ["4725362"], - "webstr_hg19": ["Expansion_CCHS/PHOX2B"], - "locus_tags": ["supported_evidence", "length_affects_onset", "length_affects_severity"], - "disease_tags": [], - "references": ["genereviews:NBK1427", "pmid:15121777", "pmid:16873766", "pmid:38467784", "pmid:15888479", "pmid:12640453", "mondo:0800026"], - "additional_literature": ["pmid:41420984", "pmid:41188450", "pmid:38467313", "pmid:38454954", "pmid:38431667", "pmid:38001308", "pmid:36394266", "pmid:35421844", "pmid:34626313", "pmid:34012823", "pmid:33958749", "pmid:33855005", "pmid:33047879", "pmid:32822965", "pmid:31950261", "pmid:30786110", "pmid:30672101", "pmid:30227298", "pmid:29058474", "pmid:28992836", "pmid:27485184", "pmid:27129232", "pmid:26378991", "pmid:26375764", "pmid:26063465", "pmid:26011159", "pmid:25975378", "pmid:25085640", "pmid:24442913", "pmid:24135798", "pmid:23460545", "pmid:23460419", "pmid:23103552", "pmid:23045564", "pmid:22922260", "pmid:22829249", "pmid:22821709", "pmid:22437207", "pmid:22278185", "pmid:22125732", "pmid:21373876", "pmid:20236122", "pmid:19881470", "pmid:19608868", "pmid:18798833", "pmid:18157832", "pmid:17928950", "pmid:17909190", "pmid:17045833", "pmid:16888290", "pmid:16258163", "pmid:16249188"] -}, -{ - "id": "MRUPAV_PLIN4", - "disease_id": "MRUPAV", - "gene": "PLIN4", - "chrom": "chr19", - "start_hg38": 4510727, - "stop_hg38": 4513659, - "start_hg19": 4510739, - "stop_hg19": 4513671, - "start_t2t": 4494212, - "stop_t2t": 4497342, - "disease": "Myopathy with Rimmed Ubiquitin-Positive Autophagic Vacuolation, PLIN4-Related Myopathy", - "inheritance": ["AD"], - "disease_description": "Autosomal dominant myopathy with rimmed ubiquitin-positive autophagic vacuolation (MRUPAV) is characterized by adult onset of slowly progressive skeletal muscle weakness variably affecting the distal or proximal lower limbs. Some patients may also have upper limb involvement or neck muscle weakness, but respiratory and bulbar involvement only rarely occurs. EMG studies show a myopathic process, and myotonia may also be observed [@omim:601846]. An early characterisation of the disease was reported in Blasi, et al. [@pmid:15236412].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Studied in patients of chinese ancestry and two families of spanish ancestry [@pmid:36151849; @pmid:40693562].", - "age_onset": "22-66 [@pmid:36151849; @pmid:37145156; @pmid:35499779; @pmid:40693562].", - "age_onset_min": 22.0, - "age_onset_max": 66.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "This is an expanded variable number tandem repeat (VNTR) in the PLIN4 gene, located in exon 3. This repeat consists of a 99 bp motif which encodes 33 amino-acids within the perilipin-4 protein [@pmid:32451610]. Expansions of this 99 bp motif leads to insertion of multiple imperfect 33–amino acid repeats. These repetitive sequences are thought to contribute to abnormal protein aggregation and dysregulated autophagy seen in affected muscle tissue [@omim:601846].", - "mechanism": "GoF", - "mechanism_detail": "The present disease is characterized by dominantly inherited progressively increasing mobilization of aggrephagy at sites of progressive accumulation of a mutated protein, suggesting that the mutation is leading to aggregation, likely through misfolding, exceeding aggrephagic capacity. [@pmid:32451610]", - "year": "2020 [@pmid:32451610]", - "location_in_gene": "Coding Exon 3", - "gene_strand": "-", - "reference_motif_reference_orientation": ["TGGTGTCCACGCCGGTCTGGATGGTTCCTTTGGCCACATTCATGGCACCAGTCACCCCACTACAGACGGTGTCCTTGGTACCTGTTAGGACAGTCTTAC"], - "pathogenic_motif_reference_orientation": ["TGGTGTCCACGCCGGTCTGGATGGTTCCTTTGGCCACATTCATGGCACCAGTCACCCCACTACAGACGGTGTCCTTGGTACCTGTTAGGACAGTCTTAC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["AAAGGAACCATCCAGACCGGCGTGGACACCAGTAAGACTGTCCTAACAGGTACCAAGGACACCGTCTGTAGTGGGGTGACTGGTGCCATGAATGTGGCC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 29, - "benign_max": 31, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 37, - "pathogenic_max": 50, - "motif_len": 99, - "ref_copies": 31.0, - "novel": "ref", - "gard": [], - "genereviews": [], - "malacard": [], - "medgen": ["355637"], - "mondo": ["0011155"], - "omim": ["601846"], - "orphanet": ["696063"], - "gnomad": [], - "stripy": [], - "tr_atlas": [], - "webstr_hg38": [], - "webstr_hg19": [], - "locus_tags": ["supported_evidence", "anticipation", "length_affects_onset"], - "disease_tags": [], - "references": ["pmid:36151849", "pmid:37145156", "pmid:35499779", "pmid:40693562", "pmid:32451610", "omim:601846", "pmid:15236412"], - "additional_literature": ["pmid:39492694"] -}, -{ - "id": "CPEO_POLG", - "disease_id": "CPEO", - "gene": "POLG", - "chrom": "chr15", - "start_hg38": 89333588, - "stop_hg38": 89333629, - "start_hg19": 89876819, - "stop_hg19": 89876860, - "start_t2t": 87088411, - "stop_t2t": 87088452, - "disease": "Progressive external ophthalmoplegia, Parkinson's disease", - "inheritance": [], - "disease_description": "sensory ataxic neuropathy, dysarthria, and ophtalmoparesis [@pmid:38876750].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Disease association unclear but largely studied in European cohorts/patients [@omim:258450; @omim:157640].", - "age_onset": "Typical: 57 [@pmid:20399836] - 59 [@pmid:20826197]; Range: 23-87 [@pmid:20399836].", - "age_onset_min": 23.0, - "age_onset_max": 87.0, - "typ_age_onset_min": 57.0, - "typ_age_onset_max": 59.0, - "details": "There is conflicting evidence for the association between this repeat expansion and Parkinson's risk [@pmid:20399836; @pmid:10196696; @pmid:22963882], as well as overall disease significance. May be predisposing factor in earlier age of onset in FRDA patients [@pmid:19043662].", - "mechanism": null, - "mechanism_detail": null, - "year": null, - "location_in_gene": "Coding Exon 2", - "gene_strand": "-", - "reference_motif_reference_orientation": ["GCT"], - "pathogenic_motif_reference_orientation": ["GCT"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["AGC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [ + "id": "SCA12_PPP2R2B", + "disease_id": "SCA12", + "gene": "PPP2R2B", + "chrom": "chr5", + "start_hg38": 146878727, + "stop_hg38": 146878759, + "start_hg19": 146258290, + "stop_hg19": 146258322, + "start_t2t": 147414733, + "stop_t2t": 147414780, + "disease": "Spinocerebellar ataxia type 12", + "inheritance": [ + "AD" + ], + "disease_description": "Spinocerebellar ataxia type 12 (SCA12) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I). It is characterized by the presence of action tremor associated with relatively mild cerebellar ataxia. Associated pyramidal and extrapyramidal signs and dementia have been reported [@mondo:0011439].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Frequent in India; rare in other populations [@pmid:34711523].", + "age_onset": "Typical: 26-50; Range: 8-56 [@omim:604326].", + "age_onset_min": 8, + "age_onset_max": 62, + "typ_age_onset_min": 26, + "typ_age_onset_max": 50, + "details": "Benign range is 6-32 repeats, intermediate range 40-49, and pathogenic range is 51-78 [@pmid:37906407]; intermediate alleles are associated with reduced penetrance [@pmid:11198281].", + "mechanism": "GoF", + "mechanism_detail": "Polyalanine gain of function associated with RAN translation [@pmid:38467784].", + "year": "1999 [@pmid:10581021]", + "location_in_gene": "5' UTR", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "GCT" + ], + "pathogenic_motif_reference_orientation": [ + "GCT" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "AGC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 6, + "benign_max": 32, + "intermediate_min": 40, + "intermediate_max": 49, + "pathogenic_min": 51, + "pathogenic_max": 78, + "motif_len": 3, + "ref_copies": 10.7, + "novel": "ref", + "gard": [ + "10476" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "SPN293" + ], + "medgen": [ + "347653" + ], + "mondo": [ + "0011439" + ], + "omim": [ + "604326" + ], + "orphanet": [ + "98762" + ], + "gnomad": [ + "PPP2R2B" + ], + "stripy": [ + "PPP2R2B" + ], + "tr_atlas": [ + "TR59714" + ], + "webstr_hg38": [ + "985593", + "6072892" + ], + "webstr_hg19": [ + "Expansion_SCA12/PPP2R2B" + ], + "locus_tags": [ + "supported_evidence", + "length_affects_penetrance" + ], + "disease_tags": [ + "spinocerebellar_ataxia" + ], + "references": [ + "omim:604326", + "pmid:38467784", + "pmid:37906407", + "pmid:11198281", + "pmid:34711523", + "pmid:10581021", + "mondo:0011439" + ], + "additional_literature": [ + "pmid:41074692", + "pmid:40488180", + "pmid:39565297", + "pmid:39469072", + "pmid:38961870", + "pmid:38798069", + "pmid:38711441", + "pmid:38227102", + "pmid:38058854", + "pmid:35531119", + "pmid:33502644", + "pmid:32675418", + "pmid:32124191", + "pmid:30130680", + "pmid:29057148", + "pmid:27864267", + "pmid:26340331", + "pmid:26077168", + "pmid:25634432", + "pmid:25586539", + "pmid:25274186", + "pmid:24269018", + "pmid:21029765", + "pmid:20937954", + "pmid:20533062", + "pmid:18940801", + "pmid:18484086", + "pmid:17961920", + "pmid:16054804", + "pmid:11171892" + ] + }, { - "motif": "GCT", - "count": 2, - "type": "flank_repeat" + "id": "HSAN-VIII_PRDM12", + "disease_id": "HSAN VIII", + "gene": "PRDM12", + "chrom": "chr9", + "start_hg38": 130681605, + "stop_hg38": 130681641, + "start_hg19": 133556992, + "stop_hg19": 133557028, + "start_t2t": 142886568, + "stop_t2t": 142886595, + "disease": "Hereditary sensory and autonomic neuropathy type VIII", + "inheritance": [ + "AR" + ], + "disease_description": "A hereditary sensory neuropathy characterized by congenital insensitivity to pain and decreased sweating and tear production that has material basis in homozygous mutation in the PRDM12 gene on chromosome 9q34 [@mondo:0014662].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Expansions found in 2 families from Pakistan and Saudi Arabia [@pmid:26005867]. All PRDM12 disease mutations < 1/1,000,000", + "age_onset": "0 (birth)", + "age_onset_min": 0, + "age_onset_max": 0, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "Pathogenic expansion found in 2 families, from whom pathogenic range (18-19) is inferred [@pmid:26005867]. Benign range (7-14) inferred from Human Gene Mutation Database [@genereviews:NBK535148].", + "mechanism": "LoF", + "mechanism_detail": "Mutations abrogate the histone-modifying potential of PRDM12, consistent with a loss of function mechanism [@omim:616488].", + "year": "2015 [@pmid:26005867]", + "location_in_gene": "Coding Exon 5", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GCC" + ], + "pathogenic_motif_reference_orientation": [ + "GCC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CCG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 7, + "benign_max": 14, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 18, + "pathogenic_max": 19, + "motif_len": 3, + "ref_copies": 12, + "novel": "ref", + "gard": [ + "17866" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "NRP044" + ], + "medgen": [ + "894363" + ], + "mondo": [ + "0014662" + ], + "omim": [ + "616488" + ], + "orphanet": [ + "478664" + ], + "gnomad": [ + "PRDM12" + ], + "stripy": [ + "PRDM12" + ], + "tr_atlas": [ + "TR97506" + ], + "webstr_hg38": [ + "1543400" + ], + "webstr_hg19": [ + "STR_1521945" + ], + "locus_tags": [ + "limited_evidence" + ], + "disease_tags": [], + "references": [ + "omim:616488", + "pmid:26005867", + "genereviews:NBK535148", + "mondo:0014662" + ], + "additional_literature": [] }, { - "motif": "GTT", - "count": 1, - "type": "flank_repeat" + "id": "CJD_PRNP", + "disease_id": "CJD", + "gene": "PRNP", + "chrom": "chr20", + "start_hg38": 4699397, + "stop_hg38": 4699493, + "start_hg19": 4680043, + "stop_hg19": 4680139, + "start_t2t": 4738633, + "stop_t2t": 4738705, + "disease": "Creutzfeldt-Jakob disease", + "inheritance": [ + "AD" + ], + "disease_description": "Inherited or familial Creutzfeldt-Jakob disease (fCJD) is a very rare form of genetic prion disease characterized by typical CJD features (rapidly progressive dementia, personality/behavioral changes, psychiatric disorders, myoclonus, and ataxia) with a genetic cause and sometimes a family history of dementia [@mondo:0007403].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "<0.0225/1,000,000: <15% of CJ variants are repeat expansions [@genereviews:NBK535148]. 15% newly diagnosed prion disease cases are genetic [@genereviews:NBK1229], 1 individual per million per year worldwide (350 cases annually in US) [@pmid:29939637]. Found worldwide [@genereviews:NBK1229].", + "age_onset": "Typical: 50-60 [@genereviews:NBK1229]; Range: 31-63 [@pmid:37379724].", + "age_onset_min": 31, + "age_onset_max": 63, + "typ_age_onset_min": 50, + "typ_age_onset_max": 60, + "details": "Normal PRNP alleles have one nonapeptide followed by four octapeptide tandem repeat sequences, each of which comprises the amino acids: Pro-(His/Gln)-Gly-Gly-Gly-(-/Trp)-Gly-Gln; any additional repeat leads to pathogenicity, with the largest repeat observed 16 motifs [@genereviews:NBK1229]. Insertion length may correspond to phenotype, such as CJD versus frontotemporal dementia [@pmid:36977684].", + "mechanism": "LoF?", + "mechanism_detail": "Loss of function hypothesized [@pmid:38467784]", + "year": "1991 [@pmid:1683708]", + "location_in_gene": "Coding Exon 2", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GGTGGTGGCTGGGGGCAGCCTCAT" + ], + "pathogenic_motif_reference_orientation": [ + "CCTCATGGTGGTGGCTGGGGGCAG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "AGCCTCATGGTGGTGGCTGGGGGC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [ + { + "motif": "CCTCAGGGCGGTGGTGGCTGGGGGCAG", + "count": 1, + "type": "flank_repeat" + }, + { + "motif": "CCTCATGGTGGTGGCTGGGGGCAG", + "count": null, + "type": "pathogenic_repeat" + } + ], + "benign_min": 4, + "benign_max": 4, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 5, + "pathogenic_max": 16, + "motif_len": 24, + "ref_copies": null, + "novel": "ref", + "gard": [ + "17307" + ], + "genereviews": [ + "NBK1229" + ], + "malacard": [ + "CRT072" + ], + "medgen": [ + "155837" + ], + "mondo": [ + "0007403" + ], + "omim": [ + "123400" + ], + "orphanet": [ + "282166" + ], + "gnomad": [ + "PRNP" + ], + "stripy": [], + "tr_atlas": [ + "TR157963", + "TR157964" + ], + "webstr_hg38": [], + "webstr_hg19": [], + "locus_tags": [ + "supported_evidence", + "length_affects_phenotype" + ], + "disease_tags": [], + "references": [ + "genereviews:NBK1229", + "pmid:37379724", + "pmid:38467784", + "pmid:36977684", + "genereviews:NBK535148", + "pmid:29939637", + "pmid:1683708", + "mondo:0007403" + ], + "additional_literature": [ + "pmid:41009775", + "pmid:40803449", + "pmid:39256877", + "pmid:35926480", + "pmid:35903139", + "pmid:35752680", + "pmid:35585119", + "pmid:33131137", + "pmid:31795947", + "pmid:31127772", + "pmid:30777654", + "pmid:30530974", + "pmid:29966485", + "pmid:28003435", + "pmid:27400454", + "pmid:25239657", + "pmid:23998997", + "pmid:21686668", + "pmid:19092329", + "pmid:18397498", + "pmid:18366654", + "pmid:17709704", + "pmid:16858508", + "pmid:15643617", + "pmid:14729275", + "pmid:12805114", + "pmid:12451210", + "pmid:11593450", + "pmid:10611945", + "pmid:9710033", + "pmid:9565627", + "pmid:8030952" + ] }, { - "motif": "GCT", - "count": null, - "type": "pathogenic_repeat" - }], - "benign_min": 10, - "benign_max": 10, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": null, - "pathogenic_max": null, - "motif_len": 3, - "ref_copies": 13.7, - "novel": "ref", - "gard": ["15215", "13174"], - "genereviews": [], - "malacard": ["PRG130", "PRK002"], - "medgen": ["897191", "371919"], - "mondo": ["0009783", "0024528"], - "omim": ["258450", "157640"], - "orphanet": ["520820"], - "gnomad": [], - "stripy": [], - "tr_atlas": ["TR137533"], - "webstr_hg38": ["5177947"], - "webstr_hg19": ["STR_493430"], - "locus_tags": ["contradictory_evidence", "proposed_modifier"], - "disease_tags": [], - "references": ["pmid:20399836", "pmid:20826197", "pmid:10196696", "pmid:22963882", "pmid:19043662", "omim:258450", "omim:157640", "pmid:38876750"], - "additional_literature": ["pmid:41009775", "pmid:40844737", "pmid:39812846", "pmid:34600502", "pmid:29029963", "pmid:28444220", "pmid:25767537", "pmid:24491464", "pmid:23912752", "pmid:23493802", "pmid:20803511", "pmid:15694274", "pmid:12036482"] -}, -{ - "id": "SCA12_PPP2R2B", - "disease_id": "SCA12", - "gene": "PPP2R2B", - "chrom": "chr5", - "start_hg38": 146878727, - "stop_hg38": 146878759, - "start_hg19": 146258290, - "stop_hg19": 146258322, - "start_t2t": 147414733, - "stop_t2t": 147414780, - "disease": "Spinocerebellar ataxia type 12", - "inheritance": ["AD"], - "disease_description": "Spinocerebellar ataxia type 12 (SCA12) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I). It is characterized by the presence of action tremor associated with relatively mild cerebellar ataxia. Associated pyramidal and extrapyramidal signs and dementia have been reported [@mondo:0011439].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Frequent in India; rare in other populations [@pmid:34711523].", - "age_onset": "Typical: 26-50; Range: 8-56 [@omim:604326].", - "age_onset_min": 8.0, - "age_onset_max": 62.0, - "typ_age_onset_min": 26.0, - "typ_age_onset_max": 50.0, - "details": "Benign range is 6-32 repeats, intermediate range 40-49, and pathogenic range is 51-78 [@pmid:37906407]; intermediate alleles are associated with reduced penetrance [@pmid:11198281].", - "mechanism": "GoF", - "mechanism_detail": "Polyalanine gain of function associated with RAN translation [@pmid:38467784].", - "year": "1999 [@pmid:10581021]", - "location_in_gene": "5' UTR", - "gene_strand": "-", - "reference_motif_reference_orientation": ["GCT"], - "pathogenic_motif_reference_orientation": ["GCT"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["AGC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 6, - "benign_max": 32, - "intermediate_min": 40, - "intermediate_max": 49, - "pathogenic_min": 51, - "pathogenic_max": 78, - "motif_len": 3, - "ref_copies": 10.7, - "novel": "ref", - "gard": ["10476"], - "genereviews": ["NBK535148"], - "malacard": ["SPN293"], - "medgen": ["347653"], - "mondo": ["0011439"], - "omim": ["604326"], - "orphanet": ["98762"], - "gnomad": ["PPP2R2B"], - "stripy": ["PPP2R2B"], - "tr_atlas": ["TR59714"], - "webstr_hg38": ["985593", "6072892"], - "webstr_hg19": ["Expansion_SCA12/PPP2R2B"], - "locus_tags": ["supported_evidence", "length_affects_penetrance"], - "disease_tags": ["spinocerebellar_ataxia"], - "references": ["omim:604326", "pmid:38467784", "pmid:37906407", "pmid:11198281", "pmid:34711523", "pmid:10581021", "mondo:0011439"], - "additional_literature": ["pmid:41074692", "pmid:40488180", "pmid:39565297", "pmid:39469072", "pmid:38961870", "pmid:38798069", "pmid:38711441", "pmid:38227102", "pmid:38058854", "pmid:35531119", "pmid:33502644", "pmid:32675418", "pmid:32124191", "pmid:30130680", "pmid:29057148", "pmid:27864267", "pmid:26340331", "pmid:26077168", "pmid:25634432", "pmid:25586539", "pmid:25274186", "pmid:24269018", "pmid:21029765", "pmid:20937954", "pmid:20533062", "pmid:18940801", "pmid:18484086", "pmid:17961920", "pmid:16054804", "pmid:11171892"] -}, -{ - "id": "HSAN-VIII_PRDM12", - "disease_id": "HSAN VIII", - "gene": "PRDM12", - "chrom": "chr9", - "start_hg38": 130681605, - "stop_hg38": 130681641, - "start_hg19": 133556992, - "stop_hg19": 133557028, - "start_t2t": 142886568, - "stop_t2t": 142886595, - "disease": "Hereditary sensory and autonomic neuropathy type VIII", - "inheritance": ["AR"], - "disease_description": "A hereditary sensory neuropathy characterized by congenital insensitivity to pain and decreased sweating and tear production that has material basis in homozygous mutation in the PRDM12 gene on chromosome 9q34 [@mondo:0014662].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Expansions found in 2 families from Pakistan and Saudi Arabia [@pmid:26005867]. All PRDM12 disease mutations < 1/1,000,000", - "age_onset": "0 (birth)", - "age_onset_min": 0.0, - "age_onset_max": 0.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "Pathogenic expansion found in 2 families, from whom pathogenic range (18-19) is inferred [@pmid:26005867]. Benign range (7-14) inferred from Human Gene Mutation Database [@genereviews:NBK535148].", - "mechanism": "LoF", - "mechanism_detail": "Mutations abrogate the histone-modifying potential of PRDM12, consistent with a loss of function mechanism [@omim:616488].", - "year": "2015 [@pmid:26005867]", - "location_in_gene": "Coding Exon 5", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GCC"], - "pathogenic_motif_reference_orientation": ["GCC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CCG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 7, - "benign_max": 14, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 18, - "pathogenic_max": 19, - "motif_len": 3, - "ref_copies": 12.0, - "novel": "ref", - "gard": ["17866"], - "genereviews": ["NBK535148"], - "malacard": ["NRP044"], - "medgen": ["894363"], - "mondo": ["0014662"], - "omim": ["616488"], - "orphanet": ["478664"], - "gnomad": ["PRDM12"], - "stripy": ["PRDM12"], - "tr_atlas": ["TR97506"], - "webstr_hg38": ["1543400"], - "webstr_hg19": ["STR_1521945"], - "locus_tags": ["limited_evidence"], - "disease_tags": [], - "references": ["omim:616488", "pmid:26005867", "genereviews:NBK535148", "mondo:0014662"], - "additional_literature": [] -}, -{ - "id": "CJD_PRNP", - "disease_id": "CJD", - "gene": "PRNP", - "chrom": "chr20", - "start_hg38": 4699397, - "stop_hg38": 4699493, - "start_hg19": 4680043, - "stop_hg19": 4680139, - "start_t2t": 4738633, - "stop_t2t": 4738705, - "disease": "Creutzfeldt-Jakob disease", - "inheritance": ["AD"], - "disease_description": "Inherited or familial Creutzfeldt-Jakob disease (fCJD) is a very rare form of genetic prion disease characterized by typical CJD features (rapidly progressive dementia, personality/behavioral changes, psychiatric disorders, myoclonus, and ataxia) with a genetic cause and sometimes a family history of dementia [@mondo:0007403].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "<0.0225/1,000,000: <15% of CJ variants are repeat expansions [@genereviews:NBK535148]. 15% newly diagnosed prion disease cases are genetic [@genereviews:NBK1229], 1 individual per million per year worldwide (350 cases annually in US) [@pmid:29939637]. Found worldwide [@genereviews:NBK1229].", - "age_onset": "Typical: 50-60 [@genereviews:NBK1229]; Range: 31-63 [@pmid:37379724].", - "age_onset_min": 31.0, - "age_onset_max": 63.0, - "typ_age_onset_min": 50.0, - "typ_age_onset_max": 60.0, - "details": "Normal PRNP alleles have one nonapeptide followed by four octapeptide tandem repeat sequences, each of which comprises the amino acids: Pro-(His/Gln)-Gly-Gly-Gly-(-/Trp)-Gly-Gln; any additional repeat leads to pathogenicity, with the largest repeat observed 16 motifs [@genereviews:NBK1229]. Insertion length may correspond to phenotype, such as CJD versus frontotemporal dementia [@pmid:36977684].", - "mechanism": "LoF?", - "mechanism_detail": "Loss of function hypothesized [@pmid:38467784]", - "year": "1991 [@pmid:1683708]", - "location_in_gene": "Coding Exon 2", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GGTGGTGGCTGGGGGCAGCCTCAT"], - "pathogenic_motif_reference_orientation": ["CCTCATGGTGGTGGCTGGGGGCAG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["AGCCTCATGGTGGTGGCTGGGGGC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [ + "id": "FAME8_RAI1", + "disease_id": "FAME8", + "gene": "RAI1", + "chrom": "chr17", + "start_hg38": 17808358, + "stop_hg38": 17808460, + "start_hg19": 17711672, + "stop_hg19": 17711774, + "start_t2t": 17754961, + "stop_t2t": 17755053, + "disease": "Familial adult myoclonic epilepsy type 8", + "inheritance": [ + "AD" + ], + "disease_description": "Cortical tremor, seizures with generalised motor (tonic-clonic) onset [@pmid:38876750].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Observed in a single family from Mali with ten affected individuals [@pmid:37994247].", + "age_onset": "7-68 (one family)", + "age_onset_min": 7, + "age_onset_max": 68, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "TTTTA repeat expansions and TTTCA repeat insertions in intron 4 of the RAI1 gene that co-segregated with disease status in a single large family from Mali [@pmid:37994247]. Ten affected individuals were studied. Both TTTTA and TTTCA motifs were observed in all eight of the affected individuals with spanning reads, with allele sizes in the range: (TTTTA)278-773(TTTCA)9-334. A single individual was observed with additional motifs and interruptions in one allele with the structure: (TTTTA)exp(GGGGT)ins(GGGAT)ins(TTTCA)ins. TTTCA repeats were absent in 200 Malian controls, who had alleles in the range: (TTTCA)16-20. Reviewed in [@pmid:38876750]. It is uncertain if expansions at both the TTTTA and TTTCA motifs, or only the TTTCA motif are required for pathogogenicity. The pathogenic range in STRchive is for the TTTCA motif only. Note: locus is partially deleted in T2T reference genome", + "mechanism": "Unknown", + "mechanism_detail": "Expression isn't changed [@pmid:7994247].", + "year": "2024 [@pmid:37994247]", + "location_in_gene": "Intron 4", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "TTTTA" + ], + "pathogenic_motif_reference_orientation": [ + "TTTCA" + ], + "benign_motif_reference_orientation": [ + "TTTTA" + ], + "unknown_motif_reference_orientation": [ + "GGGGT", + "GGGAT" + ], + "pathogenic_motif_gene_orientation": [ + "ATTTC" + ], + "benign_motif_gene_orientation": [ + "ATTTT" + ], + "unknown_motif_gene_orientation": [ + "GGGGT", + "ATGGG" + ], + "locus_structure": [ + { + "motif": "TTTTA", + "count": 18, + "type": "internal_repeat" + }, + { + "motif": "TTTCA", + "count": null, + "type": "pathogenic_repeat" + } + ], + "benign_min": null, + "benign_max": null, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 9, + "pathogenic_max": 334, + "motif_len": 5, + "ref_copies": 20.8, + "novel": "novel", + "gard": [ + "16758" + ], + "genereviews": [], + "malacard": [], + "medgen": [], + "mondo": [], + "omim": [], + "orphanet": [ + "86814" + ], + "gnomad": [], + "stripy": [], + "tr_atlas": [], + "webstr_hg38": [ + "486849" + ], + "webstr_hg19": [], + "locus_tags": [ + "limited_evidence", + "motif_affects_onset" + ], + "disease_tags": [ + "familial_adult_myoclonic_epilepsy" + ], + "references": [ + "pmid:7994247", + "pmid:37994247", + "pmid:38876750" + ], + "additional_literature": [ + "pmid:41219789", + "pmid:40541176", + "pmid:38871700", + "pmid:37339841", + "pmid:34565721", + "pmid:33186760", + "pmid:32283749", + "pmid:32281848", + "pmid:30891880", + "pmid:30622881", + "pmid:25663198", + "pmid:23897707", + "pmid:17457615", + "pmid:15148657", + "pmid:11594924", + "pmid:10915763", + "pmid:8817239" + ] + }, { - "motif": "CCTCAGGGCGGTGGTGGCTGGGGGCAG", - "count": 1, - "type": "flank_repeat" + "id": "FAME7_RAPGEF2", + "disease_id": "FAME7", + "gene": "RAPGEF2", + "chrom": "chr4", + "start_hg38": 159342526, + "stop_hg38": 159342618, + "start_hg19": 160263678, + "stop_hg19": 160263770, + "start_t2t": 162693303, + "stop_t2t": 162693405, + "disease": "Familial adult myoclonic epilepsy type 7", + "inheritance": [ + "AD" + ], + "disease_description": "Cortical tremor, seizures with generalised motor (tonic-clonic) onset [@pmid:38876750].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "FAME overall is 1/35,000 in Japan. Repeat expansion found in individuals of East Asian ancestry [@pmid:38876750].", + "age_onset": "Typical: 20-33 [@pmid:30351492]; Range: 18 [@pmid:29507423] - 37 [@pmid:30351492].", + "age_onset_min": 18, + "age_onset_max": 37, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "The locus structure is (TTTTA)exp(TTTCA)exp(TTTTA)n, where only the TTTCA is specific to affected individuals as a pathogenic insertion [@pmid:29507423; @pmid:30351492]. Pathogenic expansions range from 60 to thousands of repeats [@pmid:29507423; @pmid:30351492]. Interruptions seen: TATTA, TTTTTA [@pmid:35245110].", + "mechanism": "GoF?", + "mechanism_detail": "RNA toxicity hypothesized [@pmid:29507423].", + "year": "2018 [@pmid:29507423]", + "location_in_gene": "Intron 14", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "TTTTA" + ], + "pathogenic_motif_reference_orientation": [ + "TTTCA" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [ + "TTTTT", + "TTATG" + ], + "pathogenic_motif_gene_orientation": [ + "ATTTC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [ + "TTTTT", + "ATGTT" + ], + "locus_structure": [ + { + "motif": "TTTTA", + "count": 17, + "type": "internal_repeat" + }, + { + "motif": "TTTCA", + "count": null, + "type": "pathogenic_repeat" + } + ], + "benign_min": null, + "benign_max": null, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 60, + "pathogenic_max": 2200, + "motif_len": 5, + "ref_copies": 17.4, + "novel": "novel", + "gard": [ + "16758" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "EPL228" + ], + "medgen": [ + "1648435" + ], + "mondo": [ + "0054847" + ], + "omim": [ + "618075" + ], + "orphanet": [ + "86814" + ], + "gnomad": [ + "RAPGEF2" + ], + "stripy": [ + "RAPGEF2" + ], + "tr_atlas": [ + "TR49300" + ], + "webstr_hg38": [ + "154264", + "4792219" + ], + "webstr_hg19": [ + "STR_1096016" + ], + "locus_tags": [ + "limited_evidence", + "motif_affects_penetrance" + ], + "disease_tags": [ + "familial_adult_myoclonic_epilepsy" + ], + "references": [ + "pmid:30351492", + "pmid:29507423", + "pmid:35245110", + "pmid:38876750" + ], + "additional_literature": [ + "pmid:41219789", + "pmid:36092952", + "pmid:33040085", + "pmid:31483537" + ] }, { - "motif": "CCTCATGGTGGTGGCTGGGGGCAG", - "count": null, - "type": "pathogenic_repeat" - }], - "benign_min": 4, - "benign_max": 4, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 5, - "pathogenic_max": 16, - "motif_len": 24, - "ref_copies": null, - "novel": "ref", - "gard": ["17307"], - "genereviews": ["NBK1229"], - "malacard": ["CRT072"], - "medgen": ["155837"], - "mondo": ["0007403"], - "omim": ["123400"], - "orphanet": ["282166"], - "gnomad": ["PRNP"], - "stripy": [], - "tr_atlas": ["TR157963", "TR157964"], - "webstr_hg38": [], - "webstr_hg19": [], - "locus_tags": ["supported_evidence", "length_affects_phenotype"], - "disease_tags": [], - "references": ["genereviews:NBK1229", "pmid:37379724", "pmid:38467784", "pmid:36977684", "genereviews:NBK535148", "pmid:29939637", "pmid:1683708", "mondo:0007403"], - "additional_literature": ["pmid:41009775", "pmid:40803449", "pmid:39256877", "pmid:35926480", "pmid:35903139", "pmid:35752680", "pmid:35585119", "pmid:33131137", "pmid:31795947", "pmid:31127772", "pmid:30777654", "pmid:30530974", "pmid:29966485", "pmid:28003435", "pmid:27400454", "pmid:25239657", "pmid:23998997", "pmid:21686668", "pmid:19092329", "pmid:18397498", "pmid:18366654", "pmid:17709704", "pmid:16858508", "pmid:15643617", "pmid:14729275", "pmid:12805114", "pmid:12451210", "pmid:11593450", "pmid:10611945", "pmid:9710033", "pmid:9565627", "pmid:8030952"] -}, -{ - "id": "FAME8_RAI1", - "disease_id": "FAME8", - "gene": "RAI1", - "chrom": "chr17", - "start_hg38": 17808358, - "stop_hg38": 17808460, - "start_hg19": 17711672, - "stop_hg19": 17711774, - "start_t2t": 17754961, - "stop_t2t": 17755053, - "disease": "Familial adult myoclonic epilepsy type 8", - "inheritance": ["AD"], - "disease_description": "Cortical tremor, seizures with generalised motor (tonic-clonic) onset [@pmid:38876750].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Observed in a single family from Mali with ten affected individuals [@pmid:37994247].", - "age_onset": "7-68 (one family)", - "age_onset_min": 7.0, - "age_onset_max": 68.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "TTTTA repeat expansions and TTTCA repeat insertions in intron 4 of the RAI1 gene that co-segregated with disease status in a single large family from Mali [@pmid:37994247]. Ten affected individuals were studied. Both TTTTA and TTTCA motifs were observed in all eight of the affected individuals with spanning reads, with allele sizes in the range: (TTTTA)278-773(TTTCA)9-334. A single individual was observed with additional motifs and interruptions in one allele with the structure: (TTTTA)exp(GGGGT)ins(GGGAT)ins(TTTCA)ins. TTTCA repeats were absent in 200 Malian controls, who had alleles in the range: (TTTCA)16-20. Reviewed in [@pmid:38876750]. It is uncertain if expansions at both the TTTTA and TTTCA motifs, or only the TTTCA motif are required for pathogogenicity. The pathogenic range in STRchive is for the TTTCA motif only. Note: locus is partially deleted in T2T reference genome", - "mechanism": "Unknown", - "mechanism_detail": "Expression isn't changed [@pmid:7994247].", - "year": "2024 [@pmid:37994247]", - "location_in_gene": "Intron 4", - "gene_strand": "+", - "reference_motif_reference_orientation": ["TTTTA"], - "pathogenic_motif_reference_orientation": ["TTTCA"], - "benign_motif_reference_orientation": ["TTTTA"], - "unknown_motif_reference_orientation": ["GGGGT", "GGGAT"], - "pathogenic_motif_gene_orientation": ["ATTTC"], - "benign_motif_gene_orientation": ["ATTTT"], - "unknown_motif_gene_orientation": ["GGGGT", "ATGGG"], - "locus_structure": [ + "id": "CANVAS_RFC1", + "disease_id": "CANVAS", + "gene": "RFC1", + "chrom": "chr4", + "start_hg38": 39348424, + "stop_hg38": 39348483, + "start_hg19": 39350044, + "stop_hg19": 39350103, + "start_t2t": 39318077, + "stop_t2t": 39318136, + "disease": "Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome", + "inheritance": [ + "AR" + ], + "disease_description": "Sensory disturbances, imbalance, oscillopsia, chronic dry cough, dysarthria and dysphagia [@pmid:38876750]; Late-onset ataxia, sensory neuropathy, vestibular areflexia syndrome [@pmid:39349043]. This expansion has been implicated in the genetic etiology of Parkinson's disease [@pmid:41177915].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Carrier frequency in European is 0.7-4% and in Chinese Han population is 2.24%; estimated prevalence of 1/20,000 to 1/625 [@genereviews:NBK564656]. Many cases are likely not diagnosed due to heterogeneous presentation [@pmid:39230846]. Observed in multiple ethnicities [@pmid:38876750]; patients diagnosed with European, Chinese Han, and Maori ancestry, as well as found in Japan, Canada, Brazil, the UK, Italy, Germany, and Australia [@genereviews:NBK564656].", + "age_onset": "Typical: 36-52; Range: 19-76 [@genereviews:NBK564656].", + "age_onset_min": 19, + "age_onset_max": 76, + "typ_age_onset_min": 36, + "typ_age_onset_max": 52, + "details": "Disease is caused by an insertion of a pathogenic motif, although motif presence is variable and can expand up to 200 repeats without apparently causing a phenotype [@genereviews:NBK564656]. Pathogenic expansions (ranging from 400-2750 pathogenic motifs) may be flanked by other motifs [@genereviews:NBK564656]. For example, (AAAGG)10-25(AAGGG)exp(AAAGG)4-6 [@pmid:32851396]. Motif heterogeneity is common in unaffected individuals [@genereviews:NBK564656], and motif associations are described by Delforge et al [@pmid:38627134]. The pathogenic size threshold appears to differ for the AAAGG motif: AAAGG expansions >= 600 repeats have been observed in CANVAS patients (vs 400 with established pathogenic motif AAGGG), while ~100-380 AAAGG repeats were found in unaffected controls [@pmid:37450567]. Length appears to impact age of onset and disease severity, with particular impact from the smaller allele [@doi:10.1136/jnnp-2024-ABN.259]. Phenotypic spectrum may include Parkinsonism [@pmid:39833204] and chronic cough [@pmid:39811557].", + "mechanism": "LoF", + "mechanism_detail": "LoF; exact mechanism unknown [@pmid:38467784].", + "year": "2019 [@pmid:31230722]", + "location_in_gene": "Intron 2", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "AAAAG" + ], + "pathogenic_motif_reference_orientation": [ + "AAGGG", + "ACAGG", + "AGGGC", + "AAGGC", + "AGAGG" + ], + "benign_motif_reference_orientation": [ + "AAAAG", + "AAAGG", + "AAGAG", + "AAAGGG" + ], + "unknown_motif_reference_orientation": [ + "AAAAA", + "AAAAC", + "AACGG", + "AAGAC", + "AAGGT", + "AGAAC", + "AGGGG", + "GAAAC", + "GGGAC", + "GTGAG", + "AAAAGA", + "AAAGGA", + "GGAAAG" + ], + "pathogenic_motif_gene_orientation": [ + "CCCTT", + "CCTGT", + "CCCTG", + "CCTTG", + "CCTCT" + ], + "benign_motif_gene_orientation": [ + "CTTTT", + "CCTTT", + "CTCTT", + "CCCTTT" + ], + "unknown_motif_gene_orientation": [ + "TTTTT", + "GTTTT", + "CCGTT", + "CTTGT", + "ACCTT", + "CTGTT", + "CCCCT", + "CGTTT", + "CCCGT", + "ACCTC", + "CTTTTT", + "CCTTTT", + "CCCTTT" + ], + "locus_structure": [ + { + "motif": "AAAAG", + "count": 11, + "type": "internal_repeat" + }, + { + "motif": "AAGGG", + "count": null, + "type": "pathogenic_repeat" + } + ], + "benign_min": 0, + "benign_max": 11, + "intermediate_min": 11, + "intermediate_max": 200, + "pathogenic_min": 400, + "pathogenic_max": 2750, + "motif_len": 5, + "ref_copies": 11.8, + "novel": "novel", + "gard": [ + "17937" + ], + "genereviews": [ + "NBK564656" + ], + "malacard": [ + "CRB196" + ], + "medgen": [ + "482853" + ], + "mondo": [ + "0044720" + ], + "omim": [ + "614575" + ], + "orphanet": [ + "504476" + ], + "gnomad": [ + "RFC1" + ], + "stripy": [ + "RFC1" + ], + "tr_atlas": [ + "TR42349" + ], + "webstr_hg38": [ + "4722884", + "99101" + ], + "webstr_hg19": [ + "STR_1036603" + ], + "locus_tags": [ + "supported_evidence", + "motif_affects_penetrance", + "length_affects_onset", + "length_affects_severity" + ], + "disease_tags": [ + "ataxia", + "phenotypic_spectrum" + ], + "references": [ + "genereviews:NBK564656", + "pmid:38467784", + "pmid:32851396", + "pmid:38627134", + "pmid:37450567", + "doi:10.1136/jnnp-2024-ABN.259", + "pmid:39833204", + "pmid:39811557", + "pmid:39230846", + "pmid:38876750", + "pmid:31230722", + "pmid:39349043", + "pmid:41177915" + ], + "additional_literature": [ + "pmid:41426430", + "pmid:41327893", + "pmid:41322202", + "pmid:41278766", + "pmid:41145152", + "pmid:41118032", + "pmid:41084404", + "pmid:41074692", + "pmid:41055766", + "pmid:40898875", + "pmid:40894141", + "pmid:40802152", + "pmid:40765612", + "pmid:40637932", + "pmid:40595562", + "pmid:40594369", + "pmid:40488180", + "pmid:40481300", + "pmid:40461673", + "pmid:40417743", + "pmid:40313272", + "pmid:40273470", + "pmid:40221271", + "pmid:40211677", + "pmid:40204545", + "pmid:40141365", + "pmid:40113266", + "pmid:40007153", + "pmid:39812846", + "pmid:39721397", + "pmid:39571249", + "pmid:39543176", + "pmid:39507594", + "pmid:39416949", + "pmid:39406499", + "pmid:39342186", + "pmid:39286915", + "pmid:39231235", + "pmid:39219417", + "pmid:39152783", + "pmid:39076534", + "pmid:38978724", + "pmid:38916676", + "pmid:38789445", + "pmid:38579416", + "pmid:38487929", + "pmid:38447794", + "pmid:38381906", + "pmid:38381176", + "pmid:38324175", + "pmid:38311638", + "pmid:38306376", + "pmid:38266156", + "pmid:38193360", + "pmid:38168171", + "pmid:38145611", + "pmid:38062616", + "pmid:38054570", + "pmid:37917284", + "pmid:37892228", + "pmid:37853169", + "pmid:37747091", + "pmid:37660923", + "pmid:37578187", + "pmid:37546920", + "pmid:37476326", + "pmid:37460231", + "pmid:37414537", + "pmid:37399286", + "pmid:36805468", + "pmid:36753892", + "pmid:36705320", + "pmid:36381255", + "pmid:36289003", + "pmid:36250766", + "pmid:36227727", + "pmid:36214978", + "pmid:36177974", + "pmid:36088850", + "pmid:36061987", + "pmid:36046423", + "pmid:36034314", + "pmid:35884855", + "pmid:35883251", + "pmid:35864213", + "pmid:35633373", + "pmid:35585435", + "pmid:35502508", + "pmid:35355059", + "pmid:35306791", + "pmid:35253317", + "pmid:38835435", + "pmid:35013364", + "pmid:34968871", + "pmid:34927205", + "pmid:34600502", + "pmid:34537679", + "pmid:34101140", + "pmid:33969391", + "pmid:33940977", + "pmid:33884451", + "pmid:33807868", + "pmid:33745133", + "pmid:33666721", + "pmid:33495376", + "pmid:33188504", + "pmid:33103729", + "pmid:33068477", + "pmid:33068476", + "pmid:32949124", + "pmid:32939785", + "pmid:32910249", + "pmid:32873692", + "pmid:32732387", + "pmid:32694621", + "pmid:32682126", + "pmid:32582864", + "pmid:32151945", + "pmid:32066831", + "pmid:32040566", + "pmid:31824583", + "pmid:31817852", + "pmid:31370354", + "pmid:30926972", + "pmid:25648260", + "pmid:25007187", + "pmid:24686188", + "pmid:22086855", + "pmid:15457444", + "pmid:12556494" + ] + }, { - "motif": "TTTTA", - "count": 18, - "type": "internal_repeat" + "id": "OPDM4_RILPL1", + "disease_id": "OPDM4", + "gene": "RILPL1", + "chrom": "chr12", + "start_hg38": 123533720, + "stop_hg38": 123533750, + "start_hg19": 124018267, + "stop_hg19": 124018297, + "start_t2t": 123532573, + "stop_t2t": 123532603, + "disease": "Oculopharyngodistal myopathy type 4", + "inheritance": [ + "AD" + ], + "disease_description": "Ptosis, external ophthalmoplegia, facial weakness, and pharyngeal and distal limb weakness [@pmid:38876750].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Population dependent: 21.6% of one OPDM cohort [@pmid:35148830]. Typically found in individuals of East Asian ancestry [@pmid:38876750].", + "age_onset": "Typical: 18-30 [@pmid:35148830]; Range: 10-30 [@pmid:35700120].", + "age_onset_min": 10, + "age_onset_max": 30, + "typ_age_onset_min": 18, + "typ_age_onset_max": 30, + "details": "Benign alleles have been documented to have 6-16 repeats [@pmid:37864208], while pathogenic repeats range from 120 to 197 repeats; there is no apparent relationship between allele size and age of onset [@pmid:37864208; @pmid:35148830]. Intermediate alleles amy be associated with incomplete penetrance, or milder phenotypes [@pmid:35148830]. AGG and TGG interruptions observed [@pmid:35148830].", + "mechanism": "GoF", + "mechanism_detail": "Polyglutamine expansion leading to RNA-mediated gain-of-function mechanism [@pmid:38467784].", + "year": "2022 [@pmid:35148830]", + "location_in_gene": "5' UTR", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "GGC" + ], + "pathogenic_motif_reference_orientation": [ + "GGC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CCG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 6, + "benign_max": 16, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 120, + "pathogenic_max": 197, + "motif_len": 3, + "ref_copies": 11.7, + "novel": "ref", + "gard": [ + "12592" + ], + "genereviews": [], + "malacard": [ + "OCL085" + ], + "medgen": [ + "1809981" + ], + "mondo": [ + "0030712" + ], + "omim": [], + "orphanet": [ + "98897" + ], + "gnomad": [ + "RILPL1" + ], + "stripy": [ + "RILPL1" + ], + "tr_atlas": [ + "TR121403" + ], + "webstr_hg38": [ + "5128610", + "609239" + ], + "webstr_hg19": [ + "STR_347096" + ], + "locus_tags": [ + "supported_evidence" + ], + "disease_tags": [ + "oculopharyngodistal_myopathy" + ], + "references": [ + "pmid:35148830", + "pmid:35700120", + "pmid:38467784", + "pmid:37864208", + "pmid:38876750" + ], + "additional_literature": [ + "pmid:40645757", + "pmid:40084170", + "pmid:39044557", + "pmid:39013564", + "pmid:37923380" + ] }, { - "motif": "TTTCA", - "count": null, - "type": "pathogenic_repeat" - }], - "benign_min": null, - "benign_max": null, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 9, - "pathogenic_max": 334, - "motif_len": 5, - "ref_copies": 20.8, - "novel": "novel", - "gard": ["16758"], - "genereviews": [], - "malacard": [], - "medgen": [], - "mondo": [], - "omim": [], - "orphanet": ["86814"], - "gnomad": [], - "stripy": [], - "tr_atlas": [], - "webstr_hg38": ["486849"], - "webstr_hg19": [], - "locus_tags": ["limited_evidence", "motif_affects_onset"], - "disease_tags": ["familial_adult_myoclonic_epilepsy"], - "references": ["pmid:7994247", "pmid:37994247", "pmid:38876750"], - "additional_literature": ["pmid:41219789", "pmid:40541176", "pmid:38871700", "pmid:37339841", "pmid:34565721", "pmid:33186760", "pmid:32283749", "pmid:32281848", "pmid:30891880", "pmid:30622881", "pmid:25663198", "pmid:23897707", "pmid:17457615", "pmid:15148657", "pmid:11594924", "pmid:10915763", "pmid:8817239"] -}, -{ - "id": "FAME7_RAPGEF2", - "disease_id": "FAME7", - "gene": "RAPGEF2", - "chrom": "chr4", - "start_hg38": 159342526, - "stop_hg38": 159342618, - "start_hg19": 160263678, - "stop_hg19": 160263770, - "start_t2t": 162693303, - "stop_t2t": 162693405, - "disease": "Familial adult myoclonic epilepsy type 7", - "inheritance": ["AD"], - "disease_description": "Cortical tremor, seizures with generalised motor (tonic-clonic) onset [@pmid:38876750].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "FAME overall is 1/35,000 in Japan. Repeat expansion found in individuals of East Asian ancestry [@pmid:38876750].", - "age_onset": "Typical: 20-33 [@pmid:30351492]; Range: 18 [@pmid:29507423] - 37 [@pmid:30351492].", - "age_onset_min": 18.0, - "age_onset_max": 37.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "The locus structure is (TTTTA)exp(TTTCA)exp(TTTTA)n, where only the TTTCA is specific to affected individuals as a pathogenic insertion [@pmid:29507423; @pmid:30351492]. Pathogenic expansions range from 60 to thousands of repeats [@pmid:29507423; @pmid:30351492]. Interruptions seen: TATTA, TTTTTA [@pmid:35245110].", - "mechanism": "GoF?", - "mechanism_detail": "RNA toxicity hypothesized [@pmid:29507423].", - "year": "2018 [@pmid:29507423]", - "location_in_gene": "Intron 14", - "gene_strand": "+", - "reference_motif_reference_orientation": ["TTTTA"], - "pathogenic_motif_reference_orientation": ["TTTCA"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": ["TTTTT", "TTATG"], - "pathogenic_motif_gene_orientation": ["ATTTC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": ["TTTTT", "ATGTT"], - "locus_structure": [ + "id": "CCD_RUNX2", + "disease_id": "CCD", + "gene": "RUNX2", + "chrom": "chr6", + "start_hg38": 45422750, + "stop_hg38": 45422801, + "start_hg19": 45390487, + "stop_hg19": 45390538, + "start_t2t": 45257567, + "stop_t2t": 45257618, + "disease": "Cleidocranial dysplasia", + "inheritance": [ + "AD" + ], + "disease_description": "A condition that primarily affects the development of the bones and teeth. Characteristic features include underdeveloped or absent collarbones (clavicles); dental abnormalities; and delayed closing of the spaces between the skull bones (fontanels). Other features may include decreased bone density (osteopenia), osteoporosis, hearing loss, bone abnormalities of the hands, and recurrent sinus and ear infections. [@mondo:0007340].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "All conditions 1/1,000,000 births (likely underdiagnosed); Utah population frequency 0.12/10,000. Found in many ethnic groups [@orphanet:1452]. TR expansions causative in 2 individuals [@genereviews:NBK535148].", + "age_onset": "0 (birth) [@genereviews:NBK1513].", + "age_onset_min": 0, + "age_onset_max": 0, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "Benign range (4-17 repeats) established from gnomAD and primary literature; pathogenic ranges (20-27) reflect two clinical cases to date [@gnomad:RUNX2; @pmid:26220009]. Intermediate alleles (i.e, 18 repeats; 19 not reported) appear to not be associated with disease [@pmid:20560987; @pmid:26220009]. The gene RUNX2 was previously called CBFA1, as reflected in some of the literature [@pmid:9182765].", + "mechanism": "LoF", + "mechanism_detail": "Polyalanine expansion leading to haploinsufficiency [@pmid:26220009].", + "year": "Causation identified in 2015 [@pmid:26220009]; clinical association found in 1997 [@pmid:9182765]", + "location_in_gene": "Coding Exon 3", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GCN" + ], + "pathogenic_motif_reference_orientation": [ + "GCN" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CNG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 4, + "benign_max": 17, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 20, + "pathogenic_max": 27, + "motif_len": 3, + "ref_copies": 15, + "novel": "ref", + "gard": [ + "6118" + ], + "genereviews": [ + "NBK1513" + ], + "malacard": [ + "CLD001" + ], + "medgen": [ + "3486" + ], + "mondo": [ + "0007340" + ], + "omim": [ + "119600" + ], + "orphanet": [ + "1452" + ], + "gnomad": [ + "RUNX2" + ], + "stripy": [ + "RUNX2" + ], + "tr_atlas": [ + "TR65117" + ], + "webstr_hg38": [ + "5789216" + ], + "webstr_hg19": [], + "locus_tags": [ + "supported_evidence" + ], + "disease_tags": [], + "references": [ + "genereviews:NBK1513", + "pmid:26220009", + "gnomad:RUNX2", + "pmid:20560987", + "pmid:9182765", + "orphanet:1452", + "genereviews:NBK535148", + "mondo:0007340" + ], + "additional_literature": [ + "pmid:41468806", + "pmid:40585427", + "pmid:37365568", + "pmid:37202645", + "pmid:32386547", + "pmid:24497578", + "pmid:22912713", + "pmid:21887706", + "pmid:19264154" + ] + }, { - "motif": "TTTTA", - "count": 17, - "type": "internal_repeat" + "id": "FAME1_SAMD12", + "disease_id": "FAME1", + "gene": "SAMD12", + "chrom": "chr8", + "start_hg38": 118366812, + "stop_hg38": 118366918, + "start_hg19": 119379051, + "stop_hg19": 119379157, + "start_t2t": 119495247, + "stop_t2t": 119495353, + "disease": "Familial adult myoclonic epilepsy type 1", + "inheritance": [ + "AD" + ], + "disease_description": "Cortical tremor, seizures with generalised motor (tonic-clonic) onset [@pmid:38876750]; Adult-onset cortical myoclonus, with seizures in up to a half of patients [@pmid:39349043].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "FAME overall is 1/35,000 in Japan. Typically found in individuals of East Asian ancestry [@pmid:38876750].", + "age_onset": "Typical: 21-39 [@pmid:29939203]; Range: 8 [@pmid:40503331] - 68 [@pmid:29507423].", + "age_onset_min": 8, + "age_onset_max": 68, + "typ_age_onset_min": 21, + "typ_age_onset_max": 39, + "details": "Novel, pathogenic alleles include expansions of TTTTAn + TTTCAn, but only the TTTCA insertion is specific to affected individuals and associated with symptom age of onset [@pmid:39569876]; pathogenic expansions range from 105 to 3860 repeats [@omim:601068; @pmid:29507423]", + "mechanism": "GoF?", + "mechanism_detail": "RNA mediated gain of function proposed [@omim:601068; @pmid:38467784].", + "year": "2018 [@pmid:29507423]", + "location_in_gene": "Intron 4/4", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "TAAAA" + ], + "pathogenic_motif_reference_orientation": [ + "TGAAA" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [ + "AAAAA", + "TAAAC", + "TAACA", + "TACAA", + "TACAC" + ], + "pathogenic_motif_gene_orientation": [ + "ATTTC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [ + "TTTTT", + "AGTTT", + "ATGTT", + "ATTGT", + "AGTGT" + ], + "locus_structure": [ + { + "motif": "TAAAA", + "count": 20, + "type": "internal_repeat" + }, + { + "motif": "TGAAA", + "count": null, + "type": "pathogenic_repeat" + } + ], + "benign_min": null, + "benign_max": null, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 105, + "pathogenic_max": 3680, + "motif_len": 5, + "ref_copies": 21.6, + "novel": "novel", + "gard": [ + "18082" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "EPL201" + ], + "medgen": [ + "371424" + ], + "mondo": [ + "0010985" + ], + "omim": [ + "601068" + ], + "orphanet": [ + "86814" + ], + "gnomad": [ + "SAMD12" + ], + "stripy": [ + "SAMD12" + ], + "tr_atlas": [ + "TR89226" + ], + "webstr_hg38": [ + "1087693" + ], + "webstr_hg19": [], + "locus_tags": [ + "supported_evidence", + "somatic_instability", + "anticipation", + "motif_affects_instability", + "motif_affects_onset", + "motif_affects_penetrance", + "maternal_expansion" + ], + "disease_tags": [ + "familial_adult_myoclonic_epilepsy" + ], + "references": [ + "pmid:29939203", + "pmid:40503331", + "pmid:29507423", + "omim:601068", + "pmid:38467784", + "pmid:39569876", + "pmid:38876750", + "pmid:39349043" + ], + "additional_literature": [ + "pmid:41426430", + "pmid:41219789", + "pmid:38961870", + "pmid:38467733", + "pmid:38059543", + "pmid:37592133", + "pmid:36740228", + "pmid:36622139", + "pmid:36092952", + "pmid:33791773", + "pmid:33721773", + "pmid:33681653", + "pmid:33501421", + "pmid:33040085", + "pmid:32973343", + "pmid:32203200", + "pmid:32194077", + "pmid:32174879", + "pmid:31664039", + "pmid:31483537", + "pmid:30559482", + "pmid:30351492", + "pmid:30194086" + ] }, { - "motif": "TTTCA", - "count": null, - "type": "pathogenic_repeat" - }], - "benign_min": null, - "benign_max": null, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 60, - "pathogenic_max": 2200, - "motif_len": 5, - "ref_copies": 17.4, - "novel": "novel", - "gard": ["16758"], - "genereviews": ["NBK535148"], - "malacard": ["EPL228"], - "medgen": ["1648435"], - "mondo": ["0054847"], - "omim": ["618075"], - "orphanet": ["86814"], - "gnomad": ["RAPGEF2"], - "stripy": ["RAPGEF2"], - "tr_atlas": ["TR49300"], - "webstr_hg38": ["154264", "4792219"], - "webstr_hg19": ["STR_1096016"], - "locus_tags": ["limited_evidence", "motif_affects_penetrance"], - "disease_tags": ["familial_adult_myoclonic_epilepsy"], - "references": ["pmid:30351492", "pmid:29507423", "pmid:35245110", "pmid:38876750"], - "additional_literature": ["pmid:41219789", "pmid:36092952", "pmid:33040085", "pmid:31483537"] -}, -{ - "id": "CANVAS_RFC1", - "disease_id": "CANVAS", - "gene": "RFC1", - "chrom": "chr4", - "start_hg38": 39348424, - "stop_hg38": 39348483, - "start_hg19": 39350044, - "stop_hg19": 39350103, - "start_t2t": 39318077, - "stop_t2t": 39318136, - "disease": "Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome", - "inheritance": ["AR"], - "disease_description": "Sensory disturbances, imbalance, oscillopsia, chronic dry cough, dysarthria and dysphagia [@pmid:38876750]; Late-onset ataxia, sensory neuropathy, vestibular areflexia syndrome [@pmid:39349043]. This expansion has been implicated in the genetic etiology of Parkinson's disease [@pmid:41177915].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Carrier frequency in European is 0.7-4% and in Chinese Han population is 2.24%; estimated prevalence of 1/20,000 to 1/625 [@genereviews:NBK564656]. Many cases are likely not diagnosed due to heterogeneous presentation [@pmid:39230846]. Observed in multiple ethnicities [@pmid:38876750]; patients diagnosed with European, Chinese Han, and Maori ancestry, as well as found in Japan, Canada, Brazil, the UK, Italy, Germany, and Australia [@genereviews:NBK564656].", - "age_onset": "Typical: 36-52; Range: 19-76 [@genereviews:NBK564656].", - "age_onset_min": 19.0, - "age_onset_max": 76.0, - "typ_age_onset_min": 36.0, - "typ_age_onset_max": 52.0, - "details": "Disease is caused by an insertion of a pathogenic motif, although motif presence is variable and can expand up to 200 repeats without apparently causing a phenotype [@genereviews:NBK564656]. Pathogenic expansions (ranging from 400-2750 pathogenic motifs) may be flanked by other motifs [@genereviews:NBK564656]. For example, (AAAGG)10-25(AAGGG)exp(AAAGG)4-6 [@pmid:32851396]. Motif heterogeneity is common in unaffected individuals [@genereviews:NBK564656], and motif associations are described by Delforge et al [@pmid:38627134]. The pathogenic size threshold appears to differ for the AAAGG motif: AAAGG expansions >= 600 repeats have been observed in CANVAS patients (vs 400 with established pathogenic motif AAGGG), while ~100-380 AAAGG repeats were found in unaffected controls [@pmid:37450567]. Length appears to impact age of onset and disease severity, with particular impact from the smaller allele [@doi:10.1136/jnnp-2024-ABN.259]. Phenotypic spectrum may include Parkinsonism [@pmid:39833204] and chronic cough [@pmid:39811557].", - "mechanism": "LoF", - "mechanism_detail": "LoF; exact mechanism unknown [@pmid:38467784].", - "year": "2019 [@pmid:31230722]", - "location_in_gene": "Intron 2", - "gene_strand": "-", - "reference_motif_reference_orientation": ["AAAAG"], - "pathogenic_motif_reference_orientation": ["AAGGG", "ACAGG", "AGGGC", "AAGGC", "AGAGG"], - "benign_motif_reference_orientation": ["AAAAG", "AAAGG", "AAGAG", "AAAGGG"], - "unknown_motif_reference_orientation": ["AAAAA", "AAAAC", "AACGG", "AAGAC", "AAGGT", "AGAAC", "AGGGG", "GAAAC", "GGGAC", "GTGAG", "AAAAGA", "AAAGGA", "GGAAAG"], - "pathogenic_motif_gene_orientation": ["CCCTT", "CCTGT", "CCCTG", "CCTTG", "CCTCT"], - "benign_motif_gene_orientation": ["CTTTT", "CCTTT", "CTCTT", "CCCTTT"], - "unknown_motif_gene_orientation": ["TTTTT", "GTTTT", "CCGTT", "CTTGT", "ACCTT", "CTGTT", "CCCCT", "CGTTT", "CCCGT", "ACCTC", "CTTTTT", "CCTTTT", "CCCTTT"], - "locus_structure": [ + "id": "XLMR_SOX3", + "disease_id": "XLMR", + "gene": "SOX3", + "chrom": "chrX", + "start_hg38": 140504316, + "stop_hg38": 140504361, + "start_hg19": 139586481, + "stop_hg19": 139586526, + "start_t2t": 138816203, + "stop_t2t": 138816248, + "disease": "X-linked panhypopituitarism ; X-linked mental retardation with isolated growth hormone", + "inheritance": [ + "XR" + ], + "disease_description": "X-linked isolated growth hormone deficiency (GHD) or combined pituitary hormone deficiency (CPHD) patients with or without intellectual disability [@pmid:24346842].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "3 families reported, however they were distributed across the world [@omim:300123].", + "age_onset": "Typical: 0-3 (small sample size) [@pmid:19654509; @pmid:21289259]; range: 0-9 [@pmid:19654509].", + "age_onset_min": 0, + "age_onset_max": 9, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "Expansion to 22-26 repeats or contraction to 8 repeats can cause disease, as reported in 3 families [@genereviews:NBK535148].", + "mechanism": "LoF", + "mechanism_detail": "Polyalanine expansions leading to aggresome formation and impaired transcriptional activity [@pmid:17127446].", + "year": "2002 [@pmid:12428212]", + "location_in_gene": "Coding Exon 1", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "NGC" + ], + "pathogenic_motif_reference_orientation": [ + "NGC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CNG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 15, + "benign_max": 15, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 22, + "pathogenic_max": 26, + "motif_len": 3, + "ref_copies": 15, + "novel": "ref", + "gard": [], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "PNH005", + "INT405" + ], + "medgen": [ + "394771" + ], + "mondo": [ + "0010252" + ], + "omim": [ + "300123", + "312000" + ], + "orphanet": [ + "67045" + ], + "gnomad": [ + "SOX3" + ], + "stripy": [ + "SOX3" + ], + "tr_atlas": [ + "TR173479" + ], + "webstr_hg38": [], + "webstr_hg19": [ + "STR_1597784" + ], + "locus_tags": [ + "supported_evidence", + "contraction" + ], + "disease_tags": [], + "references": [ + "pmid:19654509", + "pmid:21289259", + "pmid:17127446", + "genereviews:NBK535148", + "omim:300123", + "pmid:12428212", + "pmid:24346842" + ], + "additional_literature": [] + }, + { + "id": "FAME2_STARD7", + "disease_id": "FAME2", + "gene": "STARD7", + "chrom": "chr2", + "start_hg38": 96197066, + "stop_hg38": 96197124, + "start_hg19": 96862804, + "stop_hg19": 96862862, + "start_t2t": 96703674, + "stop_t2t": 96703732, + "disease": "Familial adult myoclonic epilepsy 2", + "inheritance": [ + "AD" + ], + "disease_description": "Finger, hand tremor with later-onset myoclonus and generalised tonic-clonic seizures [@pmid:39349043].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "This repeat expansion is typically found in individuals of European ancestry [@pmid:38876750].", + "age_onset": "Typical: 12-30; Range: 4-60 [@pmid:31664034].", + "age_onset_min": 4, + "age_onset_max": 60, + "typ_age_onset_min": 12, + "typ_age_onset_max": 30, + "details": "Disease caused by novel insertion of pathogenic motif (not found in any controls); size of pathogenic motif observed in two probands ranged from ~274-558 repeats, while the expanded reference motif ranged from 340-390 [@pmid:31664034].", + "mechanism": "GoF?", + "mechanism_detail": "RNA toxicity theorized [@pmid:31664034; @pmid:38467784].", + "year": "2019 [@pmid:31664034]", + "location_in_gene": "Intron 1", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "AAAAT" + ], + "pathogenic_motif_reference_orientation": [ + "AAATG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [ + "AAAAA", + "AAAAC", + "AAACC", + "AAACG", + "AAACT", + "AACTC", + "AACTG", + "AATAC", + "AATAG", + "ATAAC" + ], + "pathogenic_motif_gene_orientation": [ + "ATTTC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [ + "TTTTT", + "GTTTT", + "GGTTT", + "CGTTT", + "AGTTT", + "AGTTG", + "AGTTC", + "ATTGT", + "ATTCT", + "ATGTT" + ], + "locus_structure": [ + { + "motif": "AAATG", + "count": null, + "type": "pathogenic_repeat" + }, + { + "motif": "AAAAT", + "count": 11, + "type": "internal_repeat" + } + ], + "benign_min": null, + "benign_max": null, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 274, + "pathogenic_max": 558, + "motif_len": 5, + "ref_copies": 11.6, + "novel": "novel", + "gard": [ + "18083" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "EPL203" + ], + "medgen": [ + "375031" + ], + "mondo": [ + "0011930" + ], + "omim": [ + "607876" + ], + "orphanet": [ + "86814" + ], + "gnomad": [ + "STARD7" + ], + "stripy": [ + "STARD7" + ], + "tr_atlas": [ + "TR19329" + ], + "webstr_hg38": [ + "286156" + ], + "webstr_hg19": [ + "STR_754470" + ], + "locus_tags": [ + "supported_evidence", + "somatic_instability", + "motif_affects_instability", + "motif_affects_penetrance" + ], + "disease_tags": [ + "familial_adult_myoclonic_epilepsy" + ], + "references": [ + "pmid:31664034", + "pmid:38467784", + "pmid:38876750", + "pmid:39349043" + ], + "additional_literature": [ + "pmid:41219789", + "pmid:33040085" + ] + }, + { + "id": "XDP_TAF1", + "disease_id": "XDP", + "gene": "TAF1", + "chrom": "chrX", + "start_hg38": 71453054, + "stop_hg38": 71453131, + "start_hg19": 70672904, + "stop_hg19": 70672981, + "start_t2t": 69887153, + "stop_t2t": 69887230, + "disease": "X-linked dystonia-parkinsonism (XDP) a.k.a. Dystonia 3, torsion, X-linked (DYT3)", + "inheritance": [ + "XR" + ], + "disease_description": "X-linked dystonia-parkinsonism (XDP) associated with antisense insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within an intron of TAF1. Clinical features include focal and generalised dystonia, parkinsonism, cognitive dysfunction. XX individuals who are heterozygous carriers usually do not develop the full syndrome, although some patients have non-progressive focal dystonia with parkinsonism. Disease severity is associated with number of hexanucleotide repeats within the SVA. (Adapted) [@pmid:38876750].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Philippines overall 0.34:100,000. Panay Islands 5.24:100,000. Capiz province 18.9:100,000. To date, all known cases to date are of Filipino descent [@pmid:38876750].", + "age_onset": "Average age of onset for XDP is 39.7 years in males, 52 years in females, range 12-79 years. ~99% of cases are male [@pmid:29229810; @pmid:38876750; @pmid:15596620].", + "age_onset_min": 12, + "age_onset_max": 79, + "typ_age_onset_min": 39.7, + "typ_age_onset_max": 39.7, + "details": "Strong inverse relationship between age of onset and insertion length, which varied between 35-52 repeats [@pmid:29229810].", + "mechanism": "LoF", + "mechanism_detail": "Altered splicing with intron retention, haploinsufficiency [@pmid:38876750].", + "year": "2017 [@pmid:29229810]", + "location_in_gene": "Intron 32", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "AGAGGG" + ], + "pathogenic_motif_reference_orientation": [ + "AGAGGG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "AGAGGG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": null, + "benign_max": null, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 35, + "pathogenic_max": 52, + "motif_len": 6, + "ref_copies": 4, + "novel": "ref", + "gard": [ + "10533" + ], + "genereviews": [ + "NBK1489" + ], + "malacard": [ + "DYS064" + ], + "medgen": [ + "326820" + ], + "mondo": [ + "0010747" + ], + "omim": [ + "314250" + ], + "orphanet": [ + "53351" + ], + "gnomad": [], + "stripy": [], + "tr_atlas": [ + "TR592600" + ], + "webstr_hg38": [ + "861907" + ], + "webstr_hg19": [ + "STR_1564408" + ], + "locus_tags": [ + "supported_evidence", + "length_affects_onset" + ], + "disease_tags": [], + "references": [ + "pmid:29229810", + "pmid:38876750", + "pmid:15596620" + ], + "additional_literature": [ + "pmid:41443196", + "pmid:40463055", + "pmid:38834915", + "pmid:38616406", + "pmid:37234925", + "pmid:35971992", + "pmid:38835911", + "pmid:35868859", + "pmid:35481544", + "pmid:35395816", + "pmid:38835428", + "pmid:34250228", + "pmid:34111553", + "pmid:32533168", + "pmid:32152096", + "pmid:27806289", + "pmid:18952144", + "pmid:18713817", + "pmid:17273961", + "pmid:7668293", + "pmid:7829058", + "pmid:1518853" + ] + }, { - "motif": "AAAAG", - "count": 11, - "type": "internal_repeat" + "id": "SCA17_TBP", + "disease_id": "SCA17", + "gene": "TBP", + "chrom": "chr6", + "start_hg38": 170561906, + "stop_hg38": 170562017, + "start_hg19": 170870994, + "stop_hg19": 170871105, + "start_t2t": 171935458, + "stop_t2t": 171935569, + "disease": "Spinocerebellar ataxia type 17", + "inheritance": [ + "AD" + ], + "disease_description": "A rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I). It is characterized by a variable clinical picture which can include dementia, psychiatric disorders, parkinsonism, dystonia, chorea, spasticity, and epilepsy [@mondo:0011781].", + "hpo_terms": null, + "prevalence": "0.2/100000", + "prevalence_details": "Unknown (global), <100 families, 0.47:1,000,000 (Japanese), 0.16/100,000 (England) [@genereviews:NBK1438; @pmid:29100084]: 0.2/100,000. Found across ethnicities/ancestries, with population-dependent prevalence [@genereviews:NBK1438].", + "age_onset": "Typical: 19-48; Range: 3-62, has second variant to delay onset [@omim:607136].", + "age_onset_min": 3, + "age_onset_max": 62, + "typ_age_onset_min": 19, + "typ_age_onset_max": 48, + "details": "Benign range is 25-40 repeats, pathogenic range is 49+ repeats (largest to date 66 motifs, with mild correlation between size and age of onset), and intermediate alleles (41-48 repeats) are associated with reduced penetrance and potentially milder phenotypes [@genereviews:NBK1438]. Huntington's disease like phenotype [@pmid:12805114]. Interruptions seen: CAA [@pmid:35245110]; CAA CAG CAA interruption is seen in all alleles stably transmitted across generations [@genereviews:NBK1438].", + "mechanism": "LoF/GoF", + "mechanism_detail": "Polyglutamine expansion leading to transcriptional dysregulation [@pmid:35053321].", + "year": "1999 [@pmid:10484774]", + "location_in_gene": "Coding Exon 3", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GCA" + ], + "pathogenic_motif_reference_orientation": [ + "GCA" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "AGC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 25, + "benign_max": 40, + "intermediate_min": 41, + "intermediate_max": 48, + "pathogenic_min": 49, + "pathogenic_max": 66, + "motif_len": 3, + "ref_copies": 37, + "novel": "ref", + "gard": [ + "10469" + ], + "genereviews": [ + "NBK1438" + ], + "malacard": [ + "SPN296" + ], + "medgen": [ + "337637" + ], + "mondo": [ + "0011781" + ], + "omim": [ + "607136" + ], + "orphanet": [ + "98759" + ], + "gnomad": [ + "TBP" + ], + "stripy": [ + "TBP" + ], + "tr_atlas": [ + "TR72502" + ], + "webstr_hg38": [ + "83566" + ], + "webstr_hg19": [], + "locus_tags": [ + "supported_evidence", + "somatic_instability", + "anticipation", + "paternal_expansion", + "length_affects_onset", + "length_affects_penetrance", + "length_affects_phenotype", + "motif_affects_instability" + ], + "disease_tags": [ + "spinocerebellar_ataxia" + ], + "references": [ + "omim:607136", + "pmid:35053321", + "genereviews:NBK1438", + "pmid:12805114", + "pmid:35245110", + "pmid:29100084", + "pmid:10484774", + "mondo:0011781" + ], + "additional_literature": [ + "pmid:41009775", + "pmid:40488180", + "pmid:40478462", + "pmid:39950762", + "pmid:39820777", + "pmid:39680235", + "pmid:39456985", + "pmid:39125760", + "pmid:38973070", + "pmid:38961870", + "pmid:38494459", + "pmid:37855597", + "pmid:37632648", + "pmid:37146135", + "pmid:36599645", + "pmid:36476347", + "pmid:36422518", + "pmid:35926480", + "pmid:35868859", + "pmid:35493319", + "pmid:35482253", + "pmid:35275350", + "pmid:35182509", + "pmid:34906452", + "pmid:34600502", + "pmid:34565721", + "pmid:34256333", + "pmid:34235484", + "pmid:33502644", + "pmid:33377399", + "pmid:32675418", + "pmid:32533168", + "pmid:32386547", + "pmid:31940111", + "pmid:31919387", + "pmid:31522753", + "pmid:30920184", + "pmid:30891880", + "pmid:30617627", + "pmid:30615214", + "pmid:30532692", + "pmid:30314815", + "pmid:30120431", + "pmid:29801887", + "pmid:29564144", + "pmid:29249939", + "pmid:29057148", + "pmid:28821675", + "pmid:28585930", + "pmid:28444220", + "pmid:28153533", + "pmid:27865706", + "pmid:27400454", + "pmid:27172828", + "pmid:26476771", + "pmid:26387956", + "pmid:26374734", + "pmid:26267067", + "pmid:26077168", + "pmid:25672822", + "pmid:24972706", + "pmid:24677642", + "pmid:24534762", + "pmid:23665119", + "pmid:23475385", + "pmid:21710129", + "pmid:21562248", + "pmid:21437269", + "pmid:20587494", + "pmid:20199210", + "pmid:20004653", + "pmid:19595623", + "pmid:19566714", + "pmid:18218637", + "pmid:18043721", + "pmid:17961920", + "pmid:17420317", + "pmid:17273961", + "pmid:17033685", + "pmid:16858508", + "pmid:16626296", + "pmid:16223509", + "pmid:16054804", + "pmid:15850778", + "pmid:15533937", + "pmid:15503103", + "pmid:15381080", + "pmid:15365789", + "pmid:15225551", + "pmid:15193429", + "pmid:14985389", + "pmid:14967767", + "pmid:12953269", + "pmid:12891385", + "pmid:12853230", + "pmid:12758065", + "pmid:11939898", + "pmid:11571212", + "pmid:11313753", + "pmid:9399691", + "pmid:8886170", + "pmid:7892196", + "pmid:8503450" + ] }, { - "motif": "AAGGG", - "count": null, - "type": "pathogenic_repeat" - }], - "benign_min": 0, - "benign_max": 11, - "intermediate_min": 11, - "intermediate_max": 200, - "pathogenic_min": 400, - "pathogenic_max": 2750, - "motif_len": 5, - "ref_copies": 11.8, - "novel": "novel", - "gard": ["17937"], - "genereviews": ["NBK564656"], - "malacard": ["CRB196"], - "medgen": ["482853"], - "mondo": ["0044720"], - "omim": ["614575"], - "orphanet": ["504476"], - "gnomad": ["RFC1"], - "stripy": ["RFC1"], - "tr_atlas": ["TR42349"], - "webstr_hg38": ["4722884", "99101"], - "webstr_hg19": ["STR_1036603"], - "locus_tags": ["supported_evidence", "motif_affects_penetrance", "length_affects_onset", "length_affects_severity"], - "disease_tags": ["ataxia", "phenotypic_spectrum"], - "references": ["genereviews:NBK564656", "pmid:38467784", "pmid:32851396", "pmid:38627134", "pmid:37450567", "doi:10.1136/jnnp-2024-ABN.259", "pmid:39833204", "pmid:39811557", "pmid:39230846", "pmid:38876750", "pmid:31230722", "pmid:39349043", "pmid:41177915"], - "additional_literature": ["pmid:41426430", "pmid:41327893", "pmid:41322202", "pmid:41278766", "pmid:41145152", "pmid:41118032", "pmid:41084404", "pmid:41074692", "pmid:41055766", "pmid:40898875", "pmid:40894141", "pmid:40802152", "pmid:40765612", "pmid:40637932", "pmid:40595562", "pmid:40594369", "pmid:40488180", "pmid:40481300", "pmid:40461673", "pmid:40417743", "pmid:40313272", "pmid:40273470", "pmid:40221271", "pmid:40211677", "pmid:40204545", "pmid:40141365", "pmid:40113266", "pmid:40007153", "pmid:39812846", "pmid:39721397", "pmid:39571249", "pmid:39543176", "pmid:39507594", "pmid:39416949", "pmid:39406499", "pmid:39342186", "pmid:39286915", "pmid:39231235", "pmid:39219417", "pmid:39152783", "pmid:39076534", "pmid:38978724", "pmid:38916676", "pmid:38789445", "pmid:38579416", "pmid:38487929", "pmid:38447794", "pmid:38381906", "pmid:38381176", "pmid:38324175", "pmid:38311638", "pmid:38306376", "pmid:38266156", "pmid:38193360", "pmid:38168171", "pmid:38145611", "pmid:38062616", "pmid:38054570", "pmid:37917284", "pmid:37892228", "pmid:37853169", "pmid:37747091", "pmid:37660923", "pmid:37578187", "pmid:37546920", "pmid:37476326", "pmid:37460231", "pmid:37414537", "pmid:37399286", "pmid:36805468", "pmid:36753892", "pmid:36705320", "pmid:36381255", "pmid:36289003", "pmid:36250766", "pmid:36227727", "pmid:36214978", "pmid:36177974", "pmid:36088850", "pmid:36061987", "pmid:36046423", "pmid:36034314", "pmid:35884855", "pmid:35883251", "pmid:35864213", "pmid:35633373", "pmid:35585435", "pmid:35502508", "pmid:35355059", "pmid:35306791", "pmid:35253317", "pmid:38835435", "pmid:35013364", "pmid:34968871", "pmid:34927205", "pmid:34600502", "pmid:34537679", "pmid:34101140", "pmid:33969391", "pmid:33940977", "pmid:33884451", "pmid:33807868", "pmid:33745133", "pmid:33666721", "pmid:33495376", "pmid:33188504", "pmid:33103729", "pmid:33068477", "pmid:33068476", "pmid:32949124", "pmid:32939785", "pmid:32910249", "pmid:32873692", "pmid:32732387", "pmid:32694621", "pmid:32682126", "pmid:32582864", "pmid:32151945", "pmid:32066831", "pmid:32040566", "pmid:31824583", "pmid:31817852", "pmid:31370354", "pmid:30926972", "pmid:25648260", "pmid:25007187", "pmid:24686188", "pmid:22086855", "pmid:15457444", "pmid:12556494"] -}, -{ - "id": "OPDM4_RILPL1", - "disease_id": "OPDM4", - "gene": "RILPL1", - "chrom": "chr12", - "start_hg38": 123533720, - "stop_hg38": 123533750, - "start_hg19": 124018267, - "stop_hg19": 124018297, - "start_t2t": 123532573, - "stop_t2t": 123532603, - "disease": "Oculopharyngodistal myopathy type 4", - "inheritance": ["AD"], - "disease_description": "Ptosis, external ophthalmoplegia, facial weakness, and pharyngeal and distal limb weakness [@pmid:38876750].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Population dependent: 21.6% of one OPDM cohort [@pmid:35148830]. Typically found in individuals of East Asian ancestry [@pmid:38876750].", - "age_onset": "Typical: 18-30 [@pmid:35148830]; Range: 10-30 [@pmid:35700120].", - "age_onset_min": 10.0, - "age_onset_max": 30.0, - "typ_age_onset_min": 18.0, - "typ_age_onset_max": 30.0, - "details": "Benign alleles have been documented to have 6-16 repeats [@pmid:37864208], while pathogenic repeats range from 120 to 197 repeats; there is no apparent relationship between allele size and age of onset [@pmid:37864208; @pmid:35148830]. Intermediate alleles amy be associated with incomplete penetrance, or milder phenotypes [@pmid:35148830]. AGG and TGG interruptions observed [@pmid:35148830].", - "mechanism": "GoF", - "mechanism_detail": "Polyglutamine expansion leading to RNA-mediated gain-of-function mechanism [@pmid:38467784].", - "year": "2022 [@pmid:35148830]", - "location_in_gene": "5' UTR", - "gene_strand": "-", - "reference_motif_reference_orientation": ["GGC"], - "pathogenic_motif_reference_orientation": ["GGC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CCG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 6, - "benign_max": 16, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 120, - "pathogenic_max": 197, - "motif_len": 3, - "ref_copies": 11.7, - "novel": "ref", - "gard": ["12592"], - "genereviews": [], - "malacard": ["OCL085"], - "medgen": ["1809981"], - "mondo": ["0030712"], - "omim": [], - "orphanet": ["98897"], - "gnomad": ["RILPL1"], - "stripy": ["RILPL1"], - "tr_atlas": ["TR121403"], - "webstr_hg38": ["5128610", "609239"], - "webstr_hg19": ["STR_347096"], - "locus_tags": ["supported_evidence"], - "disease_tags": ["oculopharyngodistal_myopathy"], - "references": ["pmid:35148830", "pmid:35700120", "pmid:38467784", "pmid:37864208", "pmid:38876750"], - "additional_literature": ["pmid:40645757", "pmid:40084170", "pmid:39044557", "pmid:39013564", "pmid:37923380"] -}, -{ - "id": "CCD_RUNX2", - "disease_id": "CCD", - "gene": "RUNX2", - "chrom": "chr6", - "start_hg38": 45422750, - "stop_hg38": 45422801, - "start_hg19": 45390487, - "stop_hg19": 45390538, - "start_t2t": 45257567, - "stop_t2t": 45257618, - "disease": "Cleidocranial dysplasia", - "inheritance": ["AD"], - "disease_description": "A condition that primarily affects the development of the bones and teeth. Characteristic features include underdeveloped or absent collarbones (clavicles); dental abnormalities; and delayed closing of the spaces between the skull bones (fontanels). Other features may include decreased bone density (osteopenia), osteoporosis, hearing loss, bone abnormalities of the hands, and recurrent sinus and ear infections. [@mondo:0007340].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "All conditions 1/1,000,000 births (likely underdiagnosed); Utah population frequency 0.12/10,000. Found in many ethnic groups [@orphanet:1452]. TR expansions causative in 2 individuals [@genereviews:NBK535148].", - "age_onset": "0 (birth) [@genereviews:NBK1513].", - "age_onset_min": 0.0, - "age_onset_max": 0.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "Benign range (4-17 repeats) established from gnomAD and primary literature; pathogenic ranges (20-27) reflect two clinical cases to date [@gnomad:RUNX2; @pmid:26220009]. Intermediate alleles (i.e, 18 repeats; 19 not reported) appear to not be associated with disease [@pmid:20560987; @pmid:26220009]. The gene RUNX2 was previously called CBFA1, as reflected in some of the literature [@pmid:9182765].", - "mechanism": "LoF", - "mechanism_detail": "Polyalanine expansion leading to haploinsufficiency [@pmid:26220009].", - "year": "Causation identified in 2015 [@pmid:26220009]; clinical association found in 1997 [@pmid:9182765]", - "location_in_gene": "Coding Exon 3", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GCN"], - "pathogenic_motif_reference_orientation": ["GCN"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CNG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 4, - "benign_max": 17, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 20, - "pathogenic_max": 27, - "motif_len": 3, - "ref_copies": 15.0, - "novel": "ref", - "gard": ["6118"], - "genereviews": ["NBK1513"], - "malacard": ["CLD001"], - "medgen": ["3486"], - "mondo": ["0007340"], - "omim": ["119600"], - "orphanet": ["1452"], - "gnomad": ["RUNX2"], - "stripy": ["RUNX2"], - "tr_atlas": ["TR65117"], - "webstr_hg38": ["5789216"], - "webstr_hg19": [], - "locus_tags": ["supported_evidence"], - "disease_tags": [], - "references": ["genereviews:NBK1513", "pmid:26220009", "gnomad:RUNX2", "pmid:20560987", "pmid:9182765", "orphanet:1452", "genereviews:NBK535148", "mondo:0007340"], - "additional_literature": ["pmid:41468806", "pmid:40585427", "pmid:37365568", "pmid:37202645", "pmid:32386547", "pmid:24497578", "pmid:22912713", "pmid:21887706", "pmid:19264154"] -}, -{ - "id": "FAME1_SAMD12", - "disease_id": "FAME1", - "gene": "SAMD12", - "chrom": "chr8", - "start_hg38": 118366812, - "stop_hg38": 118366918, - "start_hg19": 119379051, - "stop_hg19": 119379157, - "start_t2t": 119495247, - "stop_t2t": 119495353, - "disease": "Familial adult myoclonic epilepsy type 1", - "inheritance": ["AD"], - "disease_description": "Cortical tremor, seizures with generalised motor (tonic-clonic) onset [@pmid:38876750]; Adult-onset cortical myoclonus, with seizures in up to a half of patients [@pmid:39349043].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "FAME overall is 1/35,000 in Japan. Typically found in individuals of East Asian ancestry [@pmid:38876750].", - "age_onset": "Typical: 21-39 [@pmid:29939203]; Range: 8 [@pmid:40503331] - 68 [@pmid:29507423].", - "age_onset_min": 8.0, - "age_onset_max": 68.0, - "typ_age_onset_min": 21.0, - "typ_age_onset_max": 39.0, - "details": "Novel, pathogenic alleles include expansions of TTTTAn + TTTCAn, but only the TTTCA insertion is specific to affected individuals and associated with symptom age of onset [@pmid:39569876]; pathogenic expansions range from 105 to 3860 repeats [@omim:601068; @pmid:29507423]", - "mechanism": "GoF?", - "mechanism_detail": "RNA mediated gain of function proposed [@omim:601068; @pmid:38467784].", - "year": "2018 [@pmid:29507423]", - "location_in_gene": "Intron 4/4", - "gene_strand": "-", - "reference_motif_reference_orientation": ["TAAAA"], - "pathogenic_motif_reference_orientation": ["TGAAA"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": ["AAAAA", "TAAAC", "TAACA", "TACAA", "TACAC"], - "pathogenic_motif_gene_orientation": ["ATTTC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": ["TTTTT", "AGTTT", "ATGTT", "ATTGT", "AGTGT"], - "locus_structure": [ + "id": "TOF_TBX1", + "disease_id": "TOF", + "gene": "TBX1", + "chrom": "chr22", + "start_hg38": 19766762, + "stop_hg38": 19766807, + "start_hg19": 19754285, + "stop_hg19": 19754330, + "start_t2t": 20143615, + "stop_t2t": 20143660, + "disease": "Tetralogy of Fallot", + "inheritance": [ + "AD" + ], + "disease_description": "Tetralogy of Fallot is a congenital cardiac malformation that consists of an interventricular communication, also known as a ventricular septal defect, obstruction of the right ventricular outflow tract, override of the ventricular septum by the aortic root, and right ventricular hypertrophy [@mondo:0008542].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Found in one Turkish individual [@genereviews:NBK535148].", + "age_onset": "0", + "age_onset_min": 0, + "age_onset_max": 0, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "Found in one Turkish individual with Tetralogy of Fallot who had 25 repeats rather than 15 [@genereviews:NBK535148].", + "mechanism": "LoF/GoF", + "mechanism_detail": "Polyalanine expansion, leading to cytoplasmic aggregation [@omim:187500; @pmid:19948535].", + "year": "2010 [@pmid:19948535]", + "location_in_gene": "Coding Exon 9", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GCN" + ], + "pathogenic_motif_reference_orientation": [ + "GCN" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CNG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 15, + "benign_max": 15, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 25, + "pathogenic_max": 25, + "motif_len": 3, + "ref_copies": 15, + "novel": "ref", + "gard": [ + "2245" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "TTR001" + ], + "medgen": [ + "21498" + ], + "mondo": [ + "0008542" + ], + "omim": [ + "187500" + ], + "orphanet": [ + "3303" + ], + "gnomad": [ + "TBX1" + ], + "stripy": [ + "TBX1" + ], + "tr_atlas": [ + "TR163862" + ], + "webstr_hg38": [ + "4900984" + ], + "webstr_hg19": [ + "STR_889797" + ], + "locus_tags": [ + "limited_evidence" + ], + "disease_tags": [], + "references": [ + "omim:187500", + "pmid:19948535", + "genereviews:NBK535148", + "mondo:0008542" + ], + "additional_literature": [ + "pmid:24797903", + "pmid:16141220", + "pmid:10440825" + ] + }, { - "motif": "TAAAA", - "count": 20, - "type": "internal_repeat" + "id": "FECD3_TCF4", + "disease_id": "FECD3", + "gene": "TCF4", + "chrom": "chr18", + "start_hg38": 55586153, + "stop_hg38": 55586229, + "start_hg19": 53253384, + "stop_hg19": 53253460, + "start_t2t": 55789233, + "stop_t2t": 55789288, + "disease": "Fuchs endothelial corneal dystrophy 3", + "inheritance": [ + "AD" + ], + "disease_description": "Late-onset Fuchs endothelial corneal dystrophy (FECD) is a degenerative disorder ... distinguished from other corneal disorders by the progressive formation of guttae [@omim:613267]. Studies suggest that disease severity increases in women with greater lifetime exposure to oestrogen [@pmid:40374208].", + "hpo_terms": null, + "prevalence": "4.5/100", + "prevalence_details": "~4/100 (over 40) [@omim:613267]; 5/100 [@pmid:20825314]. Predominantly in women (~75%) [@pmid:16769829]. In one study of two cohorts (Dallas Heart Study and 1000 Genomes Project), expanded allele carrier rates were 3.1% (African American), 8.1% (European American), and 3.3% (Latinos)in DHS, and 2.7% (AFR), 9.5% (EUR), 5.2% (East Asians), 7.2% (South Asians), and 5.2% (admixed Americans) in 1KGP [@pmid:39669694]. The highest carrier prevalence (12.1%–12.5%) occurred in EUR and admixed American subpopulations, while rates were 0%–1.9% in West Africans vs 6.2% in a Kenyan subpopulation.", + "age_onset": "Typical: 40-59 [@pmid:1676829]; Range: 32 [@pmid:21245398] - 79 [@pmid:39998965].", + "age_onset_min": 32, + "age_onset_max": 79, + "typ_age_onset_min": 40, + "typ_age_onset_max": 59, + "details": "Most controls have <40 repeats while majority of patients have >50 repeats; penetrance is <100%, as unaffected individuals have been documented with >80 repeats and alleles of affected individuals range from 12-2600 [@genereviews:NBK535148; @pmid:25168903]. Expansions are causative in approximately 70% of disease cases [@genereviews:NBK535148].", + "mechanism": "GoF", + "mechanism_detail": "Sequestration of MBNL1 in RNA foci, similar to the mechanism underlying myotonic dystrophy-1 [@pmid:25593321]. Variation in RAN translation [@pmid:38467784].", + "year": "2012 [@pmid:23185296]", + "location_in_gene": "Intron 1", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "CAG" + ], + "pathogenic_motif_reference_orientation": [ + "CAG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CTG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 10, + "benign_max": 39, + "intermediate_min": 40, + "intermediate_max": 50, + "pathogenic_min": 51, + "pathogenic_max": 2600, + "motif_len": 3, + "ref_copies": 25.3, + "novel": "ref", + "gard": [ + "10018" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "FCH001", + "CRN120" + ], + "medgen": [ + "442479" + ], + "mondo": [ + "0013203" + ], + "omim": [ + "613267" + ], + "orphanet": [ + "98974" + ], + "gnomad": [ + "TCF4" + ], + "stripy": [ + "TCF4" + ], + "tr_atlas": [ + "TR151784" + ], + "webstr_hg38": [ + "6247607", + "463325" + ], + "webstr_hg19": [], + "locus_tags": [ + "supported_evidence", + "length_affects_penetrance" + ], + "disease_tags": [], + "references": [ + "pmid:1676829", + "pmid:21245398", + "pmid:39998965", + "pmid:25593321", + "pmid:38467784", + "genereviews:NBK535148", + "pmid:25168903", + "omim:613267", + "pmid:20825314", + "pmid:16769829", + "pmid:39669694", + "pmid:23185296", + "pmid:40374208" + ], + "additional_literature": [ + "pmid:41373515", + "pmid:41344296", + "pmid:41298634", + "pmid:41074692", + "pmid:40961119", + "pmid:40852795", + "pmid:40767442", + "pmid:40720054", + "pmid:40585427", + "pmid:40268158", + "pmid:40081749", + "pmid:40048186", + "pmid:39651202", + "pmid:39332053", + "pmid:39288343", + "pmid:39278108", + "pmid:39231626", + "pmid:38713708", + "pmid:38704483", + "pmid:38300219", + "pmid:37747538", + "pmid:37204786", + "pmid:37169279", + "pmid:36883248", + "pmid:36773096", + "pmid:36701310", + "pmid:36275201", + "pmid:36250467", + "pmid:34946954", + "pmid:34946867", + "pmid:34855896", + "pmid:34698281", + "pmid:34644448", + "pmid:33782268", + "pmid:36246012", + "pmid:33116252", + "pmid:32934897", + "pmid:32639312", + "pmid:31554942", + "pmid:31469403", + "pmid:31276570", + "pmid:30973406", + "pmid:30811544", + "pmid:30733599", + "pmid:30267097", + "pmid:30122888", + "pmid:30098193", + "pmid:29966009", + "pmid:29799290", + "pmid:29526280", + "pmid:29325021", + "pmid:29196769", + "pmid:29044056", + "pmid:28886202", + "pmid:28832669", + "pmid:28608272", + "pmid:28118661", + "pmid:27755191", + "pmid:26401622", + "pmid:26218914", + "pmid:26200491", + "pmid:25722209", + "pmid:25298419", + "pmid:24255041", + "pmid:20960280", + "pmid:11526470", + "pmid:10712198", + "pmid:10395212" + ] }, { - "motif": "TGAAA", - "count": null, - "type": "pathogenic_repeat" - }], - "benign_min": null, - "benign_max": null, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 105, - "pathogenic_max": 3680, - "motif_len": 5, - "ref_copies": 21.6, - "novel": "novel", - "gard": ["18082"], - "genereviews": ["NBK535148"], - "malacard": ["EPL201"], - "medgen": ["371424"], - "mondo": ["0010985"], - "omim": ["601068"], - "orphanet": ["86814"], - "gnomad": ["SAMD12"], - "stripy": ["SAMD12"], - "tr_atlas": ["TR89226"], - "webstr_hg38": ["1087693"], - "webstr_hg19": [], - "locus_tags": ["supported_evidence", "somatic_instability", "anticipation", "motif_affects_instability", "motif_affects_onset", "motif_affects_penetrance", "maternal_expansion"], - "disease_tags": ["familial_adult_myoclonic_epilepsy"], - "references": ["pmid:29939203", "pmid:40503331", "pmid:29507423", "omim:601068", "pmid:38467784", "pmid:39569876", "pmid:38876750", "pmid:39349043"], - "additional_literature": ["pmid:41426430", "pmid:41219789", "pmid:38961870", "pmid:38467733", "pmid:38059543", "pmid:37592133", "pmid:36740228", "pmid:36622139", "pmid:36092952", "pmid:33791773", "pmid:33721773", "pmid:33681653", "pmid:33501421", "pmid:33040085", "pmid:32973343", "pmid:32203200", "pmid:32194077", "pmid:32174879", "pmid:31664039", "pmid:31483537", "pmid:30559482", "pmid:30351492", "pmid:30194086"] -}, -{ - "id": "XLMR_SOX3", - "disease_id": "XLMR", - "gene": "SOX3", - "chrom": "chrX", - "start_hg38": 140504316, - "stop_hg38": 140504361, - "start_hg19": 139586481, - "stop_hg19": 139586526, - "start_t2t": 138816203, - "stop_t2t": 138816248, - "disease": "X-linked panhypopituitarism ; X-linked mental retardation with isolated growth hormone", - "inheritance": ["XR"], - "disease_description": "X-linked isolated growth hormone deficiency (GHD) or combined pituitary hormone deficiency (CPHD) patients with or without intellectual disability [@pmid:24346842].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "3 families reported, however they were distributed across the world [@omim:300123].", - "age_onset": "Typical: 0-3 (small sample size) [@pmid:19654509; @pmid:21289259]; range: 0-9 [@pmid:19654509].", - "age_onset_min": 0.0, - "age_onset_max": 9.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "Expansion to 22-26 repeats or contraction to 8 repeats can cause disease, as reported in 3 families [@genereviews:NBK535148].", - "mechanism": "LoF", - "mechanism_detail": "Polyalanine expansions leading to aggresome formation and impaired transcriptional activity [@pmid:17127446].", - "year": "2002 [@pmid:12428212]", - "location_in_gene": "Coding Exon 1", - "gene_strand": "-", - "reference_motif_reference_orientation": ["NGC"], - "pathogenic_motif_reference_orientation": ["NGC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CNG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 15, - "benign_max": 15, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 22, - "pathogenic_max": 26, - "motif_len": 3, - "ref_copies": 15.0, - "novel": "ref", - "gard": [], - "genereviews": ["NBK535148"], - "malacard": ["PNH005", "INT405"], - "medgen": ["394771"], - "mondo": ["0010252"], - "omim": ["300123", "312000"], - "orphanet": ["67045"], - "gnomad": ["SOX3"], - "stripy": ["SOX3"], - "tr_atlas": ["TR173479"], - "webstr_hg38": [], - "webstr_hg19": ["STR_1597784"], - "locus_tags": ["supported_evidence", "contraction"], - "disease_tags": [], - "references": ["pmid:19654509", "pmid:21289259", "pmid:17127446", "genereviews:NBK535148", "omim:300123", "pmid:12428212", "pmid:24346842"], - "additional_literature": [] -}, -{ - "id": "FAME2_STARD7", - "disease_id": "FAME2", - "gene": "STARD7", - "chrom": "chr2", - "start_hg38": 96197066, - "stop_hg38": 96197124, - "start_hg19": 96862804, - "stop_hg19": 96862862, - "start_t2t": 96703674, - "stop_t2t": 96703732, - "disease": "Familial adult myoclonic epilepsy 2", - "inheritance": ["AD"], - "disease_description": "Finger, hand tremor with later-onset myoclonus and generalised tonic-clonic seizures [@pmid:39349043].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "This repeat expansion is typically found in individuals of European ancestry [@pmid:38876750].", - "age_onset": "Typical: 12-30; Range: 4-60 [@pmid:31664034].", - "age_onset_min": 4.0, - "age_onset_max": 60.0, - "typ_age_onset_min": 12.0, - "typ_age_onset_max": 30.0, - "details": "Disease caused by novel insertion of pathogenic motif (not found in any controls); size of pathogenic motif observed in two probands ranged from ~274-558 repeats, while the expanded reference motif ranged from 340-390 [@pmid:31664034].", - "mechanism": "GoF?", - "mechanism_detail": "RNA toxicity theorized [@pmid:31664034; @pmid:38467784].", - "year": "2019 [@pmid:31664034]", - "location_in_gene": "Intron 1", - "gene_strand": "-", - "reference_motif_reference_orientation": ["AAAAT"], - "pathogenic_motif_reference_orientation": ["AAATG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": ["AAAAA", "AAAAC", "AAACC", "AAACG", "AAACT", "AACTC", "AACTG", "AATAC", "AATAG", "ATAAC"], - "pathogenic_motif_gene_orientation": ["ATTTC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": ["TTTTT", "GTTTT", "GGTTT", "CGTTT", "AGTTT", "AGTTG", "AGTTC", "ATTGT", "ATTCT", "ATGTT"], - "locus_structure": [ + "id": "SCA_THAP11", + "disease_id": "SCA51", + "gene": "THAP11", + "chrom": "chr16", + "start_hg38": 67842862, + "stop_hg38": 67842950, + "start_hg19": 67876765, + "stop_hg19": 67876853, + "start_t2t": 73638636, + "stop_t2t": 73638724, + "disease": "Spinocerebellar ataxia 51", + "inheritance": [ + "AD" + ], + "disease_description": "THAP11-caused SCA involves symptoms including gait ataxia, dysarthia, dysphagia, slow saccades, ptosis, and/or nystagmus [@pmid:37148549].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Has been observed in Chinese families [@pmid:37148549; @pmid:24677642]. Interruptions predisposing to expansion/disease appear to vary by ancestry [@pmid:39651830].", + "age_onset": "Typical: 8-40 (small sample size); Range: 4-51 [@pmid:37148549].", + "age_onset_min": 4, + "age_onset_max": 51, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "Expansion (45-100 repeats) found in affected individuals from 2 families and not in 500 controls (benign range: 20-38 repeats) [@pmid:37148549]. Longer alleles were associated with earlier age of onset. For example, an individual with 100 repeats had age of onset at 4 years. CAA interruptions can reduce toxicity [@pmid:37148549].", + "mechanism": "GoF", + "mechanism_detail": "Polyglutamine expansion leading to gain of function toxicity [@pmid:37148549; @pmid:38467784].", + "year": "2023 [@pmid:37148549]", + "location_in_gene": "Coding Exon 1", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "CAG" + ], + "pathogenic_motif_reference_orientation": [ + "CAG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "AGC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 20, + "benign_max": 38, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 45, + "pathogenic_max": 100, + "motif_len": 3, + "ref_copies": 29.3, + "novel": "ref", + "gard": [ + "10748" + ], + "genereviews": [], + "malacard": [], + "medgen": [ + "431598" + ], + "mondo": [], + "omim": [ + "620947" + ], + "orphanet": [], + "gnomad": [ + "THAP11" + ], + "stripy": [], + "tr_atlas": [ + "TR142069" + ], + "webstr_hg38": [ + "814002", + "5973136" + ], + "webstr_hg19": [ + "STR_540982" + ], + "locus_tags": [ + "supported_evidence", + "anticipation", + "length_affects_onset", + "length_affects_severity", + "motif_affects_onset", + "motif_affects_severity" + ], + "disease_tags": [ + "spinocerebellar_ataxia" + ], + "references": [ + "pmid:37148549", + "pmid:38467784", + "pmid:24677642", + "pmid:39651830" + ], + "additional_literature": [ + "pmid:40886825", + "pmid:40488180", + "pmid:15368101" + ] + }, { - "motif": "AAATG", - "count": null, - "type": "pathogenic_repeat" + "id": "FAME6_TNRC6A", + "disease_id": "FAME6", + "gene": "TNRC6A", + "chrom": "chr16", + "start_hg38": 24613438, + "stop_hg38": 24613532, + "start_hg19": 24624759, + "stop_hg19": 24624853, + "start_t2t": 24890366, + "stop_t2t": 24890430, + "disease": "Familial adult myoclonic epilepsy type 6", + "inheritance": [ + "AD" + ], + "disease_description": "Cortical tremor, seizures with generalised motor (tonic-clonic) onset [@pmid:38876750].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "FAME overall is 1/35,000 in Japan. This repeat expansion is typically found in individuals of East Asian ancestry [@pmid:38876750].", + "age_onset": "Limited clinical details from one family, 'early 20s to 70s'", + "age_onset_min": 23, + "age_onset_max": 74, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "Novel, reported pathogenic alleles: (TTTTA)22 (TTTCA)exp (TTTTA)exp, but only the TTTCA is specific to affected individuals (size: 1100 repeats). Non-pathogenic reference TTTTA repeat was expanded in nine healthy subjects 40-120 repeats and in two individuals was potentially even longer [@pmid:29507423].", + "mechanism": "GoF?", + "mechanism_detail": "RNA toxicity hypothesized [@pmid:29507423; @pmid:38467784].", + "year": "2018 [@pmid:29507423]", + "location_in_gene": "Intron 1/23", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "TTTTA" + ], + "pathogenic_motif_reference_orientation": [ + "TTTCA" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [ + "TTTTT" + ], + "pathogenic_motif_gene_orientation": [ + "ATTTC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [ + "TTTTT" + ], + "locus_structure": [ + { + "motif": "TTTTA", + "count": 10, + "type": "internal_repeat" + }, + { + "motif": "TTTCA", + "count": null, + "type": "pathogenic_repeat" + } + ], + "benign_min": null, + "benign_max": null, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 1100, + "pathogenic_max": 1100, + "motif_len": 3, + "ref_copies": 18.8, + "novel": "novel", + "gard": [ + "16758" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "EPL227" + ], + "medgen": [ + "1648448" + ], + "mondo": [ + "0054846" + ], + "omim": [ + "618074" + ], + "orphanet": [ + "86814" + ], + "gnomad": [ + "TNRC6A" + ], + "stripy": [ + "TNRC6A" + ], + "tr_atlas": [ + "TR139999" + ], + "webstr_hg38": [ + "5951520" + ], + "webstr_hg19": [ + "STR_519979" + ], + "locus_tags": [ + "limited_evidence", + "motif_affects_penetrance" + ], + "disease_tags": [ + "familial_adult_myoclonic_epilepsy" + ], + "references": [ + "pmid:29507423", + "pmid:38467784", + "pmid:38876750" + ], + "additional_literature": [ + "pmid:41219789", + "pmid:36092952", + "pmid:33040085", + "pmid:31483537", + "pmid:30351492", + "pmid:23042244" + ] }, { - "motif": "AAAAT", - "count": 11, - "type": "internal_repeat" - }], - "benign_min": null, - "benign_max": null, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 274, - "pathogenic_max": 558, - "motif_len": 5, - "ref_copies": 11.6, - "novel": "novel", - "gard": ["18083"], - "genereviews": ["NBK535148"], - "malacard": ["EPL203"], - "medgen": ["375031"], - "mondo": ["0011930"], - "omim": ["607876"], - "orphanet": ["86814"], - "gnomad": ["STARD7"], - "stripy": ["STARD7"], - "tr_atlas": ["TR19329"], - "webstr_hg38": ["286156"], - "webstr_hg19": ["STR_754470"], - "locus_tags": ["supported_evidence", "somatic_instability", "motif_affects_instability", "motif_affects_penetrance"], - "disease_tags": ["familial_adult_myoclonic_epilepsy"], - "references": ["pmid:31664034", "pmid:38467784", "pmid:38876750", "pmid:39349043"], - "additional_literature": ["pmid:41219789", "pmid:33040085"] -}, -{ - "id": "XDP_TAF1", - "disease_id": "XDP", - "gene": "TAF1", - "chrom": "chrX", - "start_hg38": 71453054, - "stop_hg38": 71453131, - "start_hg19": 70672904, - "stop_hg19": 70672981, - "start_t2t": 69887153, - "stop_t2t": 69887230, - "disease": "X-linked dystonia-parkinsonism (XDP) a.k.a. Dystonia 3, torsion, X-linked (DYT3)", - "inheritance": ["XR"], - "disease_description": "X-linked dystonia-parkinsonism (XDP) associated with antisense insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within an intron of TAF1. Clinical features include focal and generalised dystonia, parkinsonism, cognitive dysfunction. XX individuals who are heterozygous carriers usually do not develop the full syndrome, although some patients have non-progressive focal dystonia with parkinsonism. Disease severity is associated with number of hexanucleotide repeats within the SVA. (Adapted) [@pmid:38876750].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Philippines overall 0.34:100,000. Panay Islands 5.24:100,000. Capiz province 18.9:100,000. To date, all known cases to date are of Filipino descent [@pmid:38876750].", - "age_onset": "Average age of onset for XDP is 39.7 years in males, 52 years in females, range 12-79 years. ~99% of cases are male [@pmid:29229810; @pmid:38876750; @pmid:15596620].", - "age_onset_min": 12.0, - "age_onset_max": 79.0, - "typ_age_onset_min": 39.7, - "typ_age_onset_max": 39.7, - "details": "Strong inverse relationship between age of onset and insertion length, which varied between 35-52 repeats [@pmid:29229810].", - "mechanism": "LoF", - "mechanism_detail": "Altered splicing with intron retention, haploinsufficiency [@pmid:38876750].", - "year": "2017 [@pmid:29229810]", - "location_in_gene": "Intron 32", - "gene_strand": "+", - "reference_motif_reference_orientation": ["AGAGGG"], - "pathogenic_motif_reference_orientation": ["AGAGGG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["AGAGGG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": null, - "benign_max": null, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 35, - "pathogenic_max": 52, - "motif_len": 6, - "ref_copies": 4.0, - "novel": "ref", - "gard": ["10533"], - "genereviews": ["NBK1489"], - "malacard": ["DYS064"], - "medgen": ["326820"], - "mondo": ["0010747"], - "omim": ["314250"], - "orphanet": ["53351"], - "gnomad": [], - "stripy": [], - "tr_atlas": ["TR592600"], - "webstr_hg38": ["861907"], - "webstr_hg19": ["STR_1564408"], - "locus_tags": ["supported_evidence", "length_affects_onset"], - "disease_tags": [], - "references": ["pmid:29229810", "pmid:38876750", "pmid:15596620"], - "additional_literature": ["pmid:41443196", "pmid:40463055", "pmid:38834915", "pmid:38616406", "pmid:37234925", "pmid:35971992", "pmid:38835911", "pmid:35868859", "pmid:35481544", "pmid:35395816", "pmid:38835428", "pmid:34250228", "pmid:34111553", "pmid:32533168", "pmid:32152096", "pmid:27806289", "pmid:18952144", "pmid:18713817", "pmid:17273961", "pmid:7668293", "pmid:7829058", "pmid:1518853"] -}, -{ - "id": "SCA17_TBP", - "disease_id": "SCA17", - "gene": "TBP", - "chrom": "chr6", - "start_hg38": 170561906, - "stop_hg38": 170562017, - "start_hg19": 170870994, - "stop_hg19": 170871105, - "start_t2t": 171935458, - "stop_t2t": 171935569, - "disease": "Spinocerebellar ataxia type 17", - "inheritance": ["AD"], - "disease_description": "A rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I). It is characterized by a variable clinical picture which can include dementia, psychiatric disorders, parkinsonism, dystonia, chorea, spasticity, and epilepsy [@mondo:0011781].", - "hpo_terms": null, - "prevalence": "0.2/100000", - "prevalence_details": "Unknown (global), <100 families, 0.47:1,000,000 (Japanese), 0.16/100,000 (England) [@genereviews:NBK1438; @pmid:29100084]: 0.2/100,000. Found across ethnicities/ancestries, with population-dependent prevalence [@genereviews:NBK1438].", - "age_onset": "Typical: 19-48; Range: 3-62, has second variant to delay onset [@omim:607136].", - "age_onset_min": 3.0, - "age_onset_max": 62.0, - "typ_age_onset_min": 19.0, - "typ_age_onset_max": 48.0, - "details": "Benign range is 25-40 repeats, pathogenic range is 49+ repeats (largest to date 66 motifs, with mild correlation between size and age of onset), and intermediate alleles (41-48 repeats) are associated with reduced penetrance and potentially milder phenotypes [@genereviews:NBK1438]. Huntington's disease like phenotype [@pmid:12805114]. Interruptions seen: CAA [@pmid:35245110]; CAA CAG CAA interruption is seen in all alleles stably transmitted across generations [@genereviews:NBK1438].", - "mechanism": "LoF/GoF", - "mechanism_detail": "Polyglutamine expansion leading to transcriptional dysregulation [@pmid:35053321].", - "year": "1999 [@pmid:10484774]", - "location_in_gene": "Coding Exon 3", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GCA"], - "pathogenic_motif_reference_orientation": ["GCA"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["AGC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 25, - "benign_max": 40, - "intermediate_min": 41, - "intermediate_max": 48, - "pathogenic_min": 49, - "pathogenic_max": 66, - "motif_len": 3, - "ref_copies": 37.0, - "novel": "ref", - "gard": ["10469"], - "genereviews": ["NBK1438"], - "malacard": ["SPN296"], - "medgen": ["337637"], - "mondo": ["0011781"], - "omim": ["607136"], - "orphanet": ["98759"], - "gnomad": ["TBP"], - "stripy": ["TBP"], - "tr_atlas": ["TR72502"], - "webstr_hg38": ["83566"], - "webstr_hg19": [], - "locus_tags": ["supported_evidence", "somatic_instability", "anticipation", "paternal_expansion", "length_affects_onset", "length_affects_penetrance", "length_affects_phenotype", "motif_affects_instability"], - "disease_tags": ["spinocerebellar_ataxia"], - "references": ["omim:607136", "pmid:35053321", "genereviews:NBK1438", "pmid:12805114", "pmid:35245110", "pmid:29100084", "pmid:10484774", "mondo:0011781"], - "additional_literature": ["pmid:41009775", "pmid:40488180", "pmid:40478462", "pmid:39950762", "pmid:39820777", "pmid:39680235", "pmid:39456985", "pmid:39125760", "pmid:38973070", "pmid:38961870", "pmid:38494459", "pmid:37855597", "pmid:37632648", "pmid:37146135", "pmid:36599645", "pmid:36476347", "pmid:36422518", "pmid:35926480", "pmid:35868859", "pmid:35493319", "pmid:35482253", "pmid:35275350", "pmid:35182509", "pmid:34906452", "pmid:34600502", "pmid:34565721", "pmid:34256333", "pmid:34235484", "pmid:33502644", "pmid:33377399", "pmid:32675418", "pmid:32533168", "pmid:32386547", "pmid:31940111", "pmid:31919387", "pmid:31522753", "pmid:30920184", "pmid:30891880", "pmid:30617627", "pmid:30615214", "pmid:30532692", "pmid:30314815", "pmid:30120431", "pmid:29801887", "pmid:29564144", "pmid:29249939", "pmid:29057148", "pmid:28821675", "pmid:28585930", "pmid:28444220", "pmid:28153533", "pmid:27865706", "pmid:27400454", "pmid:27172828", "pmid:26476771", "pmid:26387956", "pmid:26374734", "pmid:26267067", "pmid:26077168", "pmid:25672822", "pmid:24972706", "pmid:24677642", "pmid:24534762", "pmid:23665119", "pmid:23475385", "pmid:21710129", "pmid:21562248", "pmid:21437269", "pmid:20587494", "pmid:20199210", "pmid:20004653", "pmid:19595623", "pmid:19566714", "pmid:18218637", "pmid:18043721", "pmid:17961920", "pmid:17420317", "pmid:17273961", "pmid:17033685", "pmid:16858508", "pmid:16626296", "pmid:16223509", "pmid:16054804", "pmid:15850778", "pmid:15533937", "pmid:15503103", "pmid:15381080", "pmid:15365789", "pmid:15225551", "pmid:15193429", "pmid:14985389", "pmid:14967767", "pmid:12953269", "pmid:12891385", "pmid:12853230", "pmid:12758065", "pmid:11939898", "pmid:11571212", "pmid:11313753", "pmid:9399691", "pmid:8886170", "pmid:7892196", "pmid:8503450"] -}, -{ - "id": "TOF_TBX1", - "disease_id": "TOF", - "gene": "TBX1", - "chrom": "chr22", - "start_hg38": 19766762, - "stop_hg38": 19766807, - "start_hg19": 19754285, - "stop_hg19": 19754330, - "start_t2t": 20143615, - "stop_t2t": 20143660, - "disease": "Tetralogy of Fallot", - "inheritance": ["AD"], - "disease_description": "Tetralogy of Fallot is a congenital cardiac malformation that consists of an interventricular communication, also known as a ventricular septal defect, obstruction of the right ventricular outflow tract, override of the ventricular septum by the aortic root, and right ventricular hypertrophy [@mondo:0008542].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Found in one Turkish individual [@genereviews:NBK535148].", - "age_onset": "0", - "age_onset_min": 0.0, - "age_onset_max": 0.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "Found in one Turkish individual with Tetralogy of Fallot who had 25 repeats rather than 15 [@genereviews:NBK535148].", - "mechanism": "LoF/GoF", - "mechanism_detail": "Polyalanine expansion, leading to cytoplasmic aggregation [@omim:187500; @pmid:19948535].", - "year": "2010 [@pmid:19948535]", - "location_in_gene": "Coding Exon 9", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GCN"], - "pathogenic_motif_reference_orientation": ["GCN"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CNG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 15, - "benign_max": 15, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 25, - "pathogenic_max": 25, - "motif_len": 3, - "ref_copies": 15.0, - "novel": "ref", - "gard": ["2245"], - "genereviews": ["NBK535148"], - "malacard": ["TTR001"], - "medgen": ["21498"], - "mondo": ["0008542"], - "omim": ["187500"], - "orphanet": ["3303"], - "gnomad": ["TBX1"], - "stripy": ["TBX1"], - "tr_atlas": ["TR163862"], - "webstr_hg38": ["4900984"], - "webstr_hg19": ["STR_889797"], - "locus_tags": ["limited_evidence"], - "disease_tags": [], - "references": ["omim:187500", "pmid:19948535", "genereviews:NBK535148", "mondo:0008542"], - "additional_literature": ["pmid:24797903", "pmid:16141220", "pmid:10440825"] -}, -{ - "id": "FECD3_TCF4", - "disease_id": "FECD3", - "gene": "TCF4", - "chrom": "chr18", - "start_hg38": 55586153, - "stop_hg38": 55586229, - "start_hg19": 53253384, - "stop_hg19": 53253460, - "start_t2t": 55789233, - "stop_t2t": 55789288, - "disease": "Fuchs endothelial corneal dystrophy 3", - "inheritance": ["AD"], - "disease_description": "Late-onset Fuchs endothelial corneal dystrophy (FECD) is a degenerative disorder ... distinguished from other corneal disorders by the progressive formation of guttae [@omim:613267]. Studies suggest that disease severity increases in women with greater lifetime exposure to oestrogen [@pmid:40374208].", - "hpo_terms": null, - "prevalence": "4.5/100", - "prevalence_details": "~4/100 (over 40) [@omim:613267]; 5/100 [@pmid:20825314]. Predominantly in women (~75%) [@pmid:16769829]. In one study of two cohorts (Dallas Heart Study and 1000 Genomes Project), expanded allele carrier rates were 3.1% (African American), 8.1% (European American), and 3.3% (Latinos)in DHS, and 2.7% (AFR), 9.5% (EUR), 5.2% (East Asians), 7.2% (South Asians), and 5.2% (admixed Americans) in 1KGP [@pmid:39669694]. The highest carrier prevalence (12.1%–12.5%) occurred in EUR and admixed American subpopulations, while rates were 0%–1.9% in West Africans vs 6.2% in a Kenyan subpopulation.", - "age_onset": "Typical: 40-59 [@pmid:1676829]; Range: 32 [@pmid:21245398] - 79 [@pmid:39998965].", - "age_onset_min": 32.0, - "age_onset_max": 79.0, - "typ_age_onset_min": 40.0, - "typ_age_onset_max": 59.0, - "details": "Most controls have <40 repeats while majority of patients have >50 repeats; penetrance is <100%, as unaffected individuals have been documented with >80 repeats and alleles of affected individuals range from 12-2600 [@genereviews:NBK535148; @pmid:25168903]. Expansions are causative in approximately 70% of disease cases [@genereviews:NBK535148].", - "mechanism": "GoF", - "mechanism_detail": "Sequestration of MBNL1 in RNA foci, similar to the mechanism underlying myotonic dystrophy-1 [@pmid:25593321]. Variation in RAN translation [@pmid:38467784].", - "year": "2012 [@pmid:23185296]", - "location_in_gene": "Intron 1", - "gene_strand": "-", - "reference_motif_reference_orientation": ["CAG"], - "pathogenic_motif_reference_orientation": ["CAG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CTG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 10, - "benign_max": 39, - "intermediate_min": 40, - "intermediate_max": 50, - "pathogenic_min": 51, - "pathogenic_max": 2600, - "motif_len": 3, - "ref_copies": 25.3, - "novel": "ref", - "gard": ["10018"], - "genereviews": ["NBK535148"], - "malacard": ["FCH001", "CRN120"], - "medgen": ["442479"], - "mondo": ["0013203"], - "omim": ["613267"], - "orphanet": ["98974"], - "gnomad": ["TCF4"], - "stripy": ["TCF4"], - "tr_atlas": ["TR151784"], - "webstr_hg38": ["6247607", "463325"], - "webstr_hg19": [], - "locus_tags": ["supported_evidence", "length_affects_penetrance"], - "disease_tags": [], - "references": ["pmid:1676829", "pmid:21245398", "pmid:39998965", "pmid:25593321", "pmid:38467784", "genereviews:NBK535148", "pmid:25168903", "omim:613267", "pmid:20825314", "pmid:16769829", "pmid:39669694", "pmid:23185296", "pmid:40374208"], - "additional_literature": ["pmid:41373515", "pmid:41344296", "pmid:41298634", "pmid:41074692", "pmid:40961119", "pmid:40852795", "pmid:40767442", "pmid:40720054", "pmid:40585427", "pmid:40268158", "pmid:40081749", "pmid:40048186", "pmid:39651202", "pmid:39332053", "pmid:39288343", "pmid:39278108", "pmid:39231626", "pmid:38713708", "pmid:38704483", "pmid:38300219", "pmid:37747538", "pmid:37204786", "pmid:37169279", "pmid:36883248", "pmid:36773096", "pmid:36701310", "pmid:36275201", "pmid:36250467", "pmid:34946954", "pmid:34946867", "pmid:34855896", "pmid:34698281", "pmid:34644448", "pmid:33782268", "pmid:36246012", "pmid:33116252", "pmid:32934897", "pmid:32639312", "pmid:31554942", "pmid:31469403", "pmid:31276570", "pmid:30973406", "pmid:30811544", "pmid:30733599", "pmid:30267097", "pmid:30122888", "pmid:30098193", "pmid:29966009", "pmid:29799290", "pmid:29526280", "pmid:29325021", "pmid:29196769", "pmid:29044056", "pmid:28886202", "pmid:28832669", "pmid:28608272", "pmid:28118661", "pmid:27755191", "pmid:26401622", "pmid:26218914", "pmid:26200491", "pmid:25722209", "pmid:25298419", "pmid:24255041", "pmid:20960280", "pmid:11526470", "pmid:10712198", "pmid:10395212"] -}, -{ - "id": "SCA_THAP11", - "disease_id": "SCA51", - "gene": "THAP11", - "chrom": "chr16", - "start_hg38": 67842862, - "stop_hg38": 67842950, - "start_hg19": 67876765, - "stop_hg19": 67876853, - "start_t2t": 73638636, - "stop_t2t": 73638724, - "disease": "Spinocerebellar ataxia 51", - "inheritance": ["AD"], - "disease_description": "THAP11-caused SCA involves symptoms including gait ataxia, dysarthia, dysphagia, slow saccades, ptosis, and/or nystagmus [@pmid:37148549].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Has been observed in Chinese families [@pmid:37148549; @pmid:24677642]. Interruptions predisposing to expansion/disease appear to vary by ancestry [@pmid:39651830].", - "age_onset": "Typical: 8-40 (small sample size); Range: 4-51 [@pmid:37148549].", - "age_onset_min": 4.0, - "age_onset_max": 51.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "Expansion (45-100 repeats) found in affected individuals from 2 families and not in 500 controls (benign range: 20-38 repeats) [@pmid:37148549]. Longer alleles were associated with earlier age of onset. For example, an individual with 100 repeats had age of onset at 4 years. CAA interruptions can reduce toxicity [@pmid:37148549].", - "mechanism": "GoF", - "mechanism_detail": "Polyglutamine expansion leading to gain of function toxicity [@pmid:37148549; @pmid:38467784].", - "year": "2023 [@pmid:37148549]", - "location_in_gene": "Coding Exon 1", - "gene_strand": "+", - "reference_motif_reference_orientation": ["CAG"], - "pathogenic_motif_reference_orientation": ["CAG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["AGC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 20, - "benign_max": 38, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 45, - "pathogenic_max": 100, - "motif_len": 3, - "ref_copies": 29.3, - "novel": "ref", - "gard": ["10748"], - "genereviews": [], - "malacard": [], - "medgen": ["431598"], - "mondo": [], - "omim": ["620947"], - "orphanet": [], - "gnomad": ["THAP11"], - "stripy": [], - "tr_atlas": ["TR142069"], - "webstr_hg38": ["814002", "5973136"], - "webstr_hg19": ["STR_540982"], - "locus_tags": ["supported_evidence", "anticipation", "length_affects_onset", "length_affects_severity", "motif_affects_onset", "motif_affects_severity"], - "disease_tags": ["spinocerebellar_ataxia"], - "references": ["pmid:37148549", "pmid:38467784", "pmid:24677642", "pmid:39651830"], - "additional_literature": ["pmid:40886825", "pmid:40488180", "pmid:15368101"] -}, -{ - "id": "FAME6_TNRC6A", - "disease_id": "FAME6", - "gene": "TNRC6A", - "chrom": "chr16", - "start_hg38": 24613438, - "stop_hg38": 24613532, - "start_hg19": 24624759, - "stop_hg19": 24624853, - "start_t2t": 24890366, - "stop_t2t": 24890430, - "disease": "Familial adult myoclonic epilepsy type 6", - "inheritance": ["AD"], - "disease_description": "Cortical tremor, seizures with generalised motor (tonic-clonic) onset [@pmid:38876750].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "FAME overall is 1/35,000 in Japan. This repeat expansion is typically found in individuals of East Asian ancestry [@pmid:38876750].", - "age_onset": "Limited clinical details from one family, 'early 20s to 70s'", - "age_onset_min": 23.0, - "age_onset_max": 74.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "Novel, reported pathogenic alleles: (TTTTA)22 (TTTCA)exp (TTTTA)exp, but only the TTTCA is specific to affected individuals (size: 1100 repeats). Non-pathogenic reference TTTTA repeat was expanded in nine healthy subjects 40-120 repeats and in two individuals was potentially even longer [@pmid:29507423].", - "mechanism": "GoF?", - "mechanism_detail": "RNA toxicity hypothesized [@pmid:29507423; @pmid:38467784].", - "year": "2018 [@pmid:29507423]", - "location_in_gene": "Intron 1/23", - "gene_strand": "+", - "reference_motif_reference_orientation": ["TTTTA"], - "pathogenic_motif_reference_orientation": ["TTTCA"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": ["TTTTT"], - "pathogenic_motif_gene_orientation": ["ATTTC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": ["TTTTT"], - "locus_structure": [ + "id": "CPUM_TYMS", + "disease_id": "CPUM", + "gene": "TYMS", + "chrom": "chr18", + "start_hg38": 666891, + "stop_hg38": 667632, + "start_hg19": 666891, + "stop_hg19": 667632, + "start_t2t": 821235, + "stop_t2t": 821905, + "disease": "Congenital Progressive Universal Melanosis", + "inheritance": [ + "AR" + ], + "disease_description": "CPUM is characterized by progressive widespread hyperpigmentation beginning at birth without accompanying symptoms. Studied children with CPUM have been born to unaffected parents. The children studied have been born with diffuse, universal, and progressive hyperpigmentaion at 15 years of age. At this time the hyperpigmentation had fully progressed [@doi:10.3892/br.2025.2016]. It is not entirely clear that this is a distinct disease as it shares features with acquired universal melanosis (most similar), erythema dyschromicum perstans, lichen planus pigmentosus, and familial progressive hypigmentation.", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Found in two monozygotic twins in Thailand [@doi:10.3892/br.2025.2016].", + "age_onset": "0 (birth) [@doi:10.3892/br.2025.2016]", + "age_onset_min": 0, + "age_onset_max": 0, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "A study has identified an intronic GATGGT hexanucleotide tandem repeat in the TYMS gene. Both parents were found to be heterozygous carriers of the expansion, suggesting a recessive inheritance pattern. Evidence is limited, only a single family with monozygotic twins have been reoprted and no change in expression of the gene has been observed [@doi:10.3892/br.2025.2016].", + "mechanism": "LoF", + "mechanism_detail": "Proposed mechanism involves repeat expansions in non-coding regions of the gene, reducing expression in melanocytes or keratinocytes, leading to a disruption in nucleotide balance in DNA repair and hyperpigmentation. Missense mutations disrupt nucleotide metabolsim, resulting in loss-of-function and genome instability [@doi:10.3892/br.2025.2016].", + "year": "2025 [@doi:10.3892/br.2025.2016]", + "location_in_gene": "Intron 3", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "GATGGT" + ], + "pathogenic_motif_reference_orientation": [ + "GATGGT" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "ACCATC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 42, + "benign_max": 172, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 210, + "pathogenic_max": 259, + "motif_len": 6, + "ref_copies": null, + "novel": "ref", + "gard": [], + "genereviews": [], + "malacard": [], + "medgen": [], + "mondo": [], + "omim": [], + "orphanet": [], + "gnomad": [], + "stripy": [], + "tr_atlas": [], + "webstr_hg38": [], + "webstr_hg19": [], + "locus_tags": [ + "limited_evidence" + ], + "disease_tags": [], + "references": [ + "doi:10.3892/br.2025.2016" + ], + "additional_literature": [ + "pmid:41181325", + "pmid:41074680", + "pmid:41024012", + "pmid:40890629", + "pmid:40589716", + "pmid:40195828", + "pmid:38625071", + "pmid:38411001", + "pmid:38379425", + "pmid:38311638", + "pmid:38280392", + "pmid:38134936", + "pmid:36398398", + "pmid:36209056", + "pmid:35608245", + "pmid:35233526", + "pmid:35055435", + "pmid:34650802", + "pmid:34526668", + "pmid:34197619", + "pmid:34149004", + "pmid:33805940", + "pmid:33086767", + "pmid:32813677", + "pmid:32695278", + "pmid:32612964", + "pmid:32110891", + "pmid:31817852", + "pmid:31370354", + "pmid:31161452", + "pmid:30838312", + "pmid:30823845", + "pmid:30533396", + "pmid:30464574", + "pmid:30222710", + "pmid:30122542", + "pmid:29995270", + "pmid:29660633", + "pmid:29394274", + "pmid:29321350", + "pmid:29162511", + "pmid:28895423", + "pmid:28349270", + "pmid:28280649", + "pmid:28074308", + "pmid:28074022", + "pmid:27995989", + "pmid:27868347", + "pmid:27864985", + "pmid:27685916", + "pmid:27375073", + "pmid:29767611", + "pmid:26745074", + "pmid:26621114", + "pmid:26277606", + "pmid:26196219", + "pmid:26189437", + "pmid:25955097", + "pmid:25648260", + "pmid:25536611", + "pmid:25366766", + "pmid:25341694", + "pmid:25294632", + "pmid:25279663", + "pmid:25258183", + "pmid:25246386", + "pmid:25028118", + "pmid:25007187", + "pmid:24726028", + "pmid:24686188", + "pmid:24641398", + "pmid:24596472", + "pmid:24554028", + "pmid:24422758", + "pmid:24415354", + "pmid:24302747", + "pmid:24137384", + "pmid:23968134", + "pmid:23571497", + "pmid:23481061", + "pmid:23232805", + "pmid:23226765", + "pmid:23148637", + "pmid:22799365", + "pmid:22763757", + "pmid:22576918", + "pmid:22086855", + "pmid:22044939", + "pmid:21630057", + "pmid:21449681", + "pmid:21269855", + "pmid:21196216", + "pmid:21075014", + "pmid:20966539", + "pmid:20962453", + "pmid:20932673", + "pmid:20880668", + "pmid:20824655", + "pmid:20651387", + "pmid:20645403", + "pmid:20570968", + "pmid:20531375", + "pmid:20372856", + "pmid:20005374", + "pmid:19998340", + "pmid:19917450", + "pmid:19798689", + "pmid:19632929", + "pmid:19349389", + "pmid:19306093", + "pmid:19200948", + "pmid:19082493", + "pmid:18843018", + "pmid:18728661", + "pmid:18704422", + "pmid:18661526", + "pmid:18406541", + "pmid:18273818", + "pmid:18267032", + "pmid:18203297", + "pmid:18095031", + "pmid:17508355", + "pmid:17396161", + "pmid:17278107", + "pmid:17273745", + "pmid:17220568", + "pmid:17201138", + "pmid:17187508", + "pmid:17047490", + "pmid:17018589", + "pmid:16929515", + "pmid:16818689", + "pmid:16596248", + "pmid:16456808", + "pmid:16334126", + "pmid:16333305", + "pmid:16234002", + "pmid:16182121", + "pmid:15897576", + "pmid:15817609", + "pmid:15749593", + "pmid:15646842", + "pmid:15579479", + "pmid:15571262", + "pmid:15510613", + "pmid:15457444", + "pmid:15386371", + "pmid:15284183", + "pmid:15115918", + "pmid:14522928", + "pmid:12684695", + "pmid:12604405", + "pmid:12460463", + "pmid:12232785", + "pmid:12215845", + "pmid:12039668", + "pmid:11913730", + "pmid:11867566", + "pmid:11751507", + "pmid:11529907", + "pmid:11445856", + "pmid:10652619", + "pmid:10636923", + "pmid:10625460", + "pmid:8751943", + "pmid:3002689" + ] + }, { - "motif": "TTTTA", - "count": 10, - "type": "internal_repeat" + "id": "HMNR7_VWA1", + "disease_id": "HMNR7", + "gene": "VWA1", + "chrom": "chr1", + "start_hg38": 1435798, + "stop_hg38": 1435818, + "start_hg19": 1371178, + "stop_hg19": 1371198, + "start_t2t": 870158, + "stop_t2t": 870178, + "disease": "Neuronopathy, distal hereditary motor, autosomal recessive 7", + "inheritance": [ + "AR" + ], + "disease_description": "Autosomal recessive distal hereditary motor neuronopathy-7 (HMNR7) is characterized by onset of lower leg weakness in the first decade. Affected individuals have difficulty climbing stairs and problems standing on the heels... Most patients have foot deformities, and some may have leg muscle atrophy. The disorder is slowly progressive and often involves the upper limbs [@omim:619216].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Biallelic variants found in 0.01% of 100 KGP participants; enriched in those with motor disease. 80% of VWA1 pathogenic variants are expansions/contractions [@genereviews:NBK535148]. The repeat expansion was found in several ethnicities; founder mutation 7,000 years prior [@pmid:33559681].", + "age_onset": "Typical: 1-3 [@pmid:33559681]; Range: 0-10 [@omim:619216].", + "age_onset_min": 0, + "age_onset_max": 10, + "typ_age_onset_min": 1, + "typ_age_onset_max": 3, + "details": "Any deviation from 2 motifs is thought to be pathogenic [@genereviews:NBK535148].", + "mechanism": "LoF", + "mechanism_detail": "Loss of function [@pmid:38467784].", + "year": "2021 [@pmid:33559681]", + "location_in_gene": "Coding Exon 1", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GGCGCGGAGC" + ], + "pathogenic_motif_reference_orientation": [ + "GGCGCGGAGC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "AGCGGCGCGG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 2, + "benign_max": 2, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 1, + "pathogenic_max": 3, + "motif_len": 10, + "ref_copies": null, + "novel": null, + "gard": [ + "18444" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "NRN074" + ], + "medgen": [ + "1786836" + ], + "mondo": [ + "0030977" + ], + "omim": [ + "619216" + ], + "orphanet": [ + "314485" + ], + "gnomad": [ + "VWA1" + ], + "stripy": [], + "tr_atlas": [ + "TR32" + ], + "webstr_hg38": [ + "1099767" + ], + "webstr_hg19": [], + "locus_tags": [ + "supported_evidence", + "contraction" + ], + "disease_tags": [], + "references": [ + "pmid:33559681", + "omim:619216", + "pmid:38467784", + "genereviews:NBK535148" + ], + "additional_literature": [] }, { - "motif": "TTTCA", - "count": null, - "type": "pathogenic_repeat" - }], - "benign_min": null, - "benign_max": null, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 1100, - "pathogenic_max": 1100, - "motif_len": 3, - "ref_copies": 18.8, - "novel": "novel", - "gard": ["16758"], - "genereviews": ["NBK535148"], - "malacard": ["EPL227"], - "medgen": ["1648448"], - "mondo": ["0054846"], - "omim": ["618074"], - "orphanet": ["86814"], - "gnomad": ["TNRC6A"], - "stripy": ["TNRC6A"], - "tr_atlas": ["TR139999"], - "webstr_hg38": ["5951520"], - "webstr_hg19": ["STR_519979"], - "locus_tags": ["limited_evidence", "motif_affects_penetrance"], - "disease_tags": ["familial_adult_myoclonic_epilepsy"], - "references": ["pmid:29507423", "pmid:38467784", "pmid:38876750"], - "additional_literature": ["pmid:41219789", "pmid:36092952", "pmid:33040085", "pmid:31483537", "pmid:30351492", "pmid:23042244"] -}, -{ - "id": "CPUM_TYMS", - "disease_id": "CPUM", - "gene": "TYMS", - "chrom": "chr18", - "start_hg38": 666891, - "stop_hg38": 667632, - "start_hg19": 666891, - "stop_hg19": 667632, - "start_t2t": 821235, - "stop_t2t": 821905, - "disease": "Congenital Progressive Universal Melanosis", - "inheritance": ["AR"], - "disease_description": "CPUM is characterized by progressive widespread hyperpigmentation beginning at birth without accompanying symptoms. Studied children with CPUM have been born to unaffected parents. The children studied have been born with diffuse, universal, and progressive hyperpigmentaion at 15 years of age. At this time the hyperpigmentation had fully progressed [@doi:10.3892/br.2025.2016]. It is not entirely clear that this is a distinct disease as it shares features with acquired universal melanosis (most similar), erythema dyschromicum perstans, lichen planus pigmentosus, and familial progressive hypigmentation.", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Found in two monozygotic twins in Thailand [@doi:10.3892/br.2025.2016].", - "age_onset": "0 (birth) [@doi:10.3892/br.2025.2016]", - "age_onset_min": 0.0, - "age_onset_max": 0.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "A study has identified an intronic GATGGT hexanucleotide tandem repeat in the TYMS gene. Both parents were found to be heterozygous carriers of the expansion, suggesting a recessive inheritance pattern. Evidence is limited, only a single family with monozygotic twins have been reoprted and no change in expression of the gene has been observed [@doi:10.3892/br.2025.2016].", - "mechanism": "LoF", - "mechanism_detail": "Proposed mechanism involves repeat expansions in non-coding regions of the gene, reducing expression in melanocytes or keratinocytes, leading to a disruption in nucleotide balance in DNA repair and hyperpigmentation. Missense mutations disrupt nucleotide metabolsim, resulting in loss-of-function and genome instability [@doi:10.3892/br.2025.2016].", - "year": "2025 [@doi:10.3892/br.2025.2016]", - "location_in_gene": "Intron 3", - "gene_strand": "-", - "reference_motif_reference_orientation": ["GATGGT"], - "pathogenic_motif_reference_orientation": ["GATGGT"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["ACCATC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 42, - "benign_max": 172, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 210, - "pathogenic_max": 259, - "motif_len": 6, - "ref_copies": null, - "novel": "ref", - "gard": [], - "genereviews": [], - "malacard": [], - "medgen": [], - "mondo": [], - "omim": [], - "orphanet": [], - "gnomad": [], - "stripy": [], - "tr_atlas": [], - "webstr_hg38": [], - "webstr_hg19": [], - "locus_tags": ["limited_evidence"], - "disease_tags": [], - "references": ["doi:10.3892/br.2025.2016"], - "additional_literature": ["pmid:41181325", "pmid:41074680", "pmid:41024012", "pmid:40890629", "pmid:40589716", "pmid:40195828", "pmid:38625071", "pmid:38411001", "pmid:38379425", "pmid:38311638", "pmid:38280392", "pmid:38134936", "pmid:36398398", "pmid:36209056", "pmid:35608245", "pmid:35233526", "pmid:35055435", "pmid:34650802", "pmid:34526668", "pmid:34197619", "pmid:34149004", "pmid:33805940", "pmid:33086767", "pmid:32813677", "pmid:32695278", "pmid:32612964", "pmid:32110891", "pmid:31817852", "pmid:31370354", "pmid:31161452", "pmid:30838312", "pmid:30823845", "pmid:30533396", "pmid:30464574", "pmid:30222710", "pmid:30122542", "pmid:29995270", "pmid:29660633", "pmid:29394274", "pmid:29321350", "pmid:29162511", "pmid:28895423", "pmid:28349270", "pmid:28280649", "pmid:28074308", "pmid:28074022", "pmid:27995989", "pmid:27868347", "pmid:27864985", "pmid:27685916", "pmid:27375073", "pmid:29767611", "pmid:26745074", "pmid:26621114", "pmid:26277606", "pmid:26196219", "pmid:26189437", "pmid:25955097", "pmid:25648260", "pmid:25536611", "pmid:25366766", "pmid:25341694", "pmid:25294632", "pmid:25279663", "pmid:25258183", "pmid:25246386", "pmid:25028118", "pmid:25007187", "pmid:24726028", "pmid:24686188", "pmid:24641398", "pmid:24596472", "pmid:24554028", "pmid:24422758", "pmid:24415354", "pmid:24302747", "pmid:24137384", "pmid:23968134", "pmid:23571497", "pmid:23481061", "pmid:23232805", "pmid:23226765", "pmid:23148637", "pmid:22799365", "pmid:22763757", "pmid:22576918", "pmid:22086855", "pmid:22044939", "pmid:21630057", "pmid:21449681", "pmid:21269855", "pmid:21196216", "pmid:21075014", "pmid:20966539", "pmid:20962453", "pmid:20932673", "pmid:20880668", "pmid:20824655", "pmid:20651387", "pmid:20645403", "pmid:20570968", "pmid:20531375", "pmid:20372856", "pmid:20005374", "pmid:19998340", "pmid:19917450", "pmid:19798689", "pmid:19632929", "pmid:19349389", "pmid:19306093", "pmid:19200948", "pmid:19082493", "pmid:18843018", "pmid:18728661", "pmid:18704422", "pmid:18661526", "pmid:18406541", "pmid:18273818", "pmid:18267032", "pmid:18203297", "pmid:18095031", "pmid:17508355", "pmid:17396161", "pmid:17278107", "pmid:17273745", "pmid:17220568", "pmid:17201138", "pmid:17187508", "pmid:17047490", "pmid:17018589", "pmid:16929515", "pmid:16818689", "pmid:16596248", "pmid:16456808", "pmid:16334126", "pmid:16333305", "pmid:16234002", "pmid:16182121", "pmid:15897576", "pmid:15817609", "pmid:15749593", "pmid:15646842", "pmid:15579479", "pmid:15571262", "pmid:15510613", "pmid:15457444", "pmid:15386371", "pmid:15284183", "pmid:15115918", "pmid:14522928", "pmid:12684695", "pmid:12604405", "pmid:12460463", "pmid:12232785", "pmid:12215845", "pmid:12039668", "pmid:11913730", "pmid:11867566", "pmid:11751507", "pmid:11529907", "pmid:11445856", "pmid:10652619", "pmid:10636923", "pmid:10625460", "pmid:8751943", "pmid:3002689"] -}, -{ - "id": "HMNR7_VWA1", - "disease_id": "HMNR7", - "gene": "VWA1", - "chrom": "chr1", - "start_hg38": 1435798, - "stop_hg38": 1435818, - "start_hg19": 1371178, - "stop_hg19": 1371198, - "start_t2t": 870158, - "stop_t2t": 870178, - "disease": "Neuronopathy, distal hereditary motor, autosomal recessive 7", - "inheritance": ["AR"], - "disease_description": "Autosomal recessive distal hereditary motor neuronopathy-7 (HMNR7) is characterized by onset of lower leg weakness in the first decade. Affected individuals have difficulty climbing stairs and problems standing on the heels... Most patients have foot deformities, and some may have leg muscle atrophy. The disorder is slowly progressive and often involves the upper limbs [@omim:619216].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Biallelic variants found in 0.01% of 100 KGP participants; enriched in those with motor disease. 80% of VWA1 pathogenic variants are expansions/contractions [@genereviews:NBK535148]. The repeat expansion was found in several ethnicities; founder mutation 7,000 years prior [@pmid:33559681].", - "age_onset": "Typical: 1-3 [@pmid:33559681]; Range: 0-10 [@omim:619216].", - "age_onset_min": 0.0, - "age_onset_max": 10.0, - "typ_age_onset_min": 1.0, - "typ_age_onset_max": 3.0, - "details": "Any deviation from 2 motifs is thought to be pathogenic [@genereviews:NBK535148].", - "mechanism": "LoF", - "mechanism_detail": "Loss of function [@pmid:38467784].", - "year": "2021 [@pmid:33559681]", - "location_in_gene": "Coding Exon 1", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GGCGCGGAGC"], - "pathogenic_motif_reference_orientation": ["GGCGCGGAGC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["AGCGGCGCGG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 2, - "benign_max": 2, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 1, - "pathogenic_max": 3, - "motif_len": 10, - "ref_copies": null, - "novel": null, - "gard": ["18444"], - "genereviews": ["NBK535148"], - "malacard": ["NRN074"], - "medgen": ["1786836"], - "mondo": ["0030977"], - "omim": ["619216"], - "orphanet": ["314485"], - "gnomad": ["VWA1"], - "stripy": [], - "tr_atlas": ["TR32"], - "webstr_hg38": ["1099767"], - "webstr_hg19": [], - "locus_tags": ["supported_evidence", "contraction"], - "disease_tags": [], - "references": ["pmid:33559681", "omim:619216", "pmid:38467784", "genereviews:NBK535148"], - "additional_literature": [] -}, -{ - "id": "DBQD2_XYLT1", - "disease_id": "DBQD2, BSS", - "gene": "XYLT1", - "chrom": "chr16", - "start_hg38": 17470907, - "stop_hg38": 17470922, - "start_hg19": 17564764, - "stop_hg19": 17564779, - "start_t2t": 17477909, - "stop_t2t": 17478002, - "disease": "Baratela-Scott Syndrome/Desbuquois dysplasia 2", - "inheritance": ["AR"], - "disease_description": "Desbuquois dysplasia, which belongs to the multiple dislocation group of disorders, is characterized by dislocations of large joints, severe pre- and postnatal growth retardation, joint laxity, and flat face with prominent eyes. Radiologic features include short long bones with an exaggerated trochanter that gives a 'monkey wrench' appearance to the proximal femur, and advanced carpal and tarsal ossification [@pmid:24581741].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "<1/1,000,000 births [@orphanet:1425]; repeat expansions comprise half of DBQD variants [@genereviews:NBK535148]. <50 DBQD cases. Has been found in Belgian, Emirati families", - "age_onset": "0 (birth)", - "age_onset_min": 0.0, - "age_onset_max": 0.0, - "typ_age_onset_min": 0.0, - "typ_age_onset_max": 0.0, - "details": "Benign range (0-20) taken from primary literatre of unaffected individuals and gnomAD data [@pmid:30554721; @gnomad:XYLT1]. Minimum repeat size to cause disease thought to range between 72 and 110 repeats [@pmid:30554721]. Repeat is within a 238bp sequence which is missing from hg38 but present in T2T-CHM13", - "mechanism": "LoF", - "mechanism_detail": "Methylation [@pmid:30554721].", - "year": "2019 [@pmid:30554721]", - "location_in_gene": "5' promoter region. Note, it can also be annotated coding or introntic depending on the reference, due to missing sequences in some reference genomes.", - "gene_strand": "-", - "reference_motif_reference_orientation": ["GCC"], - "pathogenic_motif_reference_orientation": ["GCC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CGG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [ + "id": "DBQD2_XYLT1", + "disease_id": "DBQD2, BSS", + "gene": "XYLT1", + "chrom": "chr16", + "start_hg38": 17470907, + "stop_hg38": 17470922, + "start_hg19": 17564764, + "stop_hg19": 17564779, + "start_t2t": 17477909, + "stop_t2t": 17478002, + "disease": "Baratela-Scott Syndrome/Desbuquois dysplasia 2", + "inheritance": [ + "AR" + ], + "disease_description": "Desbuquois dysplasia, which belongs to the multiple dislocation group of disorders, is characterized by dislocations of large joints, severe pre- and postnatal growth retardation, joint laxity, and flat face with prominent eyes. Radiologic features include short long bones with an exaggerated trochanter that gives a 'monkey wrench' appearance to the proximal femur, and advanced carpal and tarsal ossification [@pmid:24581741].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "<1/1,000,000 births [@orphanet:1425]; repeat expansions comprise half of DBQD variants [@genereviews:NBK535148]. <50 DBQD cases. Has been found in Belgian, Emirati families", + "age_onset": "0 (birth)", + "age_onset_min": 0, + "age_onset_max": 0, + "typ_age_onset_min": 0, + "typ_age_onset_max": 0, + "details": "Benign range (0-20) taken from primary literatre of unaffected individuals and gnomAD data [@pmid:30554721; @gnomad:XYLT1]. Minimum repeat size to cause disease thought to range between 72 and 110 repeats [@pmid:30554721]. Repeat is within a 238bp sequence which is missing from hg38 but present in T2T-CHM13", + "mechanism": "LoF", + "mechanism_detail": "Methylation [@pmid:30554721].", + "year": "2019 [@pmid:30554721]", + "location_in_gene": "5' promoter region. Note, it can also be annotated coding or introntic depending on the reference, due to missing sequences in some reference genomes.", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "GCC" + ], + "pathogenic_motif_reference_orientation": [ + "GCC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CGG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [ + { + "motif": "GCC", + "count": 0, + "type": "internal_repeat" + }, + { + "motif": "TCGGCTCGCCGCTGCTCCTCCTCC", + "count": 0, + "type": "interruption" + }, + { + "motif": "GCC", + "count": null, + "type": "pathogenic_repeat" + } + ], + "benign_min": 0, + "benign_max": 20, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 72, + "pathogenic_max": 110, + "motif_len": 3, + "ref_copies": 0, + "novel": "ref", + "gard": [ + "16466" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "DSB005" + ], + "medgen": [ + "862731" + ], + "mondo": [ + "0014343" + ], + "omim": [ + "615777" + ], + "orphanet": [ + "1425" + ], + "gnomad": [ + "XYLT1" + ], + "stripy": [ + "XYLT1" + ], + "tr_atlas": [ + "TR139509" + ], + "webstr_hg38": [ + "793606" + ], + "webstr_hg19": [], + "locus_tags": [ + "supported_evidence" + ], + "disease_tags": [], + "references": [ + "pmid:30554721", + "gnomad:XYLT1", + "orphanet:1425", + "genereviews:NBK535148", + "pmid:24581741" + ], + "additional_literature": [] + }, { - "motif": "GCC", - "count": 0, - "type": "internal_repeat" + "id": "FAME4_YEATS2", + "disease_id": "FAME4", + "gene": "YEATS2", + "chrom": "chr3", + "start_hg38": 183712187, + "stop_hg38": 183712226, + "start_hg19": 183429975, + "stop_hg19": 183430014, + "start_t2t": 186521667, + "stop_t2t": 186521706, + "disease": "Familial adult myoclonic epilepsy 4", + "inheritance": [ + "AD" + ], + "disease_description": "Cortical tremor, seizures with generalised motor (tonic-clonic) onset [@pmid:38876750].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "FAME overall is 1/35,000 in Japan. This repeat expansion is typically found in individuals of East Asian ancestry [@pmid:38876750].", + "age_onset": "Typical: 20-25 [@pmid:22713812]; Range: 10-33 [@pmid:31539032].", + "age_onset_min": 10, + "age_onset_max": 33, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "Novel insertion of ~1000 repeats observed to cause disease [@pmid:31539032].", + "mechanism": "GoF?", + "mechanism_detail": "RNA toxicity hypothesized [@pmid:31539032].", + "year": "2019 [@pmid:31539032]", + "location_in_gene": "Intron 1", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "TTTTA" + ], + "pathogenic_motif_reference_orientation": [ + "TTTCA" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [ + "TTTTT", + "TGTTA" + ], + "pathogenic_motif_gene_orientation": [ + "ATTTC" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [ + "TTTTT", + "ATGTT" + ], + "locus_structure": [ + { + "motif": "TTTTA", + "count": 7, + "type": "internal_repeat" + }, + { + "motif": "TTTCA", + "count": null, + "type": "pathogenic_repeat" + } + ], + "benign_min": null, + "benign_max": null, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 1000, + "pathogenic_max": 1000, + "motif_len": 5, + "ref_copies": 7.8, + "novel": "novel", + "gard": [ + "16758" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "EPL107" + ], + "medgen": [ + "767474" + ], + "mondo": [ + "0014055" + ], + "omim": [ + "615127" + ], + "orphanet": [ + "86814" + ], + "gnomad": [ + "YEATS2" + ], + "stripy": [ + "YEATS2" + ], + "tr_atlas": [ + "TR38932" + ], + "webstr_hg38": [ + "5034940", + "769177" + ], + "webstr_hg19": [ + "STR_1006941" + ], + "locus_tags": [ + "supported_evidence", + "motif_affects_penetrance" + ], + "disease_tags": [ + "familial_adult_myoclonic_epilepsy" + ], + "references": [ + "pmid:22713812", + "pmid:31539032", + "pmid:38876750" + ], + "additional_literature": [ + "pmid:41219789", + "pmid:38128822" + ] }, { - "motif": "TCGGCTCGCCGCTGCTCCTCCTCC", - "count": 0, - "type": "interruption" + "id": "SCA4_ZFHX3", + "disease_id": "SCA4", + "gene": "ZFHX3", + "chrom": "chr16", + "start_hg38": 72787694, + "stop_hg38": 72787758, + "start_hg19": 72821593, + "stop_hg19": 72821657, + "start_t2t": 78605502, + "stop_t2t": 78605569, + "disease": "Spinocerebellar ataxia 4", + "inheritance": [ + "AD" + ], + "disease_description": "Spinocerebellar ataxia type 4 (SCA4) is a very rare progressive subtype of type I autosomal dominant cerebellar ataxia (ADCA type I) characterized by ataxia with sensory neuropathy (adapted from Mondo) [@mondo:0010847].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Observed in Swedish individuals: 2 original kindreds and 3 additional families [@omim:600223]; common ancestral allele has been identified [@pmid:39635987].", + "age_onset": "Typical: 37- 56; Range: 12 - 65 [@pmid:39666847; @pmid:38973251].", + "age_onset_min": 12, + "age_onset_max": 65, + "typ_age_onset_min": 37, + "typ_age_onset_max": 56, + "details": "Disease-causing expansions range from 46 repeats [@pmid:38973251] to 74 repeats [@pmid:38035881]. Possible anticipation in disease [@pmid:38197134; @pmid:38035881]; intermediate alleles may correspond to premutations [@pmid:38973251]. Most unaffected individuals had 21 motifs, but benign alleles range from 14-26 repeats [@pmid:38035881].", + "mechanism": "GoF?", + "mechanism_detail": "Potential RNA-mediated gain of function mechanism theorized [@pmid:38467784]", + "year": "2023 [@pmid:38035881]", + "location_in_gene": "Coding, Last Exon (exon number is transcript dependent)", + "gene_strand": "-", + "reference_motif_reference_orientation": [ + "GCC" + ], + "pathogenic_motif_reference_orientation": [ + "GCC" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CGG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 14, + "benign_max": 26, + "intermediate_min": 27, + "intermediate_max": 45, + "pathogenic_min": 46, + "pathogenic_max": 74, + "motif_len": 3, + "ref_copies": 21.3, + "novel": "ref", + "gard": [ + "9970" + ], + "genereviews": [], + "malacard": [ + "SPN105" + ], + "medgen": [ + "199815" + ], + "mondo": [ + "0010847" + ], + "omim": [ + "600223" + ], + "orphanet": [ + "98765" + ], + "gnomad": [ + "ZFHX3" + ], + "stripy": [], + "tr_atlas": [ + "TR142346" + ], + "webstr_hg38": [ + "5977326" + ], + "webstr_hg19": [ + "STR_545217" + ], + "locus_tags": [ + "supported_evidence", + "length_affects_onset" + ], + "disease_tags": [ + "spinocerebellar_ataxia" + ], + "references": [ + "pmid:39666847", + "pmid:38973251", + "pmid:38467784", + "pmid:38035881", + "pmid:38197134", + "omim:600223", + "pmid:39635987", + "mondo:0010847" + ], + "additional_literature": [ + "pmid:40898875", + "pmid:40594369", + "pmid:40488180", + "pmid:40459184", + "pmid:40166539", + "pmid:39095619", + "pmid:38684900", + "pmid:38472396", + "pmid:38145611", + "pmid:20586826", + "pmid:10855793" + ] }, { - "motif": "GCC", - "count": null, - "type": "pathogenic_repeat" - }], - "benign_min": 0, - "benign_max": 20, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 72, - "pathogenic_max": 110, - "motif_len": 3, - "ref_copies": 0.0, - "novel": "ref", - "gard": ["16466"], - "genereviews": ["NBK535148"], - "malacard": ["DSB005"], - "medgen": ["862731"], - "mondo": ["0014343"], - "omim": ["615777"], - "orphanet": ["1425"], - "gnomad": ["XYLT1"], - "stripy": ["XYLT1"], - "tr_atlas": ["TR139509"], - "webstr_hg38": ["793606"], - "webstr_hg19": [], - "locus_tags": ["supported_evidence"], - "disease_tags": [], - "references": ["pmid:30554721", "gnomad:XYLT1", "orphanet:1425", "genereviews:NBK535148", "pmid:24581741"], - "additional_literature": [] -}, -{ - "id": "FAME4_YEATS2", - "disease_id": "FAME4", - "gene": "YEATS2", - "chrom": "chr3", - "start_hg38": 183712187, - "stop_hg38": 183712226, - "start_hg19": 183429975, - "stop_hg19": 183430014, - "start_t2t": 186521667, - "stop_t2t": 186521706, - "disease": "Familial adult myoclonic epilepsy 4", - "inheritance": ["AD"], - "disease_description": "Cortical tremor, seizures with generalised motor (tonic-clonic) onset [@pmid:38876750].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "FAME overall is 1/35,000 in Japan. This repeat expansion is typically found in individuals of East Asian ancestry [@pmid:38876750].", - "age_onset": "Typical: 20-25 [@pmid:22713812]; Range: 10-33 [@pmid:31539032].", - "age_onset_min": 10.0, - "age_onset_max": 33.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "Novel insertion of ~1000 repeats observed to cause disease [@pmid:31539032].", - "mechanism": "GoF?", - "mechanism_detail": "RNA toxicity hypothesized [@pmid:31539032].", - "year": "2019 [@pmid:31539032]", - "location_in_gene": "Intron 1", - "gene_strand": "+", - "reference_motif_reference_orientation": ["TTTTA"], - "pathogenic_motif_reference_orientation": ["TTTCA"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": ["TTTTT", "TGTTA"], - "pathogenic_motif_gene_orientation": ["ATTTC"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": ["TTTTT", "ATGTT"], - "locus_structure": [ + "id": "HPE5_ZIC2", + "disease_id": "HPE5", + "gene": "ZIC2", + "chrom": "chr13", + "start_hg38": 99985448, + "stop_hg38": 99985494, + "start_hg19": 100637702, + "stop_hg19": 100637748, + "start_t2t": 99196358, + "stop_t2t": 99196404, + "disease": "Holoprosencephaly-5", + "inheritance": [ + "AD" + ], + "disease_description": "Holoprosencephaly associated with mutations in the ZIC2 gene [@mondo:0012322].", + "hpo_terms": null, + "prevalence": "1.4/1000000", + "prevalence_details": "0.05-0.23/100,000; math done by 40% of pathogenic variants in ZIC2 are expansion [@genereviews:NBK1530]; 5% of non-syndromic HPE are ZIC2 gene [@genereviews:NBK1530], and nonsyndromic HPE is 25-50% of HPE, which affects 1/10,000 newborns [@url:medlineplus.gov/genetics/condition/nonsyndromic-holoprosencephaly/] - ZIC2 is 9.2% of HPE cases, which occur in 1/16,000 live births [@pmid:17274816]. Holoprosencephaly has worldwide distribution [@orphanet:2162], but STR-specific distribution is unknown.", + "age_onset": "0", + "age_onset_min": 0, + "age_onset_max": 0, + "typ_age_onset_min": 0, + "typ_age_onset_max": 0, + "details": "The benign allele of 15 repeats expands to 25 repeats to cause disease [@genereviews:NBK51932], although the expansion can potentially present with a mild phenotype [@doi:10.1016/j.gimo.2024.101607]", + "mechanism": "LoF", + "mechanism_detail": "Polyalanine expansion interfering with DNA binding and transcriptional activation [@pmid:19177455; @pmid:15590697].", + "year": "2001 [@pmid:11285244]", + "location_in_gene": "Coding Exon 3", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GCN" + ], + "pathogenic_motif_reference_orientation": [ + "GCN" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CNG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 15, + "benign_max": 15, + "intermediate_min": null, + "intermediate_max": null, + "pathogenic_min": 25, + "pathogenic_max": 25, + "motif_len": 3, + "ref_copies": 15.3, + "novel": "ref", + "gard": [ + "6665" + ], + "genereviews": [ + "NBK51932" + ], + "malacard": [ + "HLP028" + ], + "medgen": [ + "355304" + ], + "mondo": [ + "0012322" + ], + "omim": [ + "609637" + ], + "orphanet": [ + "2162" + ], + "gnomad": [ + "ZIC2" + ], + "stripy": [ + "ZIC2" + ], + "tr_atlas": [ + "TR127312" + ], + "webstr_hg38": [ + "5374719" + ], + "webstr_hg19": [ + "STR_395661" + ], + "locus_tags": [ + "supported_evidence" + ], + "disease_tags": [], + "references": [ + "pmid:19177455", + "pmid:15590697", + "genereviews:NBK51932", + "doi:10.1016/j.gimo.2024.101607", + "genereviews:NBK1530", + "url:medlineplus.gov/genetics/condition/nonsyndromic-holoprosencephaly/", + "pmid:17274816", + "orphanet:2162", + "pmid:11285244", + "mondo:0012322" + ], + "additional_literature": [ + "pmid:40033291" + ] + }, { - "motif": "TTTTA", - "count": 7, - "type": "internal_repeat" + "id": "VACTERLX_ZIC3", + "disease_id": "VACTERLX", + "gene": "ZIC3", + "chrom": "chrX", + "start_hg38": 137566826, + "stop_hg38": 137566856, + "start_hg19": 136648985, + "stop_hg19": 136649015, + "start_t2t": 135876774, + "stop_t2t": 135876804, + "disease": "X-linked VACTERL syndrome", + "inheritance": [ + "XR" + ], + "disease_description": "VACTERL is an acronym for vertebral anomalies (similar to those of spondylocostal dysplasia), anal atresia, cardiac malformations, tracheoesophageal fistula, renal anomalies (urethral atresia with hydronephrosis), and limb anomalies [@omim:314390].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "Found in one patient [@genereviews:NBK535148] with European ancestry [@pmid:20452998].", + "age_onset": "0", + "age_onset_min": 0, + "age_onset_max": 0, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": "Frequently genotyped as (NGC)*, although locus structure has been reported as (GCC)8(GCT)(GCC) [@pmid:38467784]. 1 patient with VACTERL died at birth with 12 repeats [@pmid:20452998]. 8 patients with X-linked oculo-auriculo-vertebral spectrum (OAVS) had 11 repeats (intermediate allele size); 1 individual in OAVS cohort with 12 repeats; likely phenotypic spectrum [@pmid:32639022].", + "mechanism": "Unknown", + "mechanism_detail": "Polyalanine expansion with unknown mechanism [@pmid:17581576].", + "year": "2010 [@pmid:20452998]", + "location_in_gene": "Coding Exon 1", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GCN" + ], + "pathogenic_motif_reference_orientation": [ + "GCN" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CNG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 10, + "benign_max": 10, + "intermediate_min": 11, + "intermediate_max": 11, + "pathogenic_min": 12, + "pathogenic_max": 12, + "motif_len": 3, + "ref_copies": 9, + "novel": "ref", + "gard": [ + "15309" + ], + "genereviews": [ + "NBK535148" + ], + "malacard": [ + "VCT005" + ], + "medgen": [ + "419019" + ], + "mondo": [ + "0010752" + ], + "omim": [ + "314390" + ], + "orphanet": [], + "gnomad": [ + "ZIC3" + ], + "stripy": [ + "ZIC3" + ], + "tr_atlas": [ + "TR173313" + ], + "webstr_hg38": [ + "883856" + ], + "webstr_hg19": [ + "STR_1596381" + ], + "locus_tags": [ + "limited_evidence" + ], + "disease_tags": [ + "phenotypic_spectrum" + ], + "references": [ + "pmid:17581576", + "pmid:38467784", + "pmid:20452998", + "pmid:32639022", + "genereviews:NBK535148", + "omim:314390" + ], + "additional_literature": [ + "pmid:40585427" + ] }, { - "motif": "TTTCA", - "count": null, - "type": "pathogenic_repeat" - }], - "benign_min": null, - "benign_max": null, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 1000, - "pathogenic_max": 1000, - "motif_len": 5, - "ref_copies": 7.8, - "novel": "novel", - "gard": ["16758"], - "genereviews": ["NBK535148"], - "malacard": ["EPL107"], - "medgen": ["767474"], - "mondo": ["0014055"], - "omim": ["615127"], - "orphanet": ["86814"], - "gnomad": ["YEATS2"], - "stripy": ["YEATS2"], - "tr_atlas": ["TR38932"], - "webstr_hg38": ["5034940", "769177"], - "webstr_hg19": ["STR_1006941"], - "locus_tags": ["supported_evidence", "motif_affects_penetrance"], - "disease_tags": ["familial_adult_myoclonic_epilepsy"], - "references": ["pmid:22713812", "pmid:31539032", "pmid:38876750"], - "additional_literature": ["pmid:41219789", "pmid:38128822"] -}, -{ - "id": "SCA4_ZFHX3", - "disease_id": "SCA4", - "gene": "ZFHX3", - "chrom": "chr16", - "start_hg38": 72787694, - "stop_hg38": 72787758, - "start_hg19": 72821593, - "stop_hg19": 72821657, - "start_t2t": 78605502, - "stop_t2t": 78605569, - "disease": "Spinocerebellar ataxia 4", - "inheritance": ["AD"], - "disease_description": "Spinocerebellar ataxia type 4 (SCA4) is a very rare progressive subtype of type I autosomal dominant cerebellar ataxia (ADCA type I) characterized by ataxia with sensory neuropathy (adapted from Mondo) [@mondo:0010847].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Observed in Swedish individuals: 2 original kindreds and 3 additional families [@omim:600223]; common ancestral allele has been identified [@pmid:39635987].", - "age_onset": "Typical: 37- 56; Range: 12 - 65 [@pmid:39666847; @pmid:38973251].", - "age_onset_min": 12.0, - "age_onset_max": 65.0, - "typ_age_onset_min": 37.0, - "typ_age_onset_max": 56.0, - "details": "Disease-causing expansions range from 46 repeats [@pmid:38973251] to 74 repeats [@pmid:38035881]. Possible anticipation in disease [@pmid:38197134; @pmid:38035881]; intermediate alleles may correspond to premutations [@pmid:38973251]. Most unaffected individuals had 21 motifs, but benign alleles range from 14-26 repeats [@pmid:38035881].", - "mechanism": "GoF?", - "mechanism_detail": "Potential RNA-mediated gain of function mechanism theorized [@pmid:38467784]", - "year": "2023 [@pmid:38035881]", - "location_in_gene": "Coding, Last Exon (exon number is transcript dependent)", - "gene_strand": "-", - "reference_motif_reference_orientation": ["GCC"], - "pathogenic_motif_reference_orientation": ["GCC"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CGG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 14, - "benign_max": 26, - "intermediate_min": 27, - "intermediate_max": 45, - "pathogenic_min": 46, - "pathogenic_max": 74, - "motif_len": 3, - "ref_copies": 21.3, - "novel": "ref", - "gard": ["9970"], - "genereviews": [], - "malacard": ["SPN105"], - "medgen": ["199815"], - "mondo": ["0010847"], - "omim": ["600223"], - "orphanet": ["98765"], - "gnomad": ["ZFHX3"], - "stripy": [], - "tr_atlas": ["TR142346"], - "webstr_hg38": ["5977326"], - "webstr_hg19": ["STR_545217"], - "locus_tags": ["supported_evidence", "length_affects_onset"], - "disease_tags": ["spinocerebellar_ataxia"], - "references": ["pmid:39666847", "pmid:38973251", "pmid:38467784", "pmid:38035881", "pmid:38197134", "omim:600223", "pmid:39635987", "mondo:0010847"], - "additional_literature": ["pmid:40898875", "pmid:40594369", "pmid:40488180", "pmid:40459184", "pmid:40166539", "pmid:39095619", "pmid:38684900", "pmid:38472396", "pmid:38145611", "pmid:20586826", "pmid:10855793"] -}, -{ - "id": "HPE5_ZIC2", - "disease_id": "HPE5", - "gene": "ZIC2", - "chrom": "chr13", - "start_hg38": 99985448, - "stop_hg38": 99985494, - "start_hg19": 100637702, - "stop_hg19": 100637748, - "start_t2t": 99196358, - "stop_t2t": 99196404, - "disease": "Holoprosencephaly-5", - "inheritance": ["AD"], - "disease_description": "Holoprosencephaly associated with mutations in the ZIC2 gene [@mondo:0012322].", - "hpo_terms": null, - "prevalence": "1.4/1000000", - "prevalence_details": "0.05-0.23/100,000; math done by 40% of pathogenic variants in ZIC2 are expansion [@genereviews:NBK1530]; 5% of non-syndromic HPE are ZIC2 gene [@genereviews:NBK1530], and nonsyndromic HPE is 25-50% of HPE, which affects 1/10,000 newborns [@url:medlineplus.gov/genetics/condition/nonsyndromic-holoprosencephaly/] - ZIC2 is 9.2% of HPE cases, which occur in 1/16,000 live births [@pmid:17274816]. Holoprosencephaly has worldwide distribution [@orphanet:2162], but STR-specific distribution is unknown.", - "age_onset": "0", - "age_onset_min": 0.0, - "age_onset_max": 0.0, - "typ_age_onset_min": 0.0, - "typ_age_onset_max": 0.0, - "details": "The benign allele of 15 repeats expands to 25 repeats to cause disease [@genereviews:NBK51932], although the expansion can potentially present with a mild phenotype [@doi:10.1016/j.gimo.2024.101607]", - "mechanism": "LoF", - "mechanism_detail": "Polyalanine expansion interfering with DNA binding and transcriptional activation [@pmid:19177455; @pmid:15590697].", - "year": "2001 [@pmid:11285244]", - "location_in_gene": "Coding Exon 3", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GCN"], - "pathogenic_motif_reference_orientation": ["GCN"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CNG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 15, - "benign_max": 15, - "intermediate_min": null, - "intermediate_max": null, - "pathogenic_min": 25, - "pathogenic_max": 25, - "motif_len": 3, - "ref_copies": 15.3, - "novel": "ref", - "gard": ["6665"], - "genereviews": ["NBK51932"], - "malacard": ["HLP028"], - "medgen": ["355304"], - "mondo": ["0012322"], - "omim": ["609637"], - "orphanet": ["2162"], - "gnomad": ["ZIC2"], - "stripy": ["ZIC2"], - "tr_atlas": ["TR127312"], - "webstr_hg38": ["5374719"], - "webstr_hg19": ["STR_395661"], - "locus_tags": ["supported_evidence"], - "disease_tags": [], - "references": ["pmid:19177455", "pmid:15590697", "genereviews:NBK51932", "doi:10.1016/j.gimo.2024.101607", "genereviews:NBK1530", "url:medlineplus.gov/genetics/condition/nonsyndromic-holoprosencephaly/", "pmid:17274816", "orphanet:2162", "pmid:11285244", "mondo:0012322"], - "additional_literature": ["pmid:40033291"] -}, -{ - "id": "VACTERLX_ZIC3", - "disease_id": "VACTERLX", - "gene": "ZIC3", - "chrom": "chrX", - "start_hg38": 137566826, - "stop_hg38": 137566856, - "start_hg19": 136648985, - "stop_hg19": 136649015, - "start_t2t": 135876774, - "stop_t2t": 135876804, - "disease": "X-linked VACTERL syndrome", - "inheritance": ["XR"], - "disease_description": "VACTERL is an acronym for vertebral anomalies (similar to those of spondylocostal dysplasia), anal atresia, cardiac malformations, tracheoesophageal fistula, renal anomalies (urethral atresia with hydronephrosis), and limb anomalies [@omim:314390].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "Found in one patient [@genereviews:NBK535148] with European ancestry [@pmid:20452998].", - "age_onset": "0", - "age_onset_min": 0.0, - "age_onset_max": 0.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": "Frequently genotyped as (NGC)*, although locus structure has been reported as (GCC)8(GCT)(GCC) [@pmid:38467784]. 1 patient with VACTERL died at birth with 12 repeats [@pmid:20452998]. 8 patients with X-linked oculo-auriculo-vertebral spectrum (OAVS) had 11 repeats (intermediate allele size); 1 individual in OAVS cohort with 12 repeats; likely phenotypic spectrum [@pmid:32639022].", - "mechanism": "Unknown", - "mechanism_detail": "Polyalanine expansion with unknown mechanism [@pmid:17581576].", - "year": "2010 [@pmid:20452998]", - "location_in_gene": "Coding Exon 1", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GCN"], - "pathogenic_motif_reference_orientation": ["GCN"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CNG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 10, - "benign_max": 10, - "intermediate_min": 11, - "intermediate_max": 11, - "pathogenic_min": 12, - "pathogenic_max": 12, - "motif_len": 3, - "ref_copies": 9.0, - "novel": "ref", - "gard": ["15309"], - "genereviews": ["NBK535148"], - "malacard": ["VCT005"], - "medgen": ["419019"], - "mondo": ["0010752"], - "omim": ["314390"], - "orphanet": [], - "gnomad": ["ZIC3"], - "stripy": ["ZIC3"], - "tr_atlas": ["TR173313"], - "webstr_hg38": ["883856"], - "webstr_hg19": ["STR_1596381"], - "locus_tags": ["limited_evidence"], - "disease_tags": ["phenotypic_spectrum"], - "references": ["pmid:17581576", "pmid:38467784", "pmid:20452998", "pmid:32639022", "genereviews:NBK535148", "omim:314390"], - "additional_literature": ["pmid:40585427"] -}, -{ - "id": "FRA7A_ZNF713", - "disease_id": "FRA7A", - "gene": "ZNF713", - "chrom": "chr7", - "start_hg38": 55887600, - "stop_hg38": 55887639, - "start_hg19": 55955293, - "stop_hg19": 55955332, - "start_t2t": 56047900, - "stop_t2t": 56047939, - "disease": "Autism spectrum disorder associated with fragile site FRA7A", - "inheritance": ["AD"], - "disease_description": "A spectrum of developmental disorders that includes autism, and Asperger syndrome. Signs and symptoms include poor communication skills, defective social interactions, and repetitive behaviors [@mondo:0005258].", - "hpo_terms": null, - "prevalence": null, - "prevalence_details": "1 proband reported alongside 3 individuals with premutations, found in 2 families without discussion of ancestry/ethnicity [@pmid:25196122].", - "age_onset": "2-3 (four individuals) [@pmid:25196122].", - "age_onset_min": 2.0, - "age_onset_max": 3.0, - "typ_age_onset_min": null, - "typ_age_onset_max": null, - "details": " 176 controls were used to establish the benign range (5-22 repeats), whereas a singular proband was identified with ~450 repeats [@pmid:25196122]. The observed intermediate alleles were presumed to function as premutations, with variable amounts of methylation [@pmid:25196122]", - "mechanism": "LoF", - "mechanism_detail": "Methylation, evidence of transcriptional misregulation [@omim:616181; @pmid:25196122].", - "year": "2014 [@pmid:25196122]", - "location_in_gene": "Intron 1", - "gene_strand": "+", - "reference_motif_reference_orientation": ["GCG"], - "pathogenic_motif_reference_orientation": ["GCG"], - "benign_motif_reference_orientation": [], - "unknown_motif_reference_orientation": [], - "pathogenic_motif_gene_orientation": ["CGG"], - "benign_motif_gene_orientation": [], - "unknown_motif_gene_orientation": [], - "locus_structure": [], - "benign_min": 5, - "benign_max": 22, - "intermediate_min": 42, - "intermediate_max": 85, - "pathogenic_min": 450, - "pathogenic_max": 450, - "motif_len": 3, - "ref_copies": 13.0, - "novel": "ref", - "gard": [], - "genereviews": [], - "malacard": ["ATS007"], - "medgen": [], - "mondo": [], - "omim": ["616181"], - "orphanet": [], - "gnomad": ["ZNF713"], - "stripy": [], - "tr_atlas": ["TR300995"], - "webstr_hg38": ["1380240", "5696269"], - "webstr_hg19": ["STR_1325788"], - "locus_tags": ["supported_evidence"], - "disease_tags": [], - "references": ["pmid:25196122", "omim:616181", "mondo:0005258"], - "additional_literature": [] -}] + "id": "FRA7A_ZNF713", + "disease_id": "FRA7A", + "gene": "ZNF713", + "chrom": "chr7", + "start_hg38": 55887600, + "stop_hg38": 55887639, + "start_hg19": 55955293, + "stop_hg19": 55955332, + "start_t2t": 56047900, + "stop_t2t": 56047939, + "disease": "Autism spectrum disorder associated with fragile site FRA7A", + "inheritance": [ + "AD" + ], + "disease_description": "A spectrum of developmental disorders that includes autism, and Asperger syndrome. Signs and symptoms include poor communication skills, defective social interactions, and repetitive behaviors [@mondo:0005258].", + "hpo_terms": null, + "prevalence": null, + "prevalence_details": "1 proband reported alongside 3 individuals with premutations, found in 2 families without discussion of ancestry/ethnicity [@pmid:25196122].", + "age_onset": "2-3 (four individuals) [@pmid:25196122].", + "age_onset_min": 2, + "age_onset_max": 3, + "typ_age_onset_min": null, + "typ_age_onset_max": null, + "details": " 176 controls were used to establish the benign range (5-22 repeats), whereas a singular proband was identified with ~450 repeats [@pmid:25196122]. The observed intermediate alleles were presumed to function as premutations, with variable amounts of methylation [@pmid:25196122]", + "mechanism": "LoF", + "mechanism_detail": "Methylation, evidence of transcriptional misregulation [@omim:616181; @pmid:25196122].", + "year": "2014 [@pmid:25196122]", + "location_in_gene": "Intron 1", + "gene_strand": "+", + "reference_motif_reference_orientation": [ + "GCG" + ], + "pathogenic_motif_reference_orientation": [ + "GCG" + ], + "benign_motif_reference_orientation": [], + "unknown_motif_reference_orientation": [], + "pathogenic_motif_gene_orientation": [ + "CGG" + ], + "benign_motif_gene_orientation": [], + "unknown_motif_gene_orientation": [], + "locus_structure": [], + "benign_min": 5, + "benign_max": 22, + "intermediate_min": 42, + "intermediate_max": 85, + "pathogenic_min": 450, + "pathogenic_max": 450, + "motif_len": 3, + "ref_copies": 13, + "novel": "ref", + "gard": [], + "genereviews": [], + "malacard": [ + "ATS007" + ], + "medgen": [], + "mondo": [], + "omim": [ + "616181" + ], + "orphanet": [], + "gnomad": [ + "ZNF713" + ], + "stripy": [], + "tr_atlas": [ + "TR300995" + ], + "webstr_hg38": [ + "1380240", + "5696269" + ], + "webstr_hg19": [ + "STR_1325788" + ], + "locus_tags": [ + "supported_evidence" + ], + "disease_tags": [], + "references": [ + "pmid:25196122", + "omim:616181", + "mondo:0005258" + ], + "additional_literature": [] + } +] \ No newline at end of file