C9orf92 pathogenic min

[bw2]

Through a conversation about outdated pathogenic thresholds on the gnomAD browser, there's a suggestion to update the ranges for C9orf72 to 25-60 as uncertain, and >= 61 as pathogenic based on GeneReviews.

STRchive currently shows the pathogenic min as 251 @ https://strchive.org/loci/ftdals1_c9orf72/

Does this still reflect your current view?

[hdashnow]

I've just done a little bit of digging. GeneReviews was last updated in 2020. There are some more recent papers that cite a pathogenic threshold of 30 and seem to describe it as the consensus threshold.

If we were to follow the papers below:

Proposed new thresholds:
Benign 2 - 23
Intermediate 24 - 30
Pathogenic 31 - 4088

But there's also the consideration of reduced/age-related penetrance in this 30-60 range so I'm a little torn.

What do you think?

Also, @Macayla-weiner do you have any thoughts?

Evidence:

https://link.springer.com/article/10.1186/s40478-019-0724-4#Sec1

A small proportion of people have an intermediate expansion, of the order of 20 to 30 repeats in size and several studies suggest that a threshold of 20 or 23 repeats could be used to discriminate between pathogenic and neutral expansions. However, the rarity of intermediate repeats and the consequential lack of statistical power, has limited the validity of these results and it remains unknown whether intermediate expansions confer risk of ALS in the same way that massive expansions do. At present, a repeat length of > 30 is typically used as the threshold to distinguish between neutral and pathogenic expansions
Our meta-analysis showed association between ALS and intermediate C9orf72 repeats of 24 to 30 repeats in size

https://www.nature.com/articles/s41582-018-0047-2

The pathological repeat length threshold has not been clearly defined; an arbitrary cut-off of 30 repeats is used in most studies

https://pmc.ncbi.nlm.nih.gov/articles/PMC6985338/#Sec2

The threshold pathogenic repeat size is unknown, but 30 is used in most publications.

https://pmc.ncbi.nlm.nih.gov/articles/PMC12715773/#fcaf482-T2

RepeatID	Disease	Inheritance	Type	Threshold	Cases (%)	Controls (%)	gnomAD (%)	PPM	Pgnomad
C9ORF72	ALS/FTD	AD	pathogenic	30	333 (6.5)	8 (0.47)	6 (0.12)	<2.2 × 10−16	0.21
--	--	AD	premutation	24	6 (0.12)	2 (0.12)	11 (0.22)	1.00	1.00

[hdashnow]

Just adding a few data points from diagnostic labs:

https://www.mayocliniclabs.com/test-catalog/overview/35377#clinical-and-interpretive

Normal alleles (reference):<20 GGGGCC repeats
Indeterminate alleles: 20-100 GGGGCC repeats
Pathogenic alleles: >100* GGGGCC repeats

https://www.invitae.com/providers/test-catalog/test-444006

Repeat size ranges- Benign (Normal Range): <25 repeat units, Uncertain: 25-30 repeat units, Pathogenic (Full Mutation): >=31 repeat units.

https://www.athenadiagnostics.com/view-full-catalog/c9orf72-dna-test1#section1

Normal <21 repeats

https://providers.genedx.com/tests/detail/c9orf72-repeat-analysis-896

Normal alleles have 24 or fewer G4C2 repeats, while disease alleles have 60 or greater repeats; disease alleles can have up to 2,000 repeats.4,5 Repeat expansions between 25-59 repeats are of uncertain clinical significance,

[Macayla-weiner]

It looks like that gap was my typo, oops! As for changing the ranges, I'm most convinced by Harriet's proposed thresholds and will update this in #324.

[hdashnow]

Thanks @Macayla-weiner! Closing this. Feel free to re-open if you'd like to discuss further.