c9 and sporadic als

[jasona]

Hi All - first time poster but been reading for a bit. The kindness and thoughtfulness that each engagement gets has been nice to see.

I have a question about the c9 mutation and how it relates to sporadic als specifically. On the ALS.org website they state that the c9 mutation accounts for 6% of sporadic als cases (ALS Genes and Mutations). Given the supposed high rate of penetrance in c9 mutations this would imply that the a child of someone with sporadic als has about a 3% chance of developing the disease themselves from just the c9 mutation alone (so the total risk would likely be a bit higher). However, there have been a few studies (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3235555/ , for example) that all indicate the lifetime risk of developing als for a child of someone with sporadic als is around 1%. This is higher than the risk for a random person but still much lower than the implied c9 risk if it actually accounts for 6% of all sporadic als cases.

Disclosure: one of my parents died from sporadic als about a decade ago in their early 50s. They got genetic testing and were negative for all als associated genes at the time but this was slightly before c9 testing was available. I know the distinction between sporadic and familial als can be blurry due to incomplete family history, early deaths, late penetrance, etc. And in my case I'm pretty positive that my parent wouldn't have inherited the c9 gene due to the massive size of our family (they have 10 siblings, none of whom have developed als yet, and over 20 blood related aunts & uncles without a history of als/neuro diseases). But I am still worried a bit about the possibility that my parent had a "de novo" c9 mutation and that my sibling and I could inherit it. Does anyone have an estimate of what percentage of sporadic als patients with the c9 mutation occurred "de novo"? In this paper (C9orf72 Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis - GeneReviews® - NCBI Bookshelf , published 2015, updated 2020) they state that "Almost all individuals diagnosed with C9orf72-FTD/ALS inherited a C9orf72 G4C2 repeat expansion from a heterozygous parent" but don't give a probability estimate or cite how they arrived there.

I guess my question is what is the likelihood, as the child of someone who died from sporadic als, that I will eventually get the disease as well? And why do those studies / implied numbers differ?

 

[Nikki J]

De novo mutations in c9 are considered to be vanishingly rare. I think the science on this has changed. You know that c9 was discovered in late 2011 so although there has been a lot of research they are still learning. Initial research was on families like mine with strong histories

they can somehow tell when a mutation happened. Not from a regular test that is done clinically but in research. That is why they know about when c9 happened and where the viking theory started. So I think now there have been more people with allegedly sporadic c9 that they have looked at enough to say they have an “ old” mutation

penetrance is hotly debated. My geneticist insists it is almost complete by 80. My family history says it is. But others have a different experience and some say it is much lower though I think the current thought is about 45% of carriers get als 45% get FTD which means my geneticist is probably right.

I know/ knew a number of people with alleged sporadic c9 all but one actually had neuro history ( usually dementia) in the family. The one who did not had parents who were only children of only children.

there are almost certainly genetic modifiers at play here. Some protective others harmful. Some families might have strong prptective ones so most escape. Other families might ave deleterious ones that make als come early and often.

the 1 in 100 number comes from a large Irish study and c9 is more common there than in the US ( those darn Vikings again). I think if your relative was negative for c9 they found the risk even lower .8 something %

with a large number of unaffected relatives with no neuro disease your risk of c9 seems low. You can of course chose to test for it but there are huge implications for that - genetic discrimination GINA notwithstanding are massive. I would not in your position

 

[jasona]

Thanks Nikki, this is a very helpful response. I will head your advice and not bother testing given the very low likelihood that my parent inherited a c9 mutation. Wishing you and your family the best

 

[Bry2k200]

Just thought I'd throw this in here Nikki, my great grandmother had Parkinsons, and my grandmother had Alzheimers. My mother had ALS, her oldest brother had ALS, and now her youngest brother has ALS and Dementia (both ALS & Dementia are very slow progressing). Not sure if that's worth a discussion or not.

 

[Nikki J]

That is utterly different than the op who has no neuro history in a very large family aside from the one parent. There is a decent chance that PD and AD were misdiagnoses back then too

 

[Bry2k200]

Well, it's also the C9 mutation