Genetics Question

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GXTrex

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The article below states that the C9 mutation for example accounts for 25-40% of familial ALS. What I dont understand is it also say C9 accounts for 7% of sporadic ALS cases. It lists familial and sporadic percentages for a number of different mutations. This does not make sense to me. If the C9 mutation is found in 7% of "sporadic" ALS cases, wouldn't that mean these were actually familial?

 
It is an extremely complicated issue and there is a lot of discussion about labels and definition. Familial is defined as multiple relatives with ALS and/or FTD. The neurogenetists are now starting to use simplex instead of sporadic for isolated cases.

people with a known genetic mutation are sometimes classified as GALS ( genetic ALS). Many GALS are FALS but not all. And not all those with a clear FALS history have a documented mutation ( though that is because they haven’t found them yet we believe)

why the 7 percent? It seems to be a mix. Some of those people turn out to have family history after all. Some come from small families and or a lot of people died young from something else. It is also possible to have a de novo mutation that happens during conception In that case no one had it before but the person can pass it on to their children but their siblings would not be at risk. There is also something called penetrance which means how likely someone with the mutation is to get the disease. My geneticist says c9 is almost fully penetrant by the 80s. This seems to be the consensus but others debate it. I have wondered ( but never asked) if some families may have other protective mutations that allows their family members to escape more often. All my mother’s siblings were affected my sister and I both were affected so it seems highly penetrant with us.

I believe your dad sees Dr Harms I am sure he was offered testing. Dr Harms is very into ALS genetics
 
@Nikki J

Thank you for your response I know you are very knowledgeable in this. That makes sense as familial meaning family members have had the disease, and GALS where you are found to have the gene but no family history.

Yes my dad sees Dr Harms. I just found out (literally like 15 mins after I posted originally) he was negative for the Invitae ALS panel (28 ALS and dementia genes) which tests for all known ALS genes except c9. We are awaiting the c9 results from gene dx. I was doing my own research in the meantime and was wondering the familial and sporadic discrepancy. Thanks again
 
Hoping for good news for you.

it is all very complicated and more than a little controversial. As with most if not all diseases ALS probably has some genetic component for all. You probably have to have some combination of genetic factors that predispose you. In most people though that combination never manifests because they don’t get exposed to enough environmental and lifestyle triggers. People with GALS need significantly fewer triggers and it seems as if there are a couple of factors at least that are inescapable as virtually everyone with the more penetrant mutations gets ALS.
 
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