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Common Genetic Mutations Associated with ALS


Jennifer Roggenbuck, MS, LGC, and Laynie Dratch, ScM, CGC, discuss common genetic mutations associated with ALS.

Jennifer Roggenbuck, MS, LGC: We see the same mutations in sporadic and familial ALS [amyotrophic lateral sclerosis]. In North America, the most common genetic cause of ALS is a change in a gene that has a funny name. It’s called the C9orf72 gene, and it’s named for the chromosomal location where it sits. We see this in about half our familial cases of ALS and in almost 10% of individuals with sporadic ALS. By far, it’s the most common genetic cause in North America. That said, this genetic change, which is an expansion in that gene, has an origin in Europe. This genetic change is more common in individuals of European descent than in other populations. If someone doesn’t have European descent, it’s much less likely that we would find this specific genetic change.

The second most common ALS gene in North America is SOD1. This accounts for about 10% of familial ALS, at least in our practice in Columbus, Ohio. It does vary somewhat geographically. In non-European populations, SOD1 is often the most common gene that’s found.

Studies have given ranges anywhere from 5% to 20%. Of course, it depends on how hard you look for a family history and what you define as a family history. Most of us define a positive family history of ALS as a first- or second-degree relative. A first-degree relative would be a parent or a sibling, second degree would be an uncle, and a cousin would be a third degree. It depends on how carefully and how hard you look. Of course, family size will also influence the likelihood of having a positive family history. If you have a super small family, there’s not much data to go on. On the whole and in North America, about 15% of individuals with ALS have a positive family history using that definition of a first- or second-degree relative.

If someone has a family history of ALS, we’re much more likely to find a genetic cause with our testing. In our practice, we find a genetic cause in individuals with familial ALS 50% to 60% of the time. By far the most common gene that we identify is the C9orf72 gene. A distant second would be SOD1. That’s not perfect. It means we’re not finding a genetic cause in 40% to 50% of individuals who have familial ALS. That’s in contrast with sporadic ALS: where there’s no family history, we find a genetic cause about 10% of the time. We’re 5 times more likely to find a genetic cause if someone has a known family history of ALS. That’s important for individuals to know because that might influence their decision whether to seek testing depending on how likely it is that we would find a genetic cause.

Laynie Dratch, ScM, CGC: There are many genes that have been discovered to be associated with familial ALS and “apparently sporadic” ALS. I don’t love the terms sporadic and apparently sporadic because they imply that it’s not genetic. In reality, it implies that there’s no known family history, and the limitations of family history have been discussed earlier in this conversation. Regardless of whether an individual has familial or apparently sporadic ALS, there are 40 or so genes that have been identified [as a potential] cause or contributor to why a individual develops ALS. Some of the most common genetic causes for ALS are a hexanucleotide repeat expansion in the C9orf72 gene, commonly referred to as C9. That’s the most common genetic cause of both ALS and the related FTD [frontotemporal dementia].

Other more common genetic causes of ALS are genetic differences in the SOD1 gene, the FUS gene, the TBK1 gene, the TARDBP gene, and the ATXN2 gene, which has an intermediate repeat expansion that’s known to be a risk factor for ALS. More gene-disease associations continue to be discovered for ALS. These numbers are likely to increase over time as more individuals do testing and technology is ever-expanding with many individuals going on to have exome or genome sequencing performed, which can identify more rare causes of disease.

The vast majority of individuals with ALS don’t have any known family members with ALS-related conditions. The numbers are a little different depending on which study you look at and how they define familial. About 90% of individuals don’t have a known family history of ALS. Among that 90%, 5% to 10% of individuals have an identifiable genetic cause. A smaller subset of individuals with no known family history have an identifiable genetic cause.

Among those 10% of individuals who have a known family history of ALS, we have much higher chances of identifying a genetic cause. The numbers change based on which papers you look at and which studies they’re based in. But we’re able to identify a genetic cause in many individuals who have a known family history, somewhere on the order of 60% to 70%. That number is likely to increase as more gene-disease association discoveries are made for ALS. Whether you have a family history shouldn’t determine if you’re offered genetic testing, but it influences our risk assessments: what are the odds that there’s a genetic cause going on here?

Transcript edited for clarity.

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