A closer look at the most common gene mutations in ALS*

Several genes have been identified as having a strong association with ALS.2,3 The first, discovered in 1993, is SOD1 (superoxide dismutase 1),4 which accounts for ~15% of fALS (familial ALS) cases and can be found in ~1% of sALS (sporadic ALS) cases.2 C9orf72 (chromosome 9 open reading frame 72) expansion mutations, discovered in 2011,5 are the most common, and account for nearly 33% of identified fALS cases and have been found in ~5% of sALS patients.2,5

The next most common mutations associated with ALS are found in the TARDBP and FUS genes. Mutations in these genes each account for approximately 3%-4% of fALS cases and approximately 1% of sALS cases.1 The discovery and investigation of these genes hold great promise for a better understanding of genetic ALS. 

*based on global population data

Genetic testing  

Genetic testing is an option for all patients living with ALS. Learn more about the potential benefits and risks of genetic testing.

Genetic architecture of fALS and sALS in European populations

 

Adapted from Zou ZY, 2017 2

  • C9orf72-ALS

    Although, worldwide, more patients with genetic ALS carry C9orf72 mutations than any other type, frequencies vary greatly by ethnicity and geographic region. For example, the highest frequencies of C9orf72 expansion mutations are found in Scandinavian countries, while SOD1 mutations are much more common in Asia.1,6,7

  • SOD1-ALS

    In patients with SOD1-ALS, the SOD1 gene has undergone a change, or mutation, which results in damage to nerves in the brain and spinal cord that control muscle movement. SOD1 gene mutations account for just 2% of all ALS cases—but 20% of those with a genetic component.1Nearly half of all patients living with SOD1-ALS, do not have a known family history of the disease.8-11

  • TARDBP-ALS

    Mutations in the TARDBP gene are found in approximately 4% of patients with fALS and 1% of patients with sALS.1,9 While these mutations are believed to be less common than those in the SOD1 and C9orf72 genes, TARDBP mutations have been identified in patients from a diverse group of countries and geographical regions, suggesting that these mutations may be a factor in who develops genetic ALS worldwide, being identified in Japan, Australia, North America, and China.1,9

  • FUS-ALS

    ALS-associated FUS mutations were first reported in 2009 and are now found in approximately 4% of patients with fALS and less than 1% of patients with sALS.1,9 While the course of disease among patients with FUS-ALS can be unpredictable, certain FUS mutations have also been linked to an earlier onset of genetic ALS.1.9 FUS mutations have been identified among patients with genetic ALS in a wide range of geographic regions, including other parts of Europe, Australia, North America, Asia, and Africa.9

Redefining sporadic and familial ALS

Historically ALS has been categorized as sporadic and familial ALS. Identifying genetic mutations related to ALS has changed our perceptions on how to categorize ALS.12

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An overview of common mutations

The first genetic link between ALS and SOD1 was identified in 1993.4 Since then, it has proven to be an important factor in both familial- and sporadic cases of ALS. 13

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Genetic penetrance

Genetic penetrance—the extent to which a genetic mutation will have an effect on the patient who carries it—can change how one patient experiences genetic ALS from another, even if they both have mutations in the same gene.14

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Heritability

Heritability is the extent to which differences in a given phenotype across a specific population can be accounted for by differences in their genes.15 This article helps uncover the relationship between genetic ALS and heritability.

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The potential role of genetic testing

It has been established that even sporadic ALS may have a genetic component.16 For Dr. Genge and her team, this supports the case for widespread genetic testing in all patients living with ALS.

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References: 1. Roggenbuck J, Quick A, Kolb SJ. Genetic testing and genetic counseling for amyotrophic lateral sclerosis: an update for clinicians. Genet Med. 2017;19(3):267-274. 2. Zou ZY, Zhou ZR, Che CH, et al. Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2017;88(7):540-549. 3. Bali T, Self W, Liu J, et al. Defining SOD1 ALS natural history to guide therapeutic clinical trial design. J Neurol Neurosurg Psychiatry. 2017;88(2):99-105. 4. Rosen DR. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature.1993;364(6435):362. 5. Balendra R, Isaacs AM. C9orf72-mediated ALS and FTD: multiple pathways to disease. Nat Rev Neurol. 2018;14(9):544-588. doi:10.1038/s41582-018-0047-2. 6. Wei Q, Zhou Q, Chen Y, et al. Analysis of SOD1 mutations in a Chinese population with amyotrophic lateral sclerosis: a case-control study and literature review. Sci Rep. 2017;7:44606. doi:10.1038/srep44606. 7. Shahrizaila N, Sobue G, Kuwabara S, et al. Amyotrophic lateral sclerosis and motor neuron syndromes in  Asia. J Neurol Neurosurg Psychiatry. 2016;87:821–830. 8. Chiò A, Mazzini L, D’Alfonso S, et al. The multistep hypothesis of ALS revisited: the role of genetic mutations. Neurology. 2018;91(7):e635-e642. doi:10.1212/WNL.0000000000005996. 9. Lattante S, Marangi G, Doronzio PN, et al. High-throughput genetic testing in ALS: the challenging path of variant classification considering the ACMG guidelines. Genes (Basel). 2020;11(10):1123. doi:10.3390/genes11101123. 10. Arthur KC, Calvo A, Price TR, et al. Projected increase in amyotrophic lateral sclerosis from 2015 to 2040. Nat Commun. 2016;7:12408. 11. Zarei S, Carr K, Reiley L, et al. A comprehensive review of amyotrophic lateral sclerosis. Surg Neurol Int. 2015;6:171. 12. Brown RH, Al-Chalabi A. Amyotrophic lateral sclerosis. N Engl J Med. 2017;377(2):162-172. 13. Shepheard SR, Parker MD, Cooper-Knock J, et al; on behalf of Project MINE Consortium. Value of systematic genetic screening of patients with amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2021;92:510-518. doi:10.1136/jnnp-2020-325014. 14. Murphy NA, Arthur KC, Tienari PI, et al. Age-related penetrance of the C9orf72 repeat expansion. Sci Rep. 2017;7:2116. Doi: 10.1038/s41598-017-02364-1. 15. MedlinePlus. What is heritability? [online] 2021 Apr 19 [cited 2021 Sep 3]. Available from: URL: https://medlineplus.gov/download/genetics/understanding/inheritance.pdf. 16. Nguyen HP, Van Broeckhoven C, van der Zee J. ALS genes in the genomic era and their implications for FTD. Trends Genet. 2018;34(6):404-423

References

1. Roggenbuck J, Quick A, Kolb SJ. Genetic testing and genetic counseling for amyotrophic lateral sclerosis: an update for clinicians. Genet Med. 2017;19(3):267-274. 2. Zou ZY, Zhou ZR, Che CH, et al. Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2017;88(7):540-549. 3. Bali T, Self W, Liu J, et al. Defining SOD1 ALS natural history to guide therapeutic clinical trial design. J Neurol Neurosurg Psychiatry. 2017;88(2):99-105. 4. Rosen DR. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature.1993;364(6435):362. 5. Balendra R, Isaacs AM. C9orf72-mediated ALS and FTD: multiple pathways to disease. Nat Rev Neurol. 2018;14(9):544-588. doi:10.1038/s41582-018-0047-2. 6. Wei Q, Zhou Q, Chen Y, et al. Analysis of SOD1 mutations in a Chinese population with amyotrophic lateral sclerosis: a case-control study and literature review. Sci Rep. 2017;7:44606. doi:10.1038/srep44606. 7. Shahrizaila N, Sobue G, Kuwabara S, et al. Amyotrophic lateral sclerosis and motor neuron syndromes in  Asia. J Neurol Neurosurg Psychiatry. 2016;87:821–830. 8. Chiò A, Mazzini L, D’Alfonso S, et al. The multistep hypothesis of ALS revisited: the role of genetic mutations. Neurology. 2018;91(7):e635-e642. doi:10.1212/WNL.0000000000005996. 9. Lattante S, Marangi G, Doronzio PN, et al. High-throughput genetic testing in ALS: the challenging path of variant classification considering the ACMG guidelines. Genes (Basel). 2020;11(10):1123. doi:10.3390/genes11101123. 10. Arthur KC, Calvo A, Price TR, et al. Projected increase in amyotrophic lateral sclerosis from 2015 to 2040. Nat Commun. 2016;7:12408. 11. Zarei S, Carr K, Reiley L, et al. A comprehensive review of amyotrophic lateral sclerosis. Surg Neurol Int. 2015;6:171. 12. Brown RH, Al-Chalabi A. Amyotrophic lateral sclerosis. N Engl J Med. 2017;377(2):162-172. 13. Shepheard SR, Parker MD, Cooper-Knock J, et al; on behalf of Project MINE Consortium. Value of systematic genetic screening of patients with amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2021;92:510-518. doi:10.1136/jnnp-2020-325014. 14. Murphy NA, Arthur KC, Tienari PI, et al. Age-related penetrance of the C9orf72 repeat expansion. Sci Rep. 2017;7:2116. Doi: 10.1038/s41598-017-02364-1. 15. MedlinePlus. What is heritability? [online] 2021 Apr 19 [cited 2021 Sep 3]. Available from: URL: https://medlineplus.gov/download/genetics/understanding/inheritance.pdf. 16. Nguyen HP, Van Broeckhoven C, van der Zee J. ALS genes in the genomic era and their implications for FTD. Trends Genet. 2018;34(6):404-423