Younger age of onset in familial amyotrophic lateral sclerosis is a result of pathogenic gene variants, rather than ascertainment bias

Puja R. Mehta, Ashley R. Jones, Sarah Opie-Martin, Aleksey Shatunov, Alfredo Iacoangeli, Ahmad Al Khleifat, Bradley N. Smith, Simon Topp, Karen E. Morrison, Pamela J. Shaw, Christopher E. Shaw, Sarah Morgan, Alan Pittman, Ammar Al-Chalabi

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Abstract

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease of motor neurons with a median survival of 2 years. Familial ALS has a younger age of onset than apparently sporadic ALS. We sought to determine whether this younger age of onset is a result of ascertainment bias or has a genetic basis.METHODS: Samples from people with ALS were sequenced for 13 ALS genes. To determine the effect of genetic variation, age of onset was compared in people with sporadic ALS carrying a pathogenic gene variant and those who do not; to determine the effect of family history, we compared those with genetic sporadic ALS and familial ALS.RESULTS: There were 941 people with a diagnosis of ALS, 100 with familial ALS. Of 841 with apparently sporadic ALS, 95 carried a pathogenic gene variant. The mean age of onset in familial ALS was 5.3 years younger than for apparently sporadic ALS (p=6.0×10-5, 95% CI 2.8 to 7.8 years). The mean age of onset of genetic sporadic ALS was 2.9 years younger than non-genetic sporadic ALS (p=0.011, 95% CI 0.7 to 5.2 years). There was no difference between the mean age of onset in genetic sporadic ALS and familial ALS (p=0.097).CONCLUSIONS: People with familial ALS have an age of onset about 5 years younger than those with apparently sporadic ALS, and we have shown that this is a result of Mendelian gene variants lowering the age of onset, rather than ascertainment bias.
Original languageEnglish
JournalJournal of neurology, neurosurgery, and psychiatry
DOIs
Publication statusPublished - 30 Sep 2018

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© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.

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    Mehta, P. R., Jones, A. R., Opie-Martin, S., Shatunov, A., Iacoangeli, A., Al Khleifat, A., Smith, B. N., Topp, S., Morrison, K. E., Shaw, P. J., Shaw, C. E., Morgan, S., Pittman, A., & Al-Chalabi, A. (2018). Younger age of onset in familial amyotrophic lateral sclerosis is a result of pathogenic gene variants, rather than ascertainment bias. Journal of neurology, neurosurgery, and psychiatry. https://doi.org/10.1136/jnnp-2018-319089