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

Abstract

Objective A myotrophic 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 S amples 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% C I 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% C I 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 P eople 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.