Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease in which the onset of motor symptoms often appears abruptly and follows an unrelenting course associated with an average survival of 2–3 years from initial weakness.1 Approximately 10% of cases are attributable to highly penetrant single-gene variants, associated with ALS that is clinically indistinguishable from apparently sporadic disease and shares the pathological hallmark of cytoplasmic TDP-43 inclusions. The gene discussed is TARDBP; the disease is amyotrophic lateral sclerosis.