C9orf72 and amyotrophic lateral sclerosis: While significant advances have been made in understanding ALS etiology by studying highly penetrant pathogenic variants in genes like SOD1, TARDBP and C9ORF72, most sporadic ALS cases are understood to arise from the intersection of lesser risk factors, both congenital and environmental, including genetic modifiers that influence disease onset, progression, and penetrance20,21.