Targeted next-generation sequencing reveals novel and rare variants in Indian patients with amyotrophic lateral sclerosis.

Studies on genetic aberrations among Indian amyotrophic lateral sclerosis (ALS) patients are limited to C9orf72 and ATXN2 repeat expansions and mutations in the SOD1 gene. In this study, we used targeted next-generation sequencing to analyze 25 ALS-associated genes in a cohort of 154 Indian ALS patients. We identified known pathogenic mutations in SOD1 (G148D; H44R), TARDBP (M337V; N267S), DAO (R199Q), and ANG (K41I). In addition, we also identified 7 potentially pathogenic missense variants that have not been previously reported in ALS patients; this includes 3 novel variants (OPTN: K489E, DAO: E121K, and SETX: L2163V) that are not reported in large population databases and 4 rare variants (CHMP2B: E45K, SQSTM1: G262R and P438L, ERBB4: R103H) with a minor allele frequency of <0.01 in large population databases. All known pathogenic, novel, and rare variants were detected in only 1 ALS patient each with the exception of the OPTN (K489E) variant that was detected in 2 patients in our cohort. In sum, we identified known and potentially pathogenic novel and rare mutations in 14 (9.1%) ALS patients in our cohort. This study represents the first comprehensive genetic analysis in the ethnically diverse population and thus provides a new insight into the genetics of Indian ALS patients.