Deciphering ALS-linked genetic variants in indian patients using targeted and exome sequencing approaches

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with marked clinical and genetic heterogeneity. Data from India remain scarce, although unique survival patterns and regional genetic variation have been suggested. Objective: To define the genetic spectrum of ALS in an Indian cohort and assess the contribution of known and novel variants. Methods: We recruited 238 patients with clinically confirmed ALS from across India, all negative for C9orf72 repeat expansions. Genetic testing included targeted panels, whole exome sequencing, and screening of ALS-associated gene curated panels. Variants were prioritized using allele frequency thresholds, in silico prediction, and ACMG criteria. Results: Pathogenic or likely pathogenic variants were identified in 13 patients (6.8%). SOD1 mutations were the most frequent, followed by TARDBP, OPTN, and NEK1. Variants of uncertain significance were more common, with recurrent SQSTM1 changes suggesting a potential modifier role. Additional rare or novel variants were detected in genes including SETX, ALS2, DISC1, CNTN4, and MATR3. Conclusion: This is among the largest genetic studies of ALS in India. The predominance of SOD1 mutations underscores population-specific differences and highlights the clinical importance of early genetic testing, particularly as gene-targeted therapies become available. The recurrent identification of SQSTM1 variants suggests modifier effects that require functional validation. These findings expand the genetic landscape of ALS in an underrepresented population and provide a foundation for precision medicine approaches in India.