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

<i>Background:</i> 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. <i>Objective:</i> To define the genetic spectrum of ALS in an Indian cohort and assess the contribution of known and novel variants. <i>Methods:</i> We recruited 238 patients with clinically confirmed ALS from across India, all negative for <i>C9orf72</i> 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. <i>Results:</i> Pathogenic or likely pathogenic variants were identified in 13 patients (6.8%). <i>SOD1</i> mutations were the most frequent, followed by <i>TARDBP</i>, <i>OPTN</i>, and <i>NEK1</i>. Variants of uncertain significance were more common, with recurrent <i>SQSTM1</i> changes suggesting a potential modifier role. Additional rare or novel variants were detected in genes including <i>SETX</i>, <i>ALS2</i>, <i>DISC1</i>, <i>CNTN4</i>, and <i>MATR3. Conclusion:</i> This is among the largest genetic studies of ALS in India. The predominance of <i>SOD1</i> 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 <i>SQSTM1</i> 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.