Genetic Spectrum of Autism Spectrum Disorder Associated Variants in the Indian Population: Insights from 1,029 IndiGenomes

BackgroundAutism spectrum disorder (ASD) is a lifelong neurodevelopmental condition characterised by social and behavioural challenges. It is highly heritable, with estimates ranging from 40-90% and a liability-scale heritability of 0.924, underscoring the role of genetic variants in its pathogenesis. Limited studies from India hinder an accurate assessment of the countrys true ASD genetic spectrum. AimTo investigate the genetic spectrum in an Indian control dataset, providing baseline variant frequency data to facilitate interpretation of disease-associated variants in the Indian population. MethodsWe compiled a strongly ASD-linked gene panel from the SFARI and ClinGen databases, followed by the extraction of gene-associated variants from the IndiGenomes dataset. A stepwise analysis pipeline was implemented, including variant annotation, filtering for minor allele frequency (MAF < 5%), prediction of deleteriousness using REVEL (>0.75), and loss-of-function prediction with LoFTEE (high confidence). Variants were then classified according to ACMG-AMP guidelines. ResultsWe identified 1,531,327 variants from 517 ASD panel genes (MAF < 5%) spanning [~]88 Mb of genomic regions. ACMG-AMP interpretation was performed for prioritised 298 missense variants (REVEL > 0.75) and 537 LoF variants (LoFTEE; high confidence). Missense and LoF variants contributed 37% and 63% of the filtered data, respectively. Fifty-five variants from 28 genes were classified as pathogenic/likely pathogenic, while 10 variants in 6 genes showed significantly higher MAF (p < 0.05; Fishers exact test). Carrier numbers were estimated for autosomal recessive inheritance models. ConclusionThis study provides a comprehensive spectrum of ASD-related genetic variants in the Indian population, offering valuable insights for ASD diagnosis, genetic interpretation, and understanding of underlying molecular mechanisms.