Elucidation of crucial metabolic pathways in the etiology of autism spectrum disorder through whole exome sequencing and chromosomal microarray

BACKGROUND: Autism spectrum disorder (ASD) has a complex genetic etiology, with limited data from Indian populations. This study delineates the genetic architecture of ASD in Indian children using whole exome sequencing (WES) and exploratory genetic association studies (GASs). METHODS: WES was performed on 142 Indian children with ASD, diagnosed per the Diagnostic and Statistical Manual V criteria. GAS compared cases to 180 age- and ethnicity-matched Indian controls (aged 4-8 years) who exhibited normal neurological development. Variants were annotated using annotate variation, classified per the American College of Medical Genetics and Genomics guidelines, and analyzed for gene ontology, Kyoto Encyclopedia of Genes and Genomes pathways, and GAS associations. Chromosomal microarray 750K was used to confirm the copy number variations. RESULTS: WES identified pathogenic/likely pathogenic variants in 20 cases (14.08%) (12 autosomal dominant, five autosomal recessive, and three X-linked) and variants of uncertain significance in 107 cases (75.35%). Chromosomal microarray analysis revealed six pathogenic variants in 49 autism cases. Functional enrichment implicated neurotransmitter function, synaptic transmission, chromatin remodeling, and glutamatergic/GABAergic imbalances. GAS revealed significant variants (rs2014562 and rs7730228) and a chromosome 11 hotspot ( MUC6 , ZDHHC13 , OR8U1 , OR9G1 ), with chr5 : 130-131 Mb single nucleotide polymorphisms (SNPs) interacting with ADAMTS19 . CONCLUSION: This study highlights genetic heterogeneity in Indian ASD cases, identifying novel variants and pathways of potential biological relevance. Moderate GAS sample size and high variants of uncertain significance burden warrant further validation.