Identification of primary copy number variations reveal enrichment of Calcium, and MAPK pathways sensitizing secondary sites for autism

Abstract

Background Autism is a neurodevelopmental condition with genetic heterogeneity. It is characterized by difficulties in reciprocal social interactions with strong repetitive behaviors and stereotyped interests. Copy number variations (CNVs) are genomic structural variations altering the genomic structure either by duplication or deletion. De novo or inherited CNVs are found in 5–10% of autistic subjects with a size range of few kilobases to several megabases. CNVs predispose humans to various diseases by altering gene regulation, generation of chimeric genes, and disruption of the coding region or through position effect. Although, CNVs are not the initiating event in pathogenesis; additional preceding mutations might be essential for disease manifestation. The present study is aimed to identify the primary CNVs responsible for autism susceptibility in healthy cohorts to sensitize secondary-hits. In the current investigation, primary-hit autism gene CNVs are characterized in 1715 healthy cohorts of varying ethnicities across 12 populations using Affymetrix high-resolution array study. Thirty-eight individuals from twelve families residing in Karnataka, India, with the age group of 13–73 years are included for the comparative CNV analysis. The findings are validated against global 179 autism whole-exome sequence datasets derived from Simons Simplex Collection. These datasets are deposited at the Simons Foundation Autism Research Initiative (SFARI) database. Results The study revealed that 34.8% of the subjects carried 2% primary-hit CNV burden with 73 singleton-autism genes in different clusters. Of these, three conserved CNV breakpoints were identified with ARHGAP11B, DUSP22, and CHRNA7 as the target genes across 12 populations. Enrichment analysis of the population-specific autism genes revealed two signaling pathways—calcium and mitogen-activated protein kinases (MAPK) in the CNV identified regions. These impaired pathways affected the downstream cascades of neuronal function and physiology, leading to autism behavior. The pathway analysis of enriched genes unravelled complex protein interaction networks, which sensitized secondary sites for autism. Further, the identification of miRNA targets associated with autism gene CNVs added severity to the condition. Conclusion These findings contribute to an atlas of primary-hit genes to detect autism susceptibility in healthy cohorts, indicating their impact on secondary sites for manifestation.