A Critical Review of the Impact of Candidate Copy Number Variants on Autism Spectrum Disorders

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder (NDD) that is caused by genetic, epigenetic, and environmental factors. Recent advances in genomic analysis have uncovered numerous candidate genes with common and/or rare mutations that increase susceptibility to ASD. In addition, there is increasing evidence that copy number variations (CNVs), single nucleotide polymorphisms (SNPs), and unusual de novo variants negatively affect neurodevelopment pathways in various ways. The overall rate of copy number variants found in patients with autism is 10%-20%, of which 3%-7% can be detected cytogenetically. Although the role of submicroscopic CNVs in ASD has been studied recently, their association with genomic loci and genes has not been properly studied. In this review, we focus on 47 ASD-associated CNV regions and their related genes. Here, we identify 1,632 protein-coding genes and long non-coding RNAs (lncRNAs) within these regions. Among them, 552 are significantly expressed in the brain. Using a list of ASD-associated genes from SFARI, we detect 17 regions containing at least one known ASD-associated protein-coding genes. Of the remaining 30 regions, we identify 24 regions containing at least one protein-coding genes with brain-enriched expression and nervous system phenotype in mouse mutant and one lncRNAs with both brain-enriched expression and upregulation in iPSC to neuron differentiation. Our analyses highlight the diversity of genetic lesions of CNV regions that contribute to ASD and provide new genetic evidence that lncRNA genes may contribute to etiology of ASD. In addition, the discovered CNVs will be a valuable resource for diagnostic facilities, therapeutic strategies, and research in terms of variation priority.