Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing

Abstract

Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.

10 Years of GWAS Discovery: Biology, Function, and Translation

“…26 However, genetic architecture, described as the mix of rare and common variants, is likely to differ between psychiatric disorders, as is already being observed for the higher rates of rare, de novo penetrant CNVs and single-nucleotide variants found in autism than in schizophrenia or bipolar disorder. [121][122][123][124][125][126][127][128][129] PRS studies are being utilized extensively to investigate disease heterogeneity and contributions from environmental risk factors.…”

Early Screening of Autism Spectrum Disorder: Recommendations for Practice and Research

“…102 However, recent data using exome and whole genome sequencing methods suggest the yield of such testing for clinically informative variants may be much higher. 103,104 Moreover, although the contribution of specific biomarkers to risk prediction may be modest, combined results from a panel of predisposing biomarkers can produce information about an individual' s probability of developing ASD. 105 Consideration of several biomarkers at once is consistent with the multitude of genetic and epigenetic factors (and potentially other biological factors [eg, immune, indices of atypical brain growth/connectivity]) that likely play a role in vulnerability to ASD in many children.…”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…Additionally, mutations in CHD7 and its binding partner CHD8, for example, have also been found in idiopathic autism [3]. Rare variants in CHD7 are thought to confer increased autism risk, even in the absence of a CHARGE syndrome diagnosis [89]. Further still, mutations in genes highly related to MECP2, such as MBD5, have been found in idiopathic autism [90].…”