Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism

Abstract

SummaryWe present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.

Integrating healthcare and research genetic data empowers the discovery of 28 novel developmental disorders

“…All 26 are now regarded as being diagnostic, and have entered routine 338 clinical diagnostic practice. Had we used a significance threshold of FDR < 10% as used in 339 Satterstrom, Kosmicki, Wang et al 37 , we would have identified 737 DD-associated genes. 340…”

VariCarta: A Comprehensive Database of Harmonized Genomic Variants Found in Autism Spectrum Disorder Sequencing Studies

“…Both representations describe the same resulting genotype. The other three papers report just one of the contiguous SNVs each [Krupp et al, 2017]: C-> A; [Ji et al, 2016]; and [Satterstrom et al, 2019]: C->G). This complex variant can also be viewed directly in VariCarta at varicarta.msl.ubc.ca/variant?chr=5&start=134059281&stop=134059281. central SFARI Human Gene module contains information about human genes that have been associated with ASD, supporting information from scientific literature, and different kinds of genetic data sets that provide evidence for linking the genes to ASD and help categorize and score genes based on the strength of that evidence.…”

Gaps in Current Autism Research: The Thoughts of the Autism Research Editorial Board and Associate Editors

“…The progress is impressive both in the number of diagnoses made and in the number of novel genes discovered [De Rubeis et al, 2014;Deciphering Developmental Disorders Study, 2017;Iossifov et al, 2014;Stessman et al, 2017]. The latest meta-analyses suggest that over 100 genes have now been identified that, when disrupted, cause autism [Coe et al, 2019;Satterstrom et al, 2018]. While the increase in genetic knowledge is by all measures spectacular, several challenges lie ahead of us.…”

“…The unprecedented genetic heterogeneity hampers the collection of larger cohorts of patients with the same underlying genetic etiology, necessary for fine-tuning the full spectrum of clinical symptoms [Arnett et al, 2018;Van Dijck et al, 2019] and discourages initiatives for therapy because of the small patient population for any given disorder. A second challenge is the interpretation of the missense variants identified in the patients in the gene-identification studies [Coe et al, 2019;Deciphering Developmental Disorders Study, 2017;Satterstrom et al, 2018]. Essentially all established diagnoses to date have either a gene inactivating variant or a missense variant belonging to the 0.1% most pathogenic sequence alterations, as judged by having a CADD score of >30 [Kircher et al, 2014], while we are uncertain of the relevance of the great majority of the missense variants.…”