Increased burden of deleterious variants in essential genes in autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior. It is estimated that hundreds of genes contribute to ASD. We asked if genes with a strong effect on survival and fitness contribute to ASD risk. Human orthologs of genes with an essential role in pre-and postnatal development in the mouse [essential genes (EGs)] are enriched for disease genes and under strong purifying selection relative to human orthologs of mouse genes with a known nonlethal phenotype [nonessential genes (NEGs)]. This intolerance to deleterious mutations, commonly observed haploinsufficiency, and the importance of EGs in development suggest a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. With a comprehensive catalog of 3,915 mammalian EGs, we provide compelling evidence for a stronger contribution of EGs to ASD risk compared with NEGs. By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, we show a significantly higher burden of damaging mutations in EGs in ASD probands compared with their non-ASD siblings. The analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Finally, we suggest a high-priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Overall, we show that large-scale studies of gene function in model organisms provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of human disease.essential genes | mouse knockouts | mutational burden | autism spectrum disorder | coexpression modules A utism spectrum disorder (ASD) is a heterogeneous, heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior (1, 2). The highly polygenic nature of ASD (3-5) suggests that the analysis of the full spectrum of sequence variants in hundreds of genes will be necessary for deeper understanding of disrupted neuronal function. Prioritization of ASD risk genes initially focused on known pathways with recognized relevance to pathogenesis of ASD, such as synaptic function and neuronal development (6). However, combined analyses of de novo, inherited, and case-control variation in over 2,500 ASD parentchild nuclear families identified around 100 genes contributing to ASD risk (7-9), converging on pathways implicated in transcriptional regulation and chromatin modeling in addition to synaptic function.The main challenge in the current understanding of genetic architecture of ASD comes from a need to study the interplay between variants with a high effect (for example, recurrent de novo variants) and a background of variants with an intermediate effect but that nevertheless still disrupt proper neuronal development. Essential genes (EGs) or genes that are necessary for successful completion of pre-and postnatal development are prime candi...

Human and mouse essentiality screens as a resource for disease gene discovery

“…Previously, human cell-essential genes have been analysed [16][17][18] in conjunction with lethal genes identified in the mouse 23 by either characterising a core set of essential genes at the intersection 14 or studying the union of the two 32 . In these studies, cellular essential genes were shown to have a nearly complete concordance with mouse lethal genes 19,23 .…”

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

“…Occasionally, the same subject could have slightly different IDs between studies: for example, Yuen et al (2015) uses "-" (dash), while Yuen et al (2017) uses "_" (underscore) in otherwise identical subject IDs from the same cohort. Another example is the omission of "p1" suffix, meant to indicate a proband, from a Simons Simplex Collection (SSC) family IDs in Iossifov et al [2012], Iossifov et al [2014], and Ji, Kember, Brown, and Bu can [2016]. We attempt to rectify such discrepancies during the curation stage.…”

“…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.…”

Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder

“…It has now been well documented using several approaches that LGD GDMs in probands show enrichments for genes that are highly conserved/intolerant to LGD mutations. 11,44,45 We reasoned that missense PMMs relating to ASD risk could also show similar enrichments. We selected two intolerant gene sets, an updated set of essential genes (n ¼ 2,455) 34 and the recently published ExAC intolerant set (n ¼ 3,232).…”