RT Journal Article SR Electronic T1 Integrated gene analyses of de novo mutations from 46,612 trios with autism and developmental disorders JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.09.15.460398 DO 10.1101/2021.09.15.460398 A1 Tianyun Wang A1 Chang Kim A1 Trygve E. Bakken A1 Madelyn A. Gillentine A1 Barbara Henning A1 Yafei Mao A1 Christian Gilissen A1 The SPARK Consortium A1 Tomasz J. Nowakowski A1 Evan E. Eichler YR 2021 UL http://biorxiv.org/content/early/2021/09/16/2021.09.15.460398.abstract AB Most genetic studies consider autism spectrum disorder (ASD) and developmental disorder (DD) separately despite overwhelming comorbidity and shared genetic etiology. Here we analyzed de novo mutations (DNMs) from 15,560 ASD (6,557 are new) and 31,052 DD trios independently and combined as broader neurodevelopmental disorders (NDD) using three models. We identify 615 candidate genes (FDR 5%, 189 potentially novel) by one or more models, including 138 reaching exome-wide significance (p < 3.64e-07) in all models. We find no evidence for ASD-specific genes in contrast to 18 genes significantly enriched for DD. There are 53 genes show particular mutational-bias including enrichments for missense (n=41) or truncating DNM (n=12). We find 22 genes with evidence of sex-bias including five X chromosome genes also with significant female burden (DDX3X, MECP2, SMC1A, WDR45, and HDAC8). NDD risk genes group into five functional networks associating with different brain developmental lineages based on single-cell nuclei transcriptomic data, which provides important insights into disease subtypes and future functional studies.Competing Interest StatementThe authors have declared no competing interest.DNMde novo mutationNDDNeurodevelopmental disorderASDAutism spectrum disorderDDDevelopmental disorderIDIntellectual disabilityWESWhole-exome sequencingWGSWhole-genome sequencingCCDGCenters for Common Disease GenomicsSFARISimons Foundation Autism Research InitiativeSPARKSimons Foundation Powering Autism Research for KnowledgeSSCSimons Simplex CollectionASCAutism Sequencing ConsortiumDDDDeciphering Developmental DisordersRUMCRadboud University Medical CenterCADD scorecombined annotation dependent depletion scoreLGDlikely gene-disruptivednLGDde novo LGD variantdnSYNde novo synonymous variantdnMISde novo missense variantdnMIS30de novo missense variant with CADD score greater than 30FDRFalse discovery rateFWERFamily-wise error ratePPIProtein-protein interactionCSEACell-type-specific expression analysisTSEATissue-specific expression analysisDDG2PDevelopment Disorder Genotype - Phenotype DatabaseOMIMOnline Mendelian Inheritance in ManLC615The 615 genes are with a lower confidence at the union significance (FDR 5%) by one or more of the three modelsHC138The 138 genes are with the highest confidence at the intersection significance (FWER 5%) supported by all three models, which are a subset of the LC615 genes