title: 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.
authors.affiliation: Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.|Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Xiao
authors.identifier: 0000-0001-5908-2774
authors.initials: X
authors.lastname: Ji
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Kember
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; chrbro@mail.med.upenn.edu bucan@mail.med.upenn.edu.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Brown
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; chrbro@mail.med.upenn.edu bucan@mail.med.upenn.edu.|Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Maja
authors.initials: M
authors.lastname: Bućan
mesh_terms: D000483:Alleles; D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D001921:Brain / Q000378:metabolism; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D005091:Exons; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020043:Genes, Essential; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype; D012306:Risk; D035781:Siblings; D012919:Social Behavior
keywords: autism spectrum disorder; coexpression modules; essential genes; mouse knockouts; mutational burden