Recessive gene disruptions in autism spectrum disorder

• Published in: Nature genetics Vol. 51; no. 7; pp. 1092 - 1098
• Main Authors: Doan, Ryan N., Lim, Elaine T., De Rubeis, Silvia, Betancur, Catalina, Cutler, David J., Chiocchetti, Andreas G., Overman, Lynne M., Soucy, Aubrie, Goetze, Susanne, Freitag, Christine M., Daly, Mark J., Walsh, Christopher A., Buxbaum, Joseph D., Yu, Timothy W.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2019; Nature Publishing Group
• Subjects: 45; 45/23; 631/208/2489; 631/208/366/1373; Agriculture; Allelic Imbalance; Animal Genetics and Genomics; Autism; Autism Spectrum Disorder; Autism Spectrum Disorder - genetics; Biomedical and Life Sciences; Biomedicine; Brain research; Cancer Research; Case-Control Studies; Circuits; Cohort Studies; Disruption; ETS protein; Exome Sequencing; Female; Females; Gene expression; Gene Function; Gene sequencing; Genes; Genes, Recessive; Genes, Recessive - genetics; Genetic Predisposition to Disease; Genome, Human; Genomes; Genomics; Haplotypes; Human Genetics; Humans; Letter; Life Sciences; Male; Missense mutation; Mutation; Mutation, Missense; Transcription factors; USH2A protein; Whole Exome Sequencing
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-019-0433-8

Autism spectrum disorder (ASD) affects up to 1 in 59 individuals 1 . Genome-wide association and large-scale sequencing studies strongly implicate both common variants 2 – 4 and rare de novo variants 5 – 10 in ASD. Recessive mutations have also been implicated 11 – 14 but their contribution remains less well defined. Here we demonstrate an excess of biallelic loss-of-function and damaging missense mutations in a large ASD cohort, corresponding to approximately 5% of total cases, including 10% of females, consistent with a female protective effect. We document biallelic disruption of known or emerging recessive neurodevelopmental genes ( CA2 , DDHD1 , NSUN2 , PAH , RARB , ROGDI , SLC1A1 , USH2A ) as well as other genes not previously implicated in ASD including FEV (FEV transcription factor, ETS family member), which encodes a key regulator of the serotonergic circuitry. Our data refine estimates of the contribution of recessive mutation to ASD and suggest new paths for illuminating previously unknown biological pathways responsible for this condition. Analysis of whole-exome sequencing data from 2,343 individuals with autism spectrum disorder compared to 5,852 unaffected individuals demonstrates an excess of biallelic, autosomal mutations for both loss-of-function and damaging missense variants.