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Recessive gene disruptions in autism spectrum disorder

Lookup NU author(s): Lynne Overman


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© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. Autism spectrum disorder (ASD) affects up to 1 in 59 individuals1. Genome-wide association and large-scale sequencing studies strongly implicate both common variants2–4 and rare de novo variants5–10 in ASD. Recessive mutations have also been implicated11–14 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.

Publication metadata

Author(s): Doan RN, Lim ET, De Rubeis S, Betancur C, Cutler DJ, Chiocchetti AG, Overman LM, Soucy A, Goetze S, Freitag CM, Daly MJ, Walsh CA, Buxbaum JD, Yu TW

Publication type: Article

Publication status: Published

Journal: Nature Genetics

Year: 2019

Volume: 51

Pages: 1092-1098

Print publication date: 01/07/2019

Online publication date: 17/06/2019

Acceptance date: 02/05/2019

ISSN (print): 1061-4036

ISSN (electronic): 1546-1718

Publisher: Nature Publishing Group


DOI: 10.1038/s41588-019-0433-8


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Funder referenceFunder name
Fundamental Neurobiology Training Grant (no. 5 T32 NS007484-14)
National Institute of Mental Health (NIMH; grant nos. MH100233, MH100229, MH100209, MH100239, MH111661, MH111660, MH111662 and MH111658).
MRC/Wellcome Trust (grant no. MR/R006237/1)