Recessive gene disruptions in autism spectrum disorder
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...
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Published in | Nature genetics Vol. 51; no. 7; pp. 1092 - 1098 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York
Nature Publishing Group US
01.07.2019
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC6629034 AUTHOR CONTRIBUTIONS T.W.Y., R.N.D., E.T.L., and M.J.D. designed the study, with important additional contributions by C.B., D.J.C, C.A.W., and J.D.B.; R.N.D., E.T.L., and A.S. performed the data analyses; S.D.R. and S.G. performed Sanger validation; A.C. and C.F. characterized the FEV family; S.G. and T.W.Y. designed the in situ expression analyses; R.N.D. and T.W.Y. wrote the manuscript and all authors reviewed and approved the manuscript. |
ISSN: | 1061-4036 1546-1718 |
DOI: | 10.1038/s41588-019-0433-8 |