Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Jul;51(7):1092-1098.
doi: 10.1038/s41588-019-0433-8. Epub 2019 Jun 17.

Recessive gene disruptions in autism spectrum disorder

Ryan N Doan  1   2 , Elaine T Lim  1   2 , Silvia De Rubeis  3   4   5 , Catalina Betancur  6 , David J Cutler  7 , Andreas G Chiocchetti  8 , Lynne M Overman  9 , Aubrie Soucy  1 , Susanne Goetze  1 ; Autism Sequencing Consortium; Christine M Freitag  8 , Mark J Daly  2   10   11 , Christopher A Walsh  1   2   10   12 , Joseph D Buxbaum  3   4   5   13   14   15 , Timothy W Yu  16   17   18
Affiliations

Recessive gene disruptions in autism spectrum disorder

Ryan N Doan et al. Nat Genet. 2019 Jul.

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

COMPETING INTERESTS

The authors declare no competing financial interests. Correspondence and requests for materials should be addressed to Timothy.yu@childrens.harvard.edu.

Figures

Figure 1.
Figure 1.
An excess of rare, damaging, biallelic mutation in ASD. (a) Rates of biallelic gene knockout (strict LOF) in the ASC, stratified by diagnosis and allele frequency. Rates of biallelic variation, considering (b) LOF variants paired with a damaging missense variant (NsynD4, predicted to be deleterious by at least 4 algorithms), (c) LOF or NsynD4 variants, or NsynD4 variants alone. Genes impacted by biallelic variation in cases exhibit (d) haploinsufficiency and (e) pLI score profiles consistent with recessive genes. Error bars represent the 95% confidence intervals.
Figure 2.
Figure 2.
Biallelic mutations in ASD: effects of sex. (a) Rates of biallelic gene knockout (strict LOF) in the ASC, stratified by diagnosis and sex. (b, c) Rates of biallelic variation stratified by sex, considering (b) LOF or damaging missense (LOF or NsynD4) variants or (c) damaging missense variants alone (NsynD4). Error bars represent the 95% confidence intervals.
Figure 3.
Figure 3.
Biallelic mutations in ASD: ExAC filtration. (a) Rates of biallelic gene knockout (strict LOF) after filtration of commonly inactivated genes in ExAC. (b) Breakdown of candidate ASD genes excluded by presence of knockouts in ExAC, or by knockouts that are common and/or in unaffected individuals of the ASC. Error bars represent the 95% confidence intervals.
See this image and copyright information in PMC

References

    1. Prevention, C. f. D. C. a. & Baio J. Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years. Morbidity and Mortality Weekly Report 63 (2014). - PubMed
    1. Robinson EB et al. Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population. Nat Genet 48, 552–555, doi: 10.1038/ng.3529 (2016). - DOI - PMC - PubMed
    1. Gaugler T et al. Most genetic risk for autism resides with common variation. Nat Genet 46, 881–885, doi: 10.1038/ng.3039 (2014). - DOI - PMC - PubMed
    1. Weiner DJ et al. Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders. Nat Genet 49, 978–985, doi: 10.1038/ng.3863 (2017). - DOI - PMC - PubMed
    1. Krumm N et al. Excess of rare, inherited truncating mutations in autism. Nat Genet 47, 582–588, doi: 10.1038/ng.3303 (2015). - DOI - PMC - PubMed

Publication types