Logo image
Back
Patterns and rates of exonic de novo mutations in autism spectrum disorders
Journal article   Open access   Peer reviewed

Patterns and rates of exonic de novo mutations in autism spectrum disorders

Benjamin Neale, Yan Kou, Li Liu, Avi Ma'Ayan, Kaitlin E Samocha, Aniko Sabo, Chiao-Feng Lin, Christine Stevens, Li-San Wang, Vladimir Makarov, …
Nature (London), v 485(7397), 242
10 May 2012
DOI: https://doi.org/10.1038/nature11011
PMID: 22495311
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://europepmc.org/articles/pmc3613847?pdf=renderView
Accepted (AM)Open Access (License Unspecified),  Open

Abstract

Autistic Disorder Case-Control Studies DNA-Binding Proteins Exome Exons Family Health Genetic Predisposition to Disease Genetics Humans Life Sciences Models, Genetic Multifactorial Inheritance Mutation Phenotype Poisson Distribution Protein Interaction Maps Transcription Factors
Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.

Metrics

14 Record Views
1352 citations in Web of Science
1399 citations in Scopus

Details

UN Sustainable Development Goals (SDGs)

This publication has contributed to the advancement of the following goals:

#3 Good Health and Well-Being

InCites Highlights

Data related to this publication, from InCites Benchmarking & Analytics tool:

Collaboration types
Domestic collaboration
International collaboration
Web of Science research areas
Genetics & Heredity
Logo image