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Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains
MR. Geisheker, G. Heymann, T. Wang, BP. Coe, TN. Turner, HAF. Stessman, K. Hoekzema, M. Kvarnung, M. Shaw, K. Friend, J. Liebelt, C. Barnett, EM. Thompson, E. Haan, H. Guo, BM. Anderlid, A. Nordgren, A. Lindstrand, G. Vandeweyer, A. Alberti, E....
Language English Country United States
Document type Journal Article
NLK
ProQuest Central
from 1998-06-01 to 1 year ago
Health & Medicine (ProQuest)
from 1998-06-01 to 1 year ago
Psychology Database (ProQuest)
from 1998-06-01 to 2017-12-31
PubMed
28628100
DOI
10.1038/nn.4589
Knihovny.cz E-resources
- MeSH
- Receptors, AMPA genetics MeSH
- Autistic Disorder genetics MeSH
- Exome genetics MeSH
- Genetic Predisposition to Disease * MeSH
- Receptors, Glutamate genetics MeSH
- Humans MeSH
- Mutation, Missense genetics MeSH
- Amino Acid Sequence genetics MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,688 patients with NDD identified 21 new patients with identical missense mutations. One recurrent site substitution (p.A636T) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology.
Centre for Human Genetics KU Leuven and Leuven Autism Research Leuven Belgium
Department of Clinical Genetics Leiden University Medical Center Leiden the Netherlands
Department of Genome Sciences University of Washington Seattle Washington USA
Department of Medical Genetics University of Antwerp Antwerp Belgium
Department of Psychiatry and Behavioral Sciences University of Washington Seattle Washington USA
Department of Psychiatry The University of Iowa Iowa City Iowa USA
Laboratory of Medical Genetics IRCCS Associazione Oasi Maria Santissima Troina Italy
South Australian Clinical Genetics Service SA Pathology Adelaide South Australia Australia
Unit of Neurology IRCCS Associazione Oasi Maria Santissima Troina Italy
Unit of Pediatrics and Medical Genetics IRCCS Associazione Oasi Maria Santissima Troina Italy
University of California San Diego Autism Center of Excellence La Jolla California USA
References provided by Crossref.org
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