Journal article
Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains
Nature neuroscience, Vol.20(8), pp.1043-1051
08/2017
DOI: 10.1038/nn.4589
PMCID: PMC5539915
PMID: 28628100
Abstract
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.
Details
- Title: Subtitle
- Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains
- Creators
- Madeleine R Geisheker - Department of Genome Sciences, University of Washington, Seattle, Washington, USAGabriel Heymann - Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USATianyun Wang - The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, ChinaBradley P Coe - Department of Genome Sciences, University of Washington, Seattle, Washington, USATychele N Turner - Department of Genome Sciences, University of Washington, Seattle, Washington, USAHolly A F Stessman - Department of Genome Sciences, University of Washington, Seattle, Washington, USAKendra Hoekzema - Department of Genome Sciences, University of Washington, Seattle, Washington, USAMalin Kvarnung - Department of Clinical Genetics, Karolinska University Hospital, Stockholm, SwedenMarie Shaw - Robinson Research Institute and the University of Adelaide at the Women's and Children's Hospital, North Adelaide, South Australia, AustraliaKathryn Friend - SA Pathology, Adelaide, South Australia, AustraliaJan Liebelt - South Australian Clinical Genetics Service, SA Pathology (at Women's and Children's Hospital), Adelaide, South Australia, AustraliaChristopher Barnett - School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, AustraliaElizabeth M Thompson - School of Medicine, University of Adelaide, Adelaide, South Australia, AustraliaEric Haan - School of Medicine, University of Adelaide, Adelaide, South Australia, AustraliaHui Guo - The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, ChinaBritt-Marie Anderlid - Department of Clinical Genetics, Karolinska University Hospital, Stockholm, SwedenAnn Nordgren - Department of Clinical Genetics, Karolinska University Hospital, Stockholm, SwedenAnna Lindstrand - Department of Clinical Genetics, Karolinska University Hospital, Stockholm, SwedenGeert Vandeweyer - Department of Medical Genetics, University of Antwerp, Antwerp, BelgiumAntonino Alberti - Unit of Pediatrics &Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, ItalyEmanuela Avola - Unit of Pediatrics &Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, ItalyMirella Vinci - Laboratory of Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, ItalyStefania Giusto - Unit of Neurology, IRCCS Associazione Oasi Maria Santissima, Troina, ItalyTiziano Pramparo - University of California, San Diego, Autism Center of Excellence, La Jolla, California, USAKaren Pierce - University of California, San Diego, Autism Center of Excellence, La Jolla, California, USASrinivasa Nalabolu - University of California, San Diego, Autism Center of Excellence, La Jolla, California, USAJacob J Michaelson - Department of Psychiatry, The University of Iowa, Iowa City, Iowa, USAZdenek Sedlacek - Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech RepublicGijs W E Santen - Department of Clinical Genetics, Leiden University Medical Center, Leiden, the NetherlandsHilde Peeters - Centre for Human Genetics, KU Leuven and Leuven Autism Research, Leuven, BelgiumHakon Hakonarson - Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USAEric Courchesne - University of California, San Diego, Autism Center of Excellence, La Jolla, California, USACorrado Romano - Unit of Pediatrics &Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, ItalyR Frank Kooy - Department of Medical Genetics, University of Antwerp, Antwerp, BelgiumRaphael A Bernier - Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USAMagnus Nordenskjöld - Department of Clinical Genetics, Karolinska University Hospital, Stockholm, SwedenJozef Gecz - South Australian Health and Medical Research Institute, Adelaide, South Australia, AustraliaKun Xia - The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, ChinaLarry S Zweifel - Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USAEvan E Eichler - Howard Hughes Medical Institute, Seattle, Washington, USA
- Resource Type
- Journal article
- Publication Details
- Nature neuroscience, Vol.20(8), pp.1043-1051
- DOI
- 10.1038/nn.4589
- PMID
- 28628100
- PMCID
- PMC5539915
- NLM abbreviation
- Nat Neurosci
- ISSN
- 1097-6256
- eISSN
- 1546-1726
- Publisher
- United States
- Grant note
- R01 DC014489 / NIDCD NIH HHS\nT32 GM007266 / NIGMS NIH HHS\nP50 MH106428 / NIMH NIH HHS\nKL2 TR001444 / NCATS NIH HHS\nR01 MH104450 / NIMH NIH HHS\nU24 MH081810 / NIMH NIH HHS\nKL2 TR000099 / NCATS NIH HHS\nU54 HD083091 / NICHD NIH HHS\nR01 MH105527 / NIMH NIH HHS\nT32 HG000035 / NHGRI NIH HHS\nR01 MH101221 / NIMH NIH HHS\nR01 MH100047 / NIMH NIH HHS
- Language
- English
- Date published
- 08/2017
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Communication Sciences and Disorders; Psychiatry; Pathology; Iowa Neuroscience Institute
- Record Identifier
- 9984070219502771
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