ArticleNature neuroscience2017
Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains.
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Article in Nature neuroscience, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 123 papers, 1 of them a synthesis that pooled it.
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123citing papers in PubMed, 1 pooled it
15.6field-weighted citation impact, top 1% of its field
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Who cites it
123 citing papers in PubMed, 1 synthesis or guideline pooled it, 179 citations in OpenAlex.
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- DSSA-PPI: enhancing binding affinity change prediction upon protein mutations using disentangled structure-sequence aware attention.Chemical science · 2026Article
- Rescuing Neurodevelopmental Deficits in AMPA Receptor Gain-of-Function Mutant.bioRxiv : the preprint server for biology · 2025Article
- Clinical and Neurodevelopmental Characteristics of Paralogous Gain-of-Function Variants at GRIA2 p.Gly792 and GRIA3 p.Gly803.Clinical genetics · 2025Article
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- Evaluation of familial phenotype deviation to measure the impact of de novo mutations in autism.Genome medicine · 2025Article
- A series of reviews in familial cancer: genetic cancer risk in context variants of uncertain significance in MMR genes: which procedures should be followed?Familial cancer · 2025Review
- DEAD/DEAH-box RNA helicases shape the risk of neurodevelopmental disorders.Trends in genetics : TIG · 2025Review
- Proteome-wide assessment of differential missense variant clustering in neurodevelopmental disorders and cancer.Cell genomics · 2025Article
- Genetic advances in neurodevelopmental disorders.Medical review (2021) · 2025Review
- OCNDS core features are conserved across variants, with loop-region mutations driving greater symptom burden.Frontiers in human neuroscience · 2025Article
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- Excitatory neurons and oligodendrocyte precursor cells are vulnerable to focal cortical dysplasia type IIIa as suggested by single-nucleus multiomics.Clinical and translational medicine · 2024Article
- Similarity of Phenotype in Three Male Patients With the c.320A>G Variant in ALG13: Possible Genotype-Phenotype Correlation.Molecular genetics & genomic medicine · 2024Article
- Discovery of a de novo ITPR1 missense mutation in a patient with early-onset cerebellar ataxia: A rare case report of spinocerebellar ataxia 29.Molecular genetics & genomic medicine · 2024Article
63 more citing papers are in PubMed but not listed here.
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Authors and funding
40 authors at 14 institutions in 8 countries.
Madeleine R GeishekerDepartment of Genome Sciences, University of Washington, Seattle, Washington, USA.
Gabriel HeymannDepartment of Pharmacology, University of Washington, Seattle, Washington, USA.
Tianyun WangThe State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
Bradley P CoeDepartment of Genome Sciences, University of Washington, Seattle, Washington, USA.
Tychele N TurnerDepartment of Genome Sciences, University of Washington, Seattle, Washington, USA.ORCID http://orcid.org/0000-0001-8246-6477
Holly A F StessmanDepartment of Genome Sciences, University of Washington, Seattle, Washington, USA.
Kendra HoekzemaDepartment of Genome Sciences, University of Washington, Seattle, Washington, USA.
Malin KvarnungDepartment of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Marie ShawRobinson Research Institute and the University of Adelaide at the Women's and Children's Hospital, North Adelaide, South Australia, Australia.
Kathryn FriendRobinson Research Institute and the University of Adelaide at the Women's and Children's Hospital, North Adelaide, South Australia, Australia.
Jan LiebeltSouth Australian Clinical Genetics Service, SA Pathology (at Women's and Children's Hospital), Adelaide, South Australia, Australia.
Christopher BarnettSouth Australian Clinical Genetics Service, SA Pathology (at Women's and Children's Hospital), Adelaide, South Australia, Australia.
Elizabeth M ThompsonSouth Australian Clinical Genetics Service, SA Pathology (at Women's and Children's Hospital), Adelaide, South Australia, Australia.
Eric HaanSouth Australian Clinical Genetics Service, SA Pathology (at Women's and Children's Hospital), Adelaide, South Australia, Australia.ORCID http://orcid.org/0000-0002-7310-5124
Hui GuoThe State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
Britt-Marie AnderlidDepartment of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Ann NordgrenDepartment of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Anna LindstrandDepartment of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Geert VandeweyerDepartment of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Antonino AlbertiUnit of Pediatrics &Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.
Emanuela AvolaUnit of Pediatrics &Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.
Mirella VinciLaboratory of Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.
Stefania GiustoUnit of Neurology, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.
Tiziano PramparoUniversity of California, San Diego, Autism Center of Excellence, La Jolla, California, USA.
Karen PierceUniversity of California, San Diego, Autism Center of Excellence, La Jolla, California, USA.
Srinivasa NalaboluUniversity of California, San Diego, Autism Center of Excellence, La Jolla, California, USA.
Jacob J MichaelsonDepartment of Psychiatry, The University of Iowa, Iowa City, Iowa, USA.ORCID http://orcid.org/0000-0001-9713-0992
Zdenek SedlacekDepartment of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
Gijs W E SantenDepartment of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
Hilde PeetersCentre for Human Genetics, KU Leuven and Leuven Autism Research, Leuven, Belgium.
Hakon HakonarsonCenter for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Eric CourchesneUniversity of California, San Diego, Autism Center of Excellence, La Jolla, California, USA.
Corrado RomanoUnit of Pediatrics &Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.ORCID http://orcid.org/0000-0003-1049-0683
R Frank KooyDepartment of Medical Genetics, University of Antwerp, Antwerp, Belgium.ORCID http://orcid.org/0000-0003-2024-0485
Raphael A BernierDepartment of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.
Magnus NordenskjöldDepartment of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Jozef GeczRobinson Research Institute and the University of Adelaide at the Women's and Children's Hospital, North Adelaide, South Australia, Australia.ORCID http://orcid.org/0000-0002-7884-6861
Kun XiaThe State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
Larry S ZweifelDepartment of Pharmacology, University of Washington, Seattle, Washington, USA.
Evan E EichlerDepartment of Genome Sciences, University of Washington, Seattle, Washington, USA.
University of Washington · USKarolinska University Hospital · SEOasi Maria SS · ITSouth Australia Pathology · AUAutism Research Institute · USCentral South University · CNUniversity of Antwerp · BEWomen's and Children's Hospital · AUCharles University · CZChildren's Hospital of Philadelphia · USHoward Hughes Medical Institute · USKU Leuven · BELeiden University Medical Center · NLUniversity of Iowa · US
Funding
University of Washington Medical Scientist Training Program: MD/PhDT32GM007266 · NIGMS · UNIVERSITY OF WASHINGTON · PI HORWITZ, MARSHALL S. · 1985 to 2023
$30.4MINTERDISCIPLINARY TRAINING IN GENOMIC SCIENCEST32HG000035 · NHGRI · UNIVERSITY OF WASHINGTON · PI Bruce Colston Trapnell · 1995 to 2026
$24.2MUC San Diego Clinical and Translational Research InstituteKL2TR001444 · NCATS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI DEPP, COLIN A. · 2015 to 2024
$15.4MSporadic Mutations and Autism Spectrum DisordersR01MH101221 · NIMH · UNIVERSITY OF WASHINGTON · PI EICHLER, EVAN · 2013 to 2025
$9.2MCenter for Genomic and Phenomic Studies in AutismU24MH081810 · NIMH · UNIVERSITY OF SOUTHERN CALIFORNIA · PI LAJONCHERE, CLARA M · 2007 to 2011
$8.3MIntellectual and Developmental Disabilities Research CenterU54HD083091 · NICHD · UNIVERSITY OF WASHINGTON · PI DOHERTY, DANIEL · 2014 to 2019
$7.9MTherapeutic Potential of Kappa Antagonists in the Adjunctive Treatment of Psychotic DepressionP50MH106428 · NIMH · UNIVERSITY OF WASHINGTON · PI CHAVKIN, CHARLES · 2015 to 2019
$7.6MPhasic Dopamine and Symptom Domains of Mental IllnessR01MH104450 · NIMH · UNIVERSITY OF WASHINGTON · PI LARRY S ZWEIFEL · 2015 to 2026
$5.5MUnderstanding the biology of language impairment through whole genome sequencingR01DC014489 · NIDCD · UNIVERSITY OF IOWA · PI MICHAELSON, JACOB JAMES · 2016 to 2020
$3.1MPhenotypic Characterization of Gene Disrupting Mutations in ASDR01MH100047 · NIMH · UNIVERSITY OF WASHINGTON · PI BERNIER, RAPHAEL A · 2014 to 2018
$2.1MEstimating the impact of genetic variants on the brain in space and timeR01MH105527 · NIMH · UNIVERSITY OF IOWA · PI MICHAELSON, JACOB JAMES · 2015 to 2017
$1.2MSan Diego Clinical and Translational Research InstituteKL2TR000099 · NCATS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI FIRESTEIN, GARY S · 2012 to 2014
$1.1MNCATS NIH HHS KL2 TR000099NCATS NIH HHS KL2 TR001444NHGRI NIH HHS T32 HG000035NICHD NIH HHS U54 HD083091NIDCD NIH HHS R01 DC014489NIGMS NIH HHS T32 GM007266NIMH NIH HHS P50 MH106428NIMH NIH HHS R01 MH100047NIMH NIH HHS R01 MH101221NIMH NIH HHS R01 MH104450NIMH NIH HHS R01 MH105527NIMH NIH HHS U24 MH081810
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.
Indexed as
Genetic Predisposition to DiseaseAmino Acid SequenceAutistic DisorderExomeFemaleHumansMaleMutation, MissenseReceptors, AMPAReceptors, GlutamateReceptors, AMPAReceptors, Glutamate
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