ArticleNature2014
The contribution of de novo coding mutations to autism spectrum disorder.
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Article in Nature, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1,595 papers, 3 of them syntheses that pooled it.
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1,595citing papers in PubMed, 3 pooled it
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What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
1,595 citing papers in PubMed, 3 syntheses or guidelines pooled it.
- Systematic Review: Convergence and Divergence Between Autism Spectrum Disorder and Obsessive-Compulsive Disorder: Genetic, Neuroimaging, and Cognitive Findings.Journal of the American Academy of Child and Adolescent Psychiatry · 2026Pooled it
- Presymptomatic Biological, Structural, and Functional Diagnostic Biomarkers of Autism Spectrum Disorder.Journal of neurochemistry · 2025Pooled it
- Copy number variations in spontaneous abortions: a meta-analysis.Journal of assisted reproduction and genetics · 2025Pooled it
- Evidence supporting the role of GIGYF2 in synapse development and autism.Molecular psychiatry · 2026Article
- Spatiotemporal AI-based modeling of gene regulation and variant effects in the developing human brain using Seal.Nature neuroscience · 2026Article
- Testing the Transferability of Perturbational Similarity Maps Across Species, Cell Systems, and Assay Modalities.Neuroinformatics · 2026Article
- Imputation of fluid intelligence scores reduces ascertainment bias and increases power for analyses of common and rare variants.Nature genetics · 2026Article
- Developmental Convergence Across Diverse Genetic Architectures in Childhood Apraxia of Speech.bioRxiv : the preprint server for biology · 2026Article
- Assessing the de novo paradigm in sporadic early-onset Alzheimer disease trios.Molecular psychiatry · 2026Article
- Homozygous CHD8 mutation intensifies ASD phenotypes and attenuates sex differences.Molecular psychiatry · 2026Article
- An ASXL3-thyroid hormone axis in parvalbumin interneurons controls autism-like behaviors.Science advances · 2026Article
- Genetic Testing Abnormalities in Children with Autism Spectrum Disorder: Prevalence, Patterns, and Clinical Associations.Neurology international · 2026Article
- Complementary vertebrateeLife · 2026Article
- De novo structural variants in autism spectrum disorder disrupt distal regulatory interactions of neuronal genes.Genome research · 2026Article
- Whole-exome sequencing in individuals with obsessive-compulsive disorder and chronic tic disorders identifies 36 large-effect risk genes.Nature neuroscience · 2026Article
- Whole-exome sequencing in individuals with obsessive-compulsive disorder and chronic tic disorders identifies 36 large-effect risk genes.Nature neuroscience · 2026Article
- Genetic overlap and shared risk loci between autism spectrum disorder and cardiometabolic traits.Molecular psychiatry · 2026Article
- Article
- Genome sequencing reveals high diagnostic yield in children with severe sporadic developmental language disorder.European journal of human genetics : EJHG · 2026Article
- SIMLINK enables accurate variant pathogenicity prediction through modeling the gene-variant-feature association structure.Bioinformatics (Oxford, England) · 2026Article
1,535 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
47 authors.
Ivan IossifovCold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Brian J O'Roak1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA [2] Molecular &Medical Genetics, Oregon Health &Science University, Portland, Oregon 97208, USA.
Stephan J Sanders1] Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA [2] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Michael RonemusCold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Niklas KrummDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Dan LevyCold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Holly A StessmanDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Kali T WitherspoonDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Laura VivesDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Karynne E PattersonDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Joshua D SmithDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Bryan PaeperDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Deborah A NickersonDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Jeanselle DeaDepartment of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA.
Shan Dong1] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China.
Luis E GonzalezChild Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Jeffrey D MandellDepartment of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA.
Shrikant M ManeYale Center for Genomic Analysis, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Michael T MurthaChild Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Catherine A SullivanChild Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Michael F WalkerDepartment of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA.
Zainulabedin WaqarChild Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Liping Wei1] Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China [2] National Institute of Biological Sciences, Beijing 102206, China.
A Jeremy Willsey1] Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA [2] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Boris YamromCold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Yoon-ha LeeCold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Ewa Grabowska1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2] New York Genome Center, New York, New York 10013, USA.
Ertugrul Dalkic1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2] Department of Medical Biology, Bulent Ecevit University School of Medicine, 67600 Zonguldak, Turkey.
Zihua WangCold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Steven MarksCold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Peter AndrewsCold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Anthony LeottaCold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Jude KendallCold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Inessa HakkerCold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Julie RosenbaumCold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Beicong MaCold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Linda RodgersCold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Jennifer TrogeCold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Giuseppe Narzisi1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2] New York Genome Center, New York, New York 10013, USA.
Seungtai YoonCold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Michael C SchatzCold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Kenny YeDepartment of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
W Richard McCombieCold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Jay ShendureDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Evan E Eichler1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA [2] Howard Hughes Medical Institute, Seattle, Washington 98195, USA.
Matthew W State1] Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA [2] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA [3] Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA [4] Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Michael WiglerCold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Funding
Yale University Clinical and Translational Science Award ProgramUL1TR000142 · NCATS · YALE UNIVERSITY · PI SHERWIN, ROBERT S · 2012 to 2015
$31.8MUniversity of Washington Medical Scientist Training Program: MD/PhDT32GM007266 · NIGMS · UNIVERSITY OF WASHINGTON · PI HORWITZ, MARSHALL S. · 1985 to 2023
$30.4MComprehensive Sequencing and Analysis of Variation in NHLBI CohortsUC2HL102925 · NHLBI · BROAD INSTITUTE, INC. · PI ALTSHULER, DAVID, GABRIEL, STACEY · 2010 to 2010
$14.7MNorthwest Genomics CenterUC2HL102926 · NHLBI · UNIVERSITY OF WASHINGTON · PI GREEN, PHILIP P, NICKERSON, DEBORAH A · 2010 to 2010
$14.0MNorthwest Genomics CenterRC2HL102926 · NHLBI · UNIVERSITY OF WASHINGTON · PI GREEN, PHILIP P, NICKERSON, DEBORAH A · 2009 to 2009
$11.0MComprehensive Sequencing and Analysis of Variation in NHLBI CohortsRC2HL102925 · NHLBI · BROAD INSTITUTE, INC. · PI ALTSHULER, DAVID, GABRIEL, STACEY · 2009 to 2009
$10.2MSporadic Mutations and Autism Spectrum DisordersR01MH101221 · NIMH · UNIVERSITY OF WASHINGTON · PI EICHLER, EVAN · 2013 to 2025
$9.2MIntellectual and Developmental Disabilities Research CenterU54HD083091 · NICHD · UNIVERSITY OF WASHINGTON · PI DOHERTY, DANIEL · 2014 to 2019
$7.9MARRA - NHLBI Lung Cohorts Sequencing ProjectRC2HL102923 · NHLBI · UNIVERSITY OF WASHINGTON · PI BAMSHAD, MICHAEL JOSEPH, BARNES, KATHLEEN C · 2009 to 2009
$2.6MARRA - NHLBI Lung Cohorts Sequencing ProjectUC2HL102923 · NHLBI · UNIVERSITY OF WASHINGTON · PI BAMSHAD, MICHAEL JOSEPH, BARNES, KATHLEEN C · 2010 to 2010
$2.6MWHI Sequencing Project (WHISP)UC2HL102924 · NHLBI · OHIO STATE UNIVERSITY · PI CARLSON, CHRISTOPHER S, JACKSON, REBECCA D · 2010 to 2010
$2.4MWHI Sequencing Project (WHISP)RC2HL102924 · NHLBI · OHIO STATE UNIVERSITY · PI CARLSON, CHRISTOPHER S, JACKSON, REBECCA D · 2009 to 2009
$2.1MCIHRHoward Hughes Medical InstituteNCATS NIH HHS UL1 TR000142NHLBI NIH HHS RC2 HL102923NHLBI NIH HHS RC2 HL102924NHLBI NIH HHS RC2 HL102925NHLBI NIH HHS RC2 HL102926NHLBI NIH HHS RC2 HL103010NHLBI NIH HHS UC2 HL102923NHLBI NIH HHS UC2 HL102924NHLBI NIH HHS UC2 HL102925NHLBI NIH HHS UC2 HL102926NHLBI NIH HHS UC2 HL103010NICHD NIH HHS U54 HD083091NIGMS NIH HHS T32 GM007266NIMH NIH HHS R01 MH101221
Abstract
Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.
Indexed as
ChildChild Development Disorders, PervasiveCluster AnalysisExomeFemaleGenesGenetic Predisposition to DiseaseHumansIntelligence TestsMaleMutationOpen Reading FramesReproducibility of Results
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