PittsburghV1, Main, Exploration, bibRecord, 004312

A framework for the interpretation of de novo mutation in human disease

Identifieur interne : 004312 ( Main/Exploration ); précédent : 004311; suivant : 004313

A framework for the interpretation of de novo mutation in human disease

Auteurs : Kaitlin E. Samocha ; Elise B. Robinson ; Stephan J. Sanders ; Christine Stevens ; Aniko Sabo ; Lauren M. Mcgrath ; Jack A. Kosmicki ; Karola Rehnström [Finlande, Royaume-Uni] ; Swapan Mallick ; Andrew Kirby ; Dennis P. Wall ; Daniel G. Macarthur ; Stacey B. Gabriel ; Mark Depristo ; Shaun M. Purcell ; Aarno Palotie [Finlande, Royaume-Uni] ; Eric Boerwinkle ; Joseph D. Buxbaum ; Edwin H. Cook [États-Unis] ; Richard A. Gibbs ; Gerard D. Schellenberg ; James S. Sutcliffe ; Bernie Devlin ; Kathryn Roeder [États-Unis] ; Benjamin M. Neale ; Mark J. Daly

Source :

Nature genetics [ 1061-4036 ] ; 2014.

RBID : PMC:4222185

Descripteurs français

KwdFr :
- Code génétique, Exome, Femelle, Génétique médicale (), Humains, Mutation, Mâle, Prédisposition génétique à une maladie, Troubles généralisés du développement de l'enfant (génétique).
MESH :
- génétique : Troubles généralisés du développement de l'enfant.
- Code génétique, Exome, Femelle, Génétique médicale, Humains, Mutation, Mâle, Prédisposition génétique à une maladie.

English descriptors

KwdEn :
- Child Development Disorders, Pervasive (genetics), Exome, Female, Genetic Code, Genetic Predisposition to Disease, Genetics, Medical (methods), Humans, Male, Mutation.
MESH :
- genetics : Child Development Disorders, Pervasive.
- methods : Genetics, Medical.
- Exome, Female, Genetic Code, Genetic Predisposition to Disease, Humans, Male, Mutation.

Abstract

Spontaneously arising (‘de novo’) mutations play an important role in medical genetics. For diseases with extensive locus heterogeneity – such as autism spectrum disorders (ASDs) – the signal from de novo mutations (DNMs) is distributed across many genes, making it difficult to distinguish disease-relevant mutations from background variation. We provide a statistical framework for the analysis of DNM excesses per gene and gene set by calibrating a model of de novo mutation. We applied this framework to DNMs collected from 1,078 ASD trios and – while affirming a significant role for loss-of-function (LoF) mutations – found no excess of de novo LoF mutations in cases with IQ above 100, suggesting that the role of DNMs in ASD may reside in fundamental neurodevelopmental processes. We also used our model to identify ~1,000 genes that are significantly lacking functional coding variation in non-ASD samples and are enriched for de novo LoF mutations identified in ASD cases.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222185

DOI: 10.1038/ng.3050
PubMed: 25086666
PubMed Central: 4222185

Affiliations:

Le document en format XML

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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A framework for the interpretation of <italic>de novo</italic>
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<wicri:noCountry code="subfield">02142</wicri:noCountry>
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<affiliation><nlm:aff id="A3">Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA, 02142</nlm:aff>
<wicri:noCountry code="subfield">02142</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Sanders, Stephan J" sort="Sanders, Stephan J" uniqKey="Sanders S" first="Stephan J." last="Sanders">Stephan J. Sanders</name>
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<wicri:noCountry code="subfield">02114</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A5">Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06520</nlm:aff>
<wicri:noCountry code="subfield">06520</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Stevens, Christine" sort="Stevens, Christine" uniqKey="Stevens C" first="Christine" last="Stevens">Christine Stevens</name>
<affiliation><nlm:aff id="A2">Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA, 02142</nlm:aff>
<wicri:noCountry code="subfield">02142</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A3">Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA, 02142</nlm:aff>
<wicri:noCountry code="subfield">02142</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Sabo, Aniko" sort="Sabo, Aniko" uniqKey="Sabo A" first="Aniko" last="Sabo">Aniko Sabo</name>
<affiliation><nlm:aff id="A7">Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030</nlm:aff>
<wicri:noCountry code="subfield">77030</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Mcgrath, Lauren M" sort="Mcgrath, Lauren M" uniqKey="Mcgrath L" first="Lauren M." last="Mcgrath">Lauren M. Mcgrath</name>
<affiliation><nlm:aff id="A8">Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114</nlm:aff>
<wicri:noCountry code="subfield">02114</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Kosmicki, Jack A" sort="Kosmicki, Jack A" uniqKey="Kosmicki J" first="Jack A." last="Kosmicki">Jack A. Kosmicki</name>
<affiliation><nlm:aff id="A1">Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114</nlm:aff>
<wicri:noCountry code="subfield">02114</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A9">Center for Biomedical Informatics, Harvard Medical School, Boston, MA, 02115</nlm:aff>
<wicri:noCountry code="subfield">02115</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A10">Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02115</nlm:aff>
<wicri:noCountry code="subfield">02115</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Rehnstrom, Karola" sort="Rehnstrom, Karola" uniqKey="Rehnstrom K" first="Karola" last="Rehnström">Karola Rehnström</name>
<affiliation wicri:level="4"><nlm:aff id="A11">Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland</nlm:aff>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki</wicri:regionArea>
<orgName type="university">Université d'Helsinki</orgName>
<placeName><settlement type="city">Helsinki</settlement>
<region type="région" nuts="2">Uusimaa</region>
</placeName>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A12">Wellcome Trust Sanger Institute, Cambridge, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Wellcome Trust Sanger Institute, Cambridge</wicri:regionArea>
<wicri:noRegion>Cambridge</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Mallick, Swapan" sort="Mallick, Swapan" uniqKey="Mallick S" first="Swapan" last="Mallick">Swapan Mallick</name>
<affiliation><nlm:aff id="A13">Department of Genetics, Harvard Medical School, Boston, MA, 02115</nlm:aff>
<wicri:noCountry code="subfield">02115</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Kirby, Andrew" sort="Kirby, Andrew" uniqKey="Kirby A" first="Andrew" last="Kirby">Andrew Kirby</name>
<affiliation><nlm:aff id="A1">Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114</nlm:aff>
<wicri:noCountry code="subfield">02114</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A2">Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA, 02142</nlm:aff>
<wicri:noCountry code="subfield">02142</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Wall, Dennis P" sort="Wall, Dennis P" uniqKey="Wall D" first="Dennis P." last="Wall">Dennis P. Wall</name>
<affiliation><nlm:aff id="A9">Center for Biomedical Informatics, Harvard Medical School, Boston, MA, 02115</nlm:aff>
<wicri:noCountry code="subfield">02115</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A10">Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02115</nlm:aff>
<wicri:noCountry code="subfield">02115</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Macarthur, Daniel G" sort="Macarthur, Daniel G" uniqKey="Macarthur D" first="Daniel G." last="Macarthur">Daniel G. Macarthur</name>
<affiliation><nlm:aff id="A1">Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114</nlm:aff>
<wicri:noCountry code="subfield">02114</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A2">Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA, 02142</nlm:aff>
<wicri:noCountry code="subfield">02142</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Gabriel, Stacey B" sort="Gabriel, Stacey B" uniqKey="Gabriel S" first="Stacey B." last="Gabriel">Stacey B. Gabriel</name>
<affiliation><nlm:aff id="A2">Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA, 02142</nlm:aff>
<wicri:noCountry code="subfield">02142</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Depristo, Mark" sort="Depristo, Mark" uniqKey="Depristo M" first="Mark" last="Depristo">Mark Depristo</name>
<affiliation><nlm:aff id="A14">Synapdx, Lexington, MA, 02421</nlm:aff>
<wicri:noCountry code="subfield">02421</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Purcell, Shaun M" sort="Purcell, Shaun M" uniqKey="Purcell S" first="Shaun M." last="Purcell">Shaun M. Purcell</name>
<affiliation><nlm:aff id="A1">Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114</nlm:aff>
<wicri:noCountry code="subfield">02114</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A2">Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA, 02142</nlm:aff>
<wicri:noCountry code="subfield">02142</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A8">Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114</nlm:aff>
<wicri:noCountry code="subfield">02114</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A15">Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029</nlm:aff>
<wicri:noCountry code="subfield">10029</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A16">Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029</nlm:aff>
<wicri:noCountry code="subfield">10029</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A17">Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029</nlm:aff>
<wicri:noCountry code="subfield">10029</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Palotie, Aarno" sort="Palotie, Aarno" uniqKey="Palotie A" first="Aarno" last="Palotie">Aarno Palotie</name>
<affiliation><nlm:aff id="A8">Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114</nlm:aff>
<wicri:noCountry code="subfield">02114</wicri:noCountry>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="A11">Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland</nlm:aff>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki</wicri:regionArea>
<orgName type="university">Université d'Helsinki</orgName>
<placeName><settlement type="city">Helsinki</settlement>
<region type="région" nuts="2">Uusimaa</region>
</placeName>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A12">Wellcome Trust Sanger Institute, Cambridge, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Wellcome Trust Sanger Institute, Cambridge</wicri:regionArea>
<wicri:noRegion>Cambridge</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Boerwinkle, Eric" sort="Boerwinkle, Eric" uniqKey="Boerwinkle E" first="Eric" last="Boerwinkle">Eric Boerwinkle</name>
<affiliation><nlm:aff id="A7">Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030</nlm:aff>
<wicri:noCountry code="subfield">77030</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A18">Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, 77030</nlm:aff>
<wicri:noCountry code="subfield">77030</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Buxbaum, Joseph D" sort="Buxbaum, Joseph D" uniqKey="Buxbaum J" first="Joseph D." last="Buxbaum">Joseph D. Buxbaum</name>
<affiliation><nlm:aff id="A15">Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029</nlm:aff>
<wicri:noCountry code="subfield">10029</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A16">Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029</nlm:aff>
<wicri:noCountry code="subfield">10029</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A17">Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029</nlm:aff>
<wicri:noCountry code="subfield">10029</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A19">Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, 10029</nlm:aff>
<wicri:noCountry code="subfield">10029</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A20">Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029</nlm:aff>
<wicri:noCountry code="subfield">10029</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A21">Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029</nlm:aff>
<wicri:noCountry code="subfield">10029</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Cook, Edwin H" sort="Cook, Edwin H" uniqKey="Cook E" first="Edwin H." last="Cook">Edwin H. Cook</name>
<affiliation wicri:level="4"><nlm:aff id="A22">Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, 60608</nlm:aff>
<orgName type="university">Université de l'Illinois à Chicago</orgName>
<country>États-Unis</country>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Gibbs, Richard A" sort="Gibbs, Richard A" uniqKey="Gibbs R" first="Richard A." last="Gibbs">Richard A. Gibbs</name>
<affiliation><nlm:aff id="A7">Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030</nlm:aff>
<wicri:noCountry code="subfield">77030</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Schellenberg, Gerard D" sort="Schellenberg, Gerard D" uniqKey="Schellenberg G" first="Gerard D." last="Schellenberg">Gerard D. Schellenberg</name>
<affiliation><nlm:aff id="A23">Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104</nlm:aff>
<wicri:noCountry code="subfield">19104</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Sutcliffe, James S" sort="Sutcliffe, James S" uniqKey="Sutcliffe J" first="James S." last="Sutcliffe">James S. Sutcliffe</name>
<affiliation><nlm:aff id="A24">Center for Molecular Neuroscience, Vanderbilt University, Nashville, TN, 37232</nlm:aff>
<wicri:noCountry code="subfield">37232</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Devlin, Bernie" sort="Devlin, Bernie" uniqKey="Devlin B" first="Bernie" last="Devlin">Bernie Devlin</name>
<affiliation><nlm:aff id="A25">Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, PA, 15213</nlm:aff>
<wicri:noCountry code="subfield">15213</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Roeder, Kathryn" sort="Roeder, Kathryn" uniqKey="Roeder K" first="Kathryn" last="Roeder">Kathryn Roeder</name>
<affiliation wicri:level="4"><nlm:aff id="A26">Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, 15232</nlm:aff>
<orgName type="university">Université Carnegie-Mellon</orgName>
<country>États-Unis</country>
<placeName><settlement type="city">Pittsburgh</settlement>
<region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="A27">Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, PA, 15232</nlm:aff>
<orgName type="university">Université Carnegie-Mellon</orgName>
<country>États-Unis</country>
<placeName><settlement type="city">Pittsburgh</settlement>
<region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Neale, Benjamin M" sort="Neale, Benjamin M" uniqKey="Neale B" first="Benjamin M." last="Neale">Benjamin M. Neale</name>
<affiliation><nlm:aff id="A1">Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114</nlm:aff>
<wicri:noCountry code="subfield">02114</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A2">Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA, 02142</nlm:aff>
<wicri:noCountry code="subfield">02142</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A3">Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA, 02142</nlm:aff>
<wicri:noCountry code="subfield">02142</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Daly, Mark J" sort="Daly, Mark J" uniqKey="Daly M" first="Mark J." last="Daly">Mark J. Daly</name>
<affiliation><nlm:aff id="A1">Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114</nlm:aff>
<wicri:noCountry code="subfield">02114</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A2">Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA, 02142</nlm:aff>
<wicri:noCountry code="subfield">02142</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A3">Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA, 02142</nlm:aff>
<wicri:noCountry code="subfield">02142</wicri:noCountry>
</affiliation>
</author>
</analytic>
<series><title level="j">Nature genetics</title>
<idno type="ISSN">1061-4036</idno>
<idno type="eISSN">1546-1718</idno>
<imprint><date when="2014">2014</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Child Development Disorders, Pervasive (genetics)</term>
<term>Exome</term>
<term>Female</term>
<term>Genetic Code</term>
<term>Genetic Predisposition to Disease</term>
<term>Genetics, Medical (methods)</term>
<term>Humans</term>
<term>Male</term>
<term>Mutation</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Code génétique</term>
<term>Exome</term>
<term>Femelle</term>
<term>Génétique médicale ()</term>
<term>Humains</term>
<term>Mutation</term>
<term>Mâle</term>
<term>Prédisposition génétique à une maladie</term>
<term>Troubles généralisés du développement de l'enfant (génétique)</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Child Development Disorders, Pervasive</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Troubles généralisés du développement de l'enfant</term>
</keywords>
<keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Genetics, Medical</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Exome</term>
<term>Female</term>
<term>Genetic Code</term>
<term>Genetic Predisposition to Disease</term>
<term>Humans</term>
<term>Male</term>
<term>Mutation</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Code génétique</term>
<term>Exome</term>
<term>Femelle</term>
<term>Génétique médicale</term>
<term>Humains</term>
<term>Mutation</term>
<term>Mâle</term>
<term>Prédisposition génétique à une maladie</term>
</keywords>
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<front><div type="abstract" xml:lang="en"><p id="P1">Spontaneously arising <italic>(‘de novo’)</italic>
 mutations play an important role in medical genetics. For diseases with extensive locus heterogeneity – such as autism spectrum disorders (ASDs) – the signal from <italic>de novo</italic>
 mutations (DNMs) is distributed across many genes, making it difficult to distinguish disease-relevant mutations from background variation. We provide a statistical framework for the analysis of DNM excesses per gene and gene set by calibrating a model of <italic>de novo</italic>
 mutation. We applied this framework to DNMs collected from 1,078 ASD trios and – while affirming a significant role for loss-of-function (LoF) mutations – found no excess of <italic>de novo</italic>
 LoF mutations in cases with IQ above 100, suggesting that the role of DNMs in ASD may reside in fundamental neurodevelopmental processes. We also used our model to identify ~1,000 genes that are significantly lacking functional coding variation in non-ASD samples and are enriched for <italic>de novo</italic>
 LoF mutations identified in ASD cases.</p>
</div>
</front>
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</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Iossifov, I" uniqKey="Iossifov I">I Iossifov</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Neale, Bm" uniqKey="Neale B">BM Neale</name>
</author>
</analytic>
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<biblStruct><analytic><author><name sortKey="O Oak, Bj" uniqKey="O Oak B">BJ O’Roak</name>
</author>
</analytic>
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<biblStruct><analytic><author><name sortKey="Sanders, Sj" uniqKey="Sanders S">SJ Sanders</name>
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<biblStruct><analytic><author><name sortKey="O Oak, Bj" uniqKey="O Oak B">BJ O’Roak</name>
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</analytic>
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<biblStruct><analytic><author><name sortKey="Antonarakis, Se" uniqKey="Antonarakis S">SE Antonarakis</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Petrovski, S" uniqKey="Petrovski S">S Petrovski</name>
</author>
<author><name sortKey="Wang, Q" uniqKey="Wang Q">Q Wang</name>
</author>
<author><name sortKey="Heinzen, El" uniqKey="Heinzen E">EL Heinzen</name>
</author>
<author><name sortKey="Allen, As" uniqKey="Allen A">AS Allen</name>
</author>
<author><name sortKey="Goldstein, Db" uniqKey="Goldstein D">DB Goldstein</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="De Ligt, J" uniqKey="De Ligt J">J de Ligt</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Rauch, A" uniqKey="Rauch A">A Rauch</name>
</author>
</analytic>
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<biblStruct><analytic><author><name sortKey="O Oak, Bj" uniqKey="O Oak B">BJ O’Roak</name>
</author>
</analytic>
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<biblStruct><analytic><author><name sortKey="Betancur, C" uniqKey="Betancur C">C Betancur</name>
</author>
</analytic>
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<biblStruct><analytic><author><name sortKey="Darnell, Jc" uniqKey="Darnell J">JC Darnell</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Sanders, Sj" uniqKey="Sanders S">SJ Sanders</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Xu, B" uniqKey="Xu B">B Xu</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bustamante, Cd" uniqKey="Bustamante C">CD Bustamante</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mcdonald, Jh" uniqKey="Mcdonald J">JH McDonald</name>
</author>
<author><name sortKey="Kreitman, M" uniqKey="Kreitman M">M Kreitman</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Epi, Kc" uniqKey="Epi K">KC Epi</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Depristo, Ma" uniqKey="Depristo M">MA DePristo</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Li, H" uniqKey="Li H">H Li</name>
</author>
<author><name sortKey="Durbin, R" uniqKey="Durbin R">R Durbin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mckenna, A" uniqKey="Mckenna A">A McKenna</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Koren, A" uniqKey="Koren A">A Koren</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kryukov, Gv" uniqKey="Kryukov G">GV Kryukov</name>
</author>
<author><name sortKey="Pennacchio, La" uniqKey="Pennacchio L">LA Pennacchio</name>
</author>
<author><name sortKey="Sunyaev, Sr" uniqKey="Sunyaev S">SR Sunyaev</name>
</author>
</analytic>
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<biblStruct><analytic><author><name sortKey="Campbell, Cd" uniqKey="Campbell C">CD Campbell</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Conrad, Df" uniqKey="Conrad D">DF Conrad</name>
</author>
</analytic>
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</TEI>
<affiliations><list><country><li>Finlande</li>
<li>Royaume-Uni</li>
<li>États-Unis</li>
</country>
<region><li>Illinois</li>
<li>Pennsylvanie</li>
<li>Uusimaa</li>
</region>
<settlement><li>Chicago</li>
<li>Helsinki</li>
<li>Pittsburgh</li>
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A framework for the interpretation of de novo mutation in human disease

A framework for the interpretation of de novo mutation in human disease

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