Patterns and rates of exonic de novo mutations in autism spectrum disorders
Identifieur interne : 001724 ( PascalFrancis/Curation ); précédent : 001723; suivant : 001725Patterns and rates of exonic de novo mutations in autism spectrum disorders
Auteurs : Benjamin M. Neale [États-Unis] ; YAN KOU [États-Unis] ; LI LIU [États-Unis] ; Avi Ma'Ayan [États-Unis] ; Kaitlin E. Samocha [États-Unis] ; Aniko Sabo [États-Unis] ; Chiao-Feng Lin [États-Unis] ; Christine Stevens [États-Unis] ; Li-San Wang [États-Unis] ; Vladimir Makarov [États-Unis] ; Paz Polak [États-Unis] ; Seungtai Yoon [États-Unis] ; Jared Maguire [États-Unis] ; Emily L. Crawford [États-Unis] ; Nicholas G. Campbell [États-Unis] ; Evan T. Geher [États-Unis] ; Otto Valladares [États-Unis] ; Chad Schafer [États-Unis] ; Han Liul [États-Unis] ; TUO ZHAO [États-Unis] ; GUIQING CAI [États-Unis] ; Jayon Lihm [États-Unis] ; Ruth Dannenfelser [États-Unis] ; Omar Jabado [États-Unis] ; Zuleyma Peralta [États-Unis] ; Uma Nagaswamy [États-Unis] ; Donna Muzny [États-Unis] ; Jeffrey G. Reid [États-Unis] ; Irene Newsham [États-Unis] ; YUANQING WU [États-Unis] ; Lora Lewis [États-Unis] ; YI HAN [États-Unis] ; Benjamin F. Voight [États-Unis] ; Elaine Lim [États-Unis] ; Elizabeth Rossin [États-Unis] ; Andrew Kirby [États-Unis] ; Jason Flannick [États-Unis] ; Menachem Fromer [États-Unis] ; Khalid Shakir [États-Unis] ; Tim Fennell [États-Unis] ; Kiran Garimella [États-Unis] ; Eric Banks [États-Unis] ; Ryan Poplin [États-Unis] ; Stacey Gabriel [États-Unis] ; Mark Depristo [États-Unis] ; Jack R. Wimbish [États-Unis] ; Braden E. Boone [États-Unis] ; Shawn E. Levy [États-Unis] ; Catalina Betancur [France] ; Shamil Sunyaev [États-Unis] ; Eric Boerwinkle [États-Unis] ; Joseph D. Buxbaum [États-Unis] ; Edwin H. Jr Cook [États-Unis] ; Bernie Devlin ; Richard A. Gibbs [États-Unis] ; Kathryn Roeder [États-Unis] ; Gerard D. Schellenberg [États-Unis] ; James S. Sutcliffe [États-Unis] ; Mark J. Daly [États-Unis]Source :
- Nature : (London) [ 0028-0836 ] ; 2012.
Descripteurs français
English descriptors
Abstract
Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified1,2, To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes3 as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.
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<author><name sortKey="Yan Kou" sort="Yan Kou" uniqKey="Yan Kou" last="Yan Kou">YAN KOU</name>
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<author><name sortKey="Li Liu" sort="Li Liu" uniqKey="Li Liu" last="Li Liu">LI LIU</name>
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<author><name sortKey="Sabo, Aniko" sort="Sabo, Aniko" uniqKey="Sabo A" first="Aniko" last="Sabo">Aniko Sabo</name>
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<author><name sortKey="Lin, Chiao Feng" sort="Lin, Chiao Feng" uniqKey="Lin C" first="Chiao-Feng" last="Lin">Chiao-Feng Lin</name>
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<author><name sortKey="Stevens, Christine" sort="Stevens, Christine" uniqKey="Stevens C" first="Christine" last="Stevens">Christine Stevens</name>
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<author><name sortKey="Wang, Li San" sort="Wang, Li San" uniqKey="Wang L" first="Li-San" last="Wang">Li-San Wang</name>
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<author><name sortKey="Makarov, Vladimir" sort="Makarov, Vladimir" uniqKey="Makarov V" first="Vladimir" last="Makarov">Vladimir Makarov</name>
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<author><name sortKey="Polak, Paz" sort="Polak, Paz" uniqKey="Polak P" first="Paz" last="Polak">Paz Polak</name>
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<affiliation wicri:level="1"><inist:fA14 i1="09"><s1>Division of Genetics, Department of Medicine Brigham & Women's Hospital and Harvard Medical School</s1>
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<author><name sortKey="Yoon, Seungtai" sort="Yoon, Seungtai" uniqKey="Yoon S" first="Seungtai" last="Yoon">Seungtai Yoon</name>
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<affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Department of Psychiatry, Mount Sinai School of Medicine</s1>
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<author><name sortKey="Maguire, Jared" sort="Maguire, Jared" uniqKey="Maguire J" first="Jared" last="Maguire">Jared Maguire</name>
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<author><name sortKey="Crawford, Emily L" sort="Crawford, Emily L" uniqKey="Crawford E" first="Emily L." last="Crawford">Emily L. Crawford</name>
<affiliation wicri:level="1"><inist:fA14 i1="10"><s1>Vanderbilt Brain institute, Departments of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University</s1>
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<author><name sortKey="Campbell, Nicholas G" sort="Campbell, Nicholas G" uniqKey="Campbell N" first="Nicholas G." last="Campbell">Nicholas G. Campbell</name>
<affiliation wicri:level="1"><inist:fA14 i1="10"><s1>Vanderbilt Brain institute, Departments of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University</s1>
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<author><name sortKey="Geher, Evan T" sort="Geher, Evan T" uniqKey="Geher E" first="Evan T." last="Geher">Evan T. Geher</name>
<affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Patho ogy and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania</s1>
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<author><name sortKey="Valladares, Otto" sort="Valladares, Otto" uniqKey="Valladares O" first="Otto" last="Valladares">Otto Valladares</name>
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<author><name sortKey="Schafer, Chad" sort="Schafer, Chad" uniqKey="Schafer C" first="Chad" last="Schafer">Chad Schafer</name>
<affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Department of Statistics, Carnegie Mellon University</s1>
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<author><name sortKey="Liul, Han" sort="Liul, Han" uniqKey="Liul H" first="Han" last="Liul">Han Liul</name>
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<author><name sortKey="Tuo Zhao" sort="Tuo Zhao" uniqKey="Tuo Zhao" last="Tuo Zhao">TUO ZHAO</name>
<affiliation wicri:level="1"><inist:fA14 i1="11"><s1>Biostatistics Department and Computer Science Department, Johns Hopkins University</s1>
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<author><name sortKey="Guiqing Cai" sort="Guiqing Cai" uniqKey="Guiqing Cai" last="Guiqing Cai">GUIQING CAI</name>
<affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine</s1>
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<affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Department of Psychiatry, Mount Sinai School of Medicine</s1>
<s2>New York, New York 10029</s2>
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<author><name sortKey="Lihm, Jayon" sort="Lihm, Jayon" uniqKey="Lihm J" first="Jayon" last="Lihm">Jayon Lihm</name>
<affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine</s1>
<s2>New York, New York 10029</s2>
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<affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Department of Psychiatry, Mount Sinai School of Medicine</s1>
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<author><name sortKey="Dannenfelser, Ruth" sort="Dannenfelser, Ruth" uniqKey="Dannenfelser R" first="Ruth" last="Dannenfelser">Ruth Dannenfelser</name>
<affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine</s1>
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<author><name sortKey="Jabado, Omar" sort="Jabado, Omar" uniqKey="Jabado O" first="Omar" last="Jabado">Omar Jabado</name>
<affiliation wicri:level="1"><inist:fA14 i1="12"><s1>Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine</s1>
<s2>New York, New York 10029</s2>
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<country>États-Unis</country>
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<author><name sortKey="Peralta, Zuleyma" sort="Peralta, Zuleyma" uniqKey="Peralta Z" first="Zuleyma" last="Peralta">Zuleyma Peralta</name>
<affiliation wicri:level="1"><inist:fA14 i1="12"><s1>Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine</s1>
<s2>New York, New York 10029</s2>
<s3>USA</s3>
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<country>États-Unis</country>
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<author><name sortKey="Nagaswamy, Uma" sort="Nagaswamy, Uma" uniqKey="Nagaswamy U" first="Uma" last="Nagaswamy">Uma Nagaswamy</name>
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</affiliation>
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<author><name sortKey="Muzny, Donna" sort="Muzny, Donna" uniqKey="Muzny D" first="Donna" last="Muzny">Donna Muzny</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Human Genome Sequencing Center, Baylor College of Medicine</s1>
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</affiliation>
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<author><name sortKey="Reid, Jeffrey G" sort="Reid, Jeffrey G" uniqKey="Reid J" first="Jeffrey G." last="Reid">Jeffrey G. Reid</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Human Genome Sequencing Center, Baylor College of Medicine</s1>
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</affiliation>
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<author><name sortKey="Newsham, Irene" sort="Newsham, Irene" uniqKey="Newsham I" first="Irene" last="Newsham">Irene Newsham</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Human Genome Sequencing Center, Baylor College of Medicine</s1>
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<country>États-Unis</country>
</affiliation>
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<author><name sortKey="Yuanqing Wu" sort="Yuanqing Wu" uniqKey="Yuanqing Wu" last="Yuanqing Wu">YUANQING WU</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Human Genome Sequencing Center, Baylor College of Medicine</s1>
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<country>États-Unis</country>
</affiliation>
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<author><name sortKey="Lewis, Lora" sort="Lewis, Lora" uniqKey="Lewis L" first="Lora" last="Lewis">Lora Lewis</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Human Genome Sequencing Center, Baylor College of Medicine</s1>
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<country>États-Unis</country>
</affiliation>
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<author><name sortKey="Yi Han" sort="Yi Han" uniqKey="Yi Han" last="Yi Han">YI HAN</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Human Genome Sequencing Center, Baylor College of Medicine</s1>
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<country>États-Unis</country>
</affiliation>
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<author><name sortKey="Voight, Benjamin F" sort="Voight, Benjamin F" uniqKey="Voight B" first="Benjamin F." last="Voight">Benjamin F. Voight</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
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<country>États-Unis</country>
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<affiliation wicri:level="1"><inist:fA14 i1="13"><s1>Department of Pharmacology, University of Pennsylvania, Perelman School of Medicine</s1>
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<country>États-Unis</country>
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<author><name sortKey="Lim, Elaine" sort="Lim, Elaine" uniqKey="Lim E" first="Elaine" last="Lim">Elaine Lim</name>
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<country>États-Unis</country>
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<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
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<author><name sortKey="Rossin, Elizabeth" sort="Rossin, Elizabeth" uniqKey="Rossin E" first="Elizabeth" last="Rossin">Elizabeth Rossin</name>
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<country>États-Unis</country>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
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<country>États-Unis</country>
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<author><name sortKey="Kirby, Andrew" sort="Kirby, Andrew" uniqKey="Kirby A" first="Andrew" last="Kirby">Andrew Kirby</name>
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<country>États-Unis</country>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
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<author><name sortKey="Flannick, Jason" sort="Flannick, Jason" uniqKey="Flannick J" first="Jason" last="Flannick">Jason Flannick</name>
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<country>États-Unis</country>
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<author><name sortKey="Fromer, Menachem" sort="Fromer, Menachem" uniqKey="Fromer M" first="Menachem" last="Fromer">Menachem Fromer</name>
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<country>États-Unis</country>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
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<country>États-Unis</country>
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<author><name sortKey="Shakir, Khalid" sort="Shakir, Khalid" uniqKey="Shakir K" first="Khalid" last="Shakir">Khalid Shakir</name>
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<country>États-Unis</country>
</affiliation>
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<author><name sortKey="Fennell, Tim" sort="Fennell, Tim" uniqKey="Fennell T" first="Tim" last="Fennell">Tim Fennell</name>
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<country>États-Unis</country>
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<author><name sortKey="Garimella, Kiran" sort="Garimella, Kiran" uniqKey="Garimella K" first="Kiran" last="Garimella">Kiran Garimella</name>
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<country>États-Unis</country>
</affiliation>
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<author><name sortKey="Banks, Eric" sort="Banks, Eric" uniqKey="Banks E" first="Eric" last="Banks">Eric Banks</name>
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<country>États-Unis</country>
</affiliation>
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<author><name sortKey="Poplin, Ryan" sort="Poplin, Ryan" uniqKey="Poplin R" first="Ryan" last="Poplin">Ryan Poplin</name>
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<country>États-Unis</country>
</affiliation>
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<author><name sortKey="Gabriel, Stacey" sort="Gabriel, Stacey" uniqKey="Gabriel S" first="Stacey" last="Gabriel">Stacey Gabriel</name>
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<author><name sortKey="Wimbish, Jack R" sort="Wimbish, Jack R" uniqKey="Wimbish J" first="Jack R." last="Wimbish">Jack R. Wimbish</name>
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<affiliation wicri:level="1"><inist:fA14 i1="14"><s1>HudsonAlpha Institute for Biotechnology</s1>
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<author><name sortKey="Sunyaev, Shamil" sort="Sunyaev, Shamil" uniqKey="Sunyaev S" first="Shamil" last="Sunyaev">Shamil Sunyaev</name>
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<author><name sortKey="Buxbaum, Joseph D" sort="Buxbaum, Joseph D" uniqKey="Buxbaum J" first="Joseph D." last="Buxbaum">Joseph D. Buxbaum</name>
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<affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Department of Psychiatry, Mount Sinai School of Medicine</s1>
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<affiliation wicri:level="1"><inist:fA14 i1="12"><s1>Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine</s1>
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<author><name sortKey="Cook, Edwin H Jr" sort="Cook, Edwin H Jr" uniqKey="Cook E" first="Edwin H. Jr" last="Cook">Edwin H. Jr Cook</name>
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<author><name sortKey="Gibbs, Richard A" sort="Gibbs, Richard A" uniqKey="Gibbs R" first="Richard A." last="Gibbs">Richard A. Gibbs</name>
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</affiliation>
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<author><name sortKey="Roeder, Kathryn" sort="Roeder, Kathryn" uniqKey="Roeder K" first="Kathryn" last="Roeder">Kathryn Roeder</name>
<affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Department of Statistics, Carnegie Mellon University</s1>
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<author><name sortKey="Schellenberg, Gerard D" sort="Schellenberg, Gerard D" uniqKey="Schellenberg G" first="Gerard D." last="Schellenberg">Gerard D. Schellenberg</name>
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<author><name sortKey="Sutcliffe, James S" sort="Sutcliffe, James S" uniqKey="Sutcliffe J" first="James S." last="Sutcliffe">James S. Sutcliffe</name>
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<author><name sortKey="Daly, Mark J" sort="Daly, Mark J" uniqKey="Daly M" first="Mark J." last="Daly">Mark J. Daly</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School</s1>
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</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
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</titleStmt>
<publicationStmt><idno type="wicri:source">INIST</idno>
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<idno type="wicri:Area/PascalFrancis/Corpus">004F65</idno>
<idno type="wicri:Area/PascalFrancis/Curation">001724</idno>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Patterns and rates of exonic de novo mutations in autism spectrum disorders</title>
<author><name sortKey="Neale, Benjamin M" sort="Neale, Benjamin M" uniqKey="Neale B" first="Benjamin M." last="Neale">Benjamin M. Neale</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School</s1>
<s2>Boston, Massachusetts 02114</s2>
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<sZ>1 aut.</sZ>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
<s2>Cambridge, Massachusetts 02142</s2>
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<sZ>1 aut.</sZ>
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<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Yan Kou" sort="Yan Kou" uniqKey="Yan Kou" last="Yan Kou">YAN KOU</name>
<affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine</s1>
<s2>New York, New York 10029</s2>
<s3>USA</s3>
<sZ>2 aut.</sZ>
<sZ>4 aut.</sZ>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine</s1>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Li Liu" sort="Li Liu" uniqKey="Li Liu" last="Li Liu">LI LIU</name>
<affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Department of Statistics, Carnegie Mellon University</s1>
<s2>Pittsburgh, Pennsylvania 15232</s2>
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<sZ>3 aut.</sZ>
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</affiliation>
</author>
<author><name sortKey="Ma Ayan, Avi" sort="Ma Ayan, Avi" uniqKey="Ma Ayan A" first="Avi" last="Ma'Ayan">Avi Ma'Ayan</name>
<affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine</s1>
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<sZ>2 aut.</sZ>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Samocha, Kaitlin E" sort="Samocha, Kaitlin E" uniqKey="Samocha K" first="Kaitlin E." last="Samocha">Kaitlin E. Samocha</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School</s1>
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<country>États-Unis</country>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
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<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Sabo, Aniko" sort="Sabo, Aniko" uniqKey="Sabo A" first="Aniko" last="Sabo">Aniko Sabo</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Human Genome Sequencing Center, Baylor College of Medicine</s1>
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<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Lin, Chiao Feng" sort="Lin, Chiao Feng" uniqKey="Lin C" first="Chiao-Feng" last="Lin">Chiao-Feng Lin</name>
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<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Stevens, Christine" sort="Stevens, Christine" uniqKey="Stevens C" first="Christine" last="Stevens">Christine Stevens</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
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<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Wang, Li San" sort="Wang, Li San" uniqKey="Wang L" first="Li-San" last="Wang">Li-San Wang</name>
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<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Makarov, Vladimir" sort="Makarov, Vladimir" uniqKey="Makarov V" first="Vladimir" last="Makarov">Vladimir Makarov</name>
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<sZ>10 aut.</sZ>
<sZ>12 aut.</sZ>
<sZ>21 aut.</sZ>
<sZ>22 aut.</sZ>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Department of Psychiatry, Mount Sinai School of Medicine</s1>
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<country>États-Unis</country>
</affiliation>
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<author><name sortKey="Polak, Paz" sort="Polak, Paz" uniqKey="Polak P" first="Paz" last="Polak">Paz Polak</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
<s2>Cambridge, Massachusetts 02142</s2>
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<sZ>50 aut.</sZ>
<sZ>59 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="09"><s1>Division of Genetics, Department of Medicine Brigham & Women's Hospital and Harvard Medical School</s1>
<s2>Boston, Massachusetts 02115</s2>
<s3>USA</s3>
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<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Yoon, Seungtai" sort="Yoon, Seungtai" uniqKey="Yoon S" first="Seungtai" last="Yoon">Seungtai Yoon</name>
<affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine</s1>
<s2>New York, New York 10029</s2>
<s3>USA</s3>
<sZ>2 aut.</sZ>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Department of Psychiatry, Mount Sinai School of Medicine</s1>
<s2>New York, New York 10029</s2>
<s3>USA</s3>
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<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Maguire, Jared" sort="Maguire, Jared" uniqKey="Maguire J" first="Jared" last="Maguire">Jared Maguire</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
<s2>Cambridge, Massachusetts 02142</s2>
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<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Crawford, Emily L" sort="Crawford, Emily L" uniqKey="Crawford E" first="Emily L." last="Crawford">Emily L. Crawford</name>
<affiliation wicri:level="1"><inist:fA14 i1="10"><s1>Vanderbilt Brain institute, Departments of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University</s1>
<s2>Nashville, Tennessee 37232</s2>
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<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Campbell, Nicholas G" sort="Campbell, Nicholas G" uniqKey="Campbell N" first="Nicholas G." last="Campbell">Nicholas G. Campbell</name>
<affiliation wicri:level="1"><inist:fA14 i1="10"><s1>Vanderbilt Brain institute, Departments of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University</s1>
<s2>Nashville, Tennessee 37232</s2>
<s3>USA</s3>
<sZ>14 aut.</sZ>
<sZ>15 aut.</sZ>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Geher, Evan T" sort="Geher, Evan T" uniqKey="Geher E" first="Evan T." last="Geher">Evan T. Geher</name>
<affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Patho ogy and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania</s1>
<s2>Philadelphia, Pennsylvania 19104</s2>
<s3>USA</s3>
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<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Valladares, Otto" sort="Valladares, Otto" uniqKey="Valladares O" first="Otto" last="Valladares">Otto Valladares</name>
<affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Patho ogy and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania</s1>
<s2>Philadelphia, Pennsylvania 19104</s2>
<s3>USA</s3>
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<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Schafer, Chad" sort="Schafer, Chad" uniqKey="Schafer C" first="Chad" last="Schafer">Chad Schafer</name>
<affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Department of Statistics, Carnegie Mellon University</s1>
<s2>Pittsburgh, Pennsylvania 15232</s2>
<s3>USA</s3>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Liul, Han" sort="Liul, Han" uniqKey="Liul H" first="Han" last="Liul">Han Liul</name>
<affiliation wicri:level="1"><inist:fA14 i1="11"><s1>Biostatistics Department and Computer Science Department, Johns Hopkins University</s1>
<s2>Baltimore, Maryland 21205</s2>
<s3>USA</s3>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Tuo Zhao" sort="Tuo Zhao" uniqKey="Tuo Zhao" last="Tuo Zhao">TUO ZHAO</name>
<affiliation wicri:level="1"><inist:fA14 i1="11"><s1>Biostatistics Department and Computer Science Department, Johns Hopkins University</s1>
<s2>Baltimore, Maryland 21205</s2>
<s3>USA</s3>
<sZ>19 aut.</sZ>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Guiqing Cai" sort="Guiqing Cai" uniqKey="Guiqing Cai" last="Guiqing Cai">GUIQING CAI</name>
<affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine</s1>
<s2>New York, New York 10029</s2>
<s3>USA</s3>
<sZ>2 aut.</sZ>
<sZ>10 aut.</sZ>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Department of Psychiatry, Mount Sinai School of Medicine</s1>
<s2>New York, New York 10029</s2>
<s3>USA</s3>
<sZ>10 aut.</sZ>
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<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Lihm, Jayon" sort="Lihm, Jayon" uniqKey="Lihm J" first="Jayon" last="Lihm">Jayon Lihm</name>
<affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine</s1>
<s2>New York, New York 10029</s2>
<s3>USA</s3>
<sZ>2 aut.</sZ>
<sZ>10 aut.</sZ>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Department of Psychiatry, Mount Sinai School of Medicine</s1>
<s2>New York, New York 10029</s2>
<s3>USA</s3>
<sZ>10 aut.</sZ>
<sZ>12 aut.</sZ>
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<sZ>22 aut.</sZ>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Dannenfelser, Ruth" sort="Dannenfelser, Ruth" uniqKey="Dannenfelser R" first="Ruth" last="Dannenfelser">Ruth Dannenfelser</name>
<affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine</s1>
<s2>New York, New York 10029</s2>
<s3>USA</s3>
<sZ>2 aut.</sZ>
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<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Jabado, Omar" sort="Jabado, Omar" uniqKey="Jabado O" first="Omar" last="Jabado">Omar Jabado</name>
<affiliation wicri:level="1"><inist:fA14 i1="12"><s1>Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine</s1>
<s2>New York, New York 10029</s2>
<s3>USA</s3>
<sZ>24 aut.</sZ>
<sZ>25 aut.</sZ>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Peralta, Zuleyma" sort="Peralta, Zuleyma" uniqKey="Peralta Z" first="Zuleyma" last="Peralta">Zuleyma Peralta</name>
<affiliation wicri:level="1"><inist:fA14 i1="12"><s1>Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine</s1>
<s2>New York, New York 10029</s2>
<s3>USA</s3>
<sZ>24 aut.</sZ>
<sZ>25 aut.</sZ>
<sZ>52 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Nagaswamy, Uma" sort="Nagaswamy, Uma" uniqKey="Nagaswamy U" first="Uma" last="Nagaswamy">Uma Nagaswamy</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Human Genome Sequencing Center, Baylor College of Medicine</s1>
<s2>Houston, Texas 77030</s2>
<s3>USA</s3>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Muzny, Donna" sort="Muzny, Donna" uniqKey="Muzny D" first="Donna" last="Muzny">Donna Muzny</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Human Genome Sequencing Center, Baylor College of Medicine</s1>
<s2>Houston, Texas 77030</s2>
<s3>USA</s3>
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<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Reid, Jeffrey G" sort="Reid, Jeffrey G" uniqKey="Reid J" first="Jeffrey G." last="Reid">Jeffrey G. Reid</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Human Genome Sequencing Center, Baylor College of Medicine</s1>
<s2>Houston, Texas 77030</s2>
<s3>USA</s3>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Newsham, Irene" sort="Newsham, Irene" uniqKey="Newsham I" first="Irene" last="Newsham">Irene Newsham</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Human Genome Sequencing Center, Baylor College of Medicine</s1>
<s2>Houston, Texas 77030</s2>
<s3>USA</s3>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Yuanqing Wu" sort="Yuanqing Wu" uniqKey="Yuanqing Wu" last="Yuanqing Wu">YUANQING WU</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Human Genome Sequencing Center, Baylor College of Medicine</s1>
<s2>Houston, Texas 77030</s2>
<s3>USA</s3>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Lewis, Lora" sort="Lewis, Lora" uniqKey="Lewis L" first="Lora" last="Lewis">Lora Lewis</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Human Genome Sequencing Center, Baylor College of Medicine</s1>
<s2>Houston, Texas 77030</s2>
<s3>USA</s3>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Yi Han" sort="Yi Han" uniqKey="Yi Han" last="Yi Han">YI HAN</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Human Genome Sequencing Center, Baylor College of Medicine</s1>
<s2>Houston, Texas 77030</s2>
<s3>USA</s3>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Voight, Benjamin F" sort="Voight, Benjamin F" uniqKey="Voight B" first="Benjamin F." last="Voight">Benjamin F. Voight</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
<s2>Cambridge, Massachusetts 02142</s2>
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<sZ>1 aut.</sZ>
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<sZ>45 aut.</sZ>
<sZ>50 aut.</sZ>
<sZ>59 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="13"><s1>Department of Pharmacology, University of Pennsylvania, Perelman School of Medicine</s1>
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<s3>USA</s3>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Lim, Elaine" sort="Lim, Elaine" uniqKey="Lim E" first="Elaine" last="Lim">Elaine Lim</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School</s1>
<s2>Boston, Massachusetts 02114</s2>
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<sZ>1 aut.</sZ>
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<sZ>38 aut.</sZ>
<sZ>59 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
<s2>Cambridge, Massachusetts 02142</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
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<sZ>50 aut.</sZ>
<sZ>59 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Rossin, Elizabeth" sort="Rossin, Elizabeth" uniqKey="Rossin E" first="Elizabeth" last="Rossin">Elizabeth Rossin</name>
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<s2>Boston, Massachusetts 02114</s2>
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<sZ>1 aut.</sZ>
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<sZ>38 aut.</sZ>
<sZ>59 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
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<s3>USA</s3>
<sZ>1 aut.</sZ>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Kirby, Andrew" sort="Kirby, Andrew" uniqKey="Kirby A" first="Andrew" last="Kirby">Andrew Kirby</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School</s1>
<s2>Boston, Massachusetts 02114</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>5 aut.</sZ>
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<sZ>36 aut.</sZ>
<sZ>38 aut.</sZ>
<sZ>59 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
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<author><name sortKey="Fromer, Menachem" sort="Fromer, Menachem" uniqKey="Fromer M" first="Menachem" last="Fromer">Menachem Fromer</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School</s1>
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<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
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<author><name sortKey="Shakir, Khalid" sort="Shakir, Khalid" uniqKey="Shakir K" first="Khalid" last="Shakir">Khalid Shakir</name>
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<author><name sortKey="Fennell, Tim" sort="Fennell, Tim" uniqKey="Fennell T" first="Tim" last="Fennell">Tim Fennell</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
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<author><name sortKey="Garimella, Kiran" sort="Garimella, Kiran" uniqKey="Garimella K" first="Kiran" last="Garimella">Kiran Garimella</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
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<author><name sortKey="Banks, Eric" sort="Banks, Eric" uniqKey="Banks E" first="Eric" last="Banks">Eric Banks</name>
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<country>États-Unis</country>
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<author><name sortKey="Poplin, Ryan" sort="Poplin, Ryan" uniqKey="Poplin R" first="Ryan" last="Poplin">Ryan Poplin</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
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<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Gabriel, Stacey" sort="Gabriel, Stacey" uniqKey="Gabriel S" first="Stacey" last="Gabriel">Stacey Gabriel</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
<s2>Cambridge, Massachusetts 02142</s2>
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<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Depristo, Mark" sort="Depristo, Mark" uniqKey="Depristo M" first="Mark" last="Depristo">Mark Depristo</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
<s2>Cambridge, Massachusetts 02142</s2>
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<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Wimbish, Jack R" sort="Wimbish, Jack R" uniqKey="Wimbish J" first="Jack R." last="Wimbish">Jack R. Wimbish</name>
<affiliation wicri:level="1"><inist:fA14 i1="14"><s1>HudsonAlpha Institute for Biotechnology</s1>
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<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Boone, Braden E" sort="Boone, Braden E" uniqKey="Boone B" first="Braden E." last="Boone">Braden E. Boone</name>
<affiliation wicri:level="1"><inist:fA14 i1="14"><s1>HudsonAlpha Institute for Biotechnology</s1>
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<sZ>46 aut.</sZ>
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<country>États-Unis</country>
</affiliation>
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<author><name sortKey="Levy, Shawn E" sort="Levy, Shawn E" uniqKey="Levy S" first="Shawn E." last="Levy">Shawn E. Levy</name>
<affiliation wicri:level="1"><inist:fA14 i1="14"><s1>HudsonAlpha Institute for Biotechnology</s1>
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<s3>USA</s3>
<sZ>46 aut.</sZ>
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</affiliation>
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<author><name sortKey="Betancur, Catalina" sort="Betancur, Catalina" uniqKey="Betancur C" first="Catalina" last="Betancur">Catalina Betancur</name>
<affiliation wicri:level="1"><inist:fA14 i1="15"><s1>INSERM U952 and CNRS UMR 7224 and UPMC Univ Paris 06</s1>
<s2>75005 Paris</s2>
<s3>FRA</s3>
<sZ>49 aut.</sZ>
</inist:fA14>
<country>France</country>
</affiliation>
</author>
<author><name sortKey="Sunyaev, Shamil" sort="Sunyaev, Shamil" uniqKey="Sunyaev S" first="Shamil" last="Sunyaev">Shamil Sunyaev</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
<s2>Cambridge, Massachusetts 02142</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="09"><s1>Division of Genetics, Department of Medicine Brigham & Women's Hospital and Harvard Medical School</s1>
<s2>Boston, Massachusetts 02115</s2>
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</affiliation>
</author>
<author><name sortKey="Boerwinkle, Eric" sort="Boerwinkle, Eric" uniqKey="Boerwinkle E" first="Eric" last="Boerwinkle">Eric Boerwinkle</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Human Genome Sequencing Center, Baylor College of Medicine</s1>
<s2>Houston, Texas 77030</s2>
<s3>USA</s3>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="16"><s1>Human Genetics Center, University of Texas Health Science Center at Houston</s1>
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<sZ>51 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
</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 wicri:level="1"><inist:fA14 i1="04"><s1>Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine</s1>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Department of Psychiatry, Mount Sinai School of Medicine</s1>
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<s3>USA</s3>
<sZ>10 aut.</sZ>
<sZ>12 aut.</sZ>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="12"><s1>Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine</s1>
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<s3>USA</s3>
<sZ>24 aut.</sZ>
<sZ>25 aut.</sZ>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="17"><s1>Friedman Brain Institute, Mount Sinai School of Medicine</s1>
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<sZ>52 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Cook, Edwin H Jr" sort="Cook, Edwin H Jr" uniqKey="Cook E" first="Edwin H. Jr" last="Cook">Edwin H. Jr Cook</name>
<affiliation wicri:level="1"><inist:fA14 i1="18"><s1>Department of Psychiatry, University of Illinois at Chicago</s1>
<s2>Chicago, Illinois 60608</s2>
<s3>USA</s3>
<sZ>53 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Devlin, Bernie" sort="Devlin, Bernie" uniqKey="Devlin B" first="Bernie" last="Devlin">Bernie Devlin</name>
</author>
<author><name sortKey="Gibbs, Richard A" sort="Gibbs, Richard A" uniqKey="Gibbs R" first="Richard A." last="Gibbs">Richard A. Gibbs</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Human Genome Sequencing Center, Baylor College of Medicine</s1>
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<sZ>6 aut.</sZ>
<sZ>26 aut.</sZ>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Roeder, Kathryn" sort="Roeder, Kathryn" uniqKey="Roeder K" first="Kathryn" last="Roeder">Kathryn Roeder</name>
<affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Department of Statistics, Carnegie Mellon University</s1>
<s2>Pittsburgh, Pennsylvania 15232</s2>
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<sZ>3 aut.</sZ>
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</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 wicri:level="1"><inist:fA14 i1="07"><s1>Patho ogy and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania</s1>
<s2>Philadelphia, Pennsylvania 19104</s2>
<s3>USA</s3>
<sZ>7 aut.</sZ>
<sZ>9 aut.</sZ>
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<country>États-Unis</country>
</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 wicri:level="1"><inist:fA14 i1="10"><s1>Vanderbilt Brain institute, Departments of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University</s1>
<s2>Nashville, Tennessee 37232</s2>
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<sZ>14 aut.</sZ>
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</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 wicri:level="1"><inist:fA14 i1="01"><s1>Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School</s1>
<s2>Boston, Massachusetts 02114</s2>
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<sZ>1 aut.</sZ>
<sZ>5 aut.</sZ>
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<sZ>38 aut.</sZ>
<sZ>59 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center</s1>
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<sZ>1 aut.</sZ>
<sZ>5 aut.</sZ>
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</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
</analytic>
<series><title level="j" type="main">Nature : (London)</title>
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<term>Mutation</term>
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<front><div type="abstract" xml:lang="en">Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified<sup>1,2</sup>
, To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes<sup>3</sup>
as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.</div>
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