AustralieFrV1, Main, Exploration, bibRecord, 001E23

Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures

Identifieur interne : 001E23 ( Main/Exploration ); précédent : 001E22; suivant : 001E24

Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures

Auteurs : Slavé Petrovski [États-Unis, Australie] ; Sébastien Küry [France] ; Candace T. Myers [États-Unis] ; Kwame Anyane-Yeboa [États-Unis] ; Benjamin Cogné [France] ; Martin Bialer [États-Unis] ; Fan Xia [États-Unis] ; Parisa Hemati [États-Unis] ; James Riviello [États-Unis] ; Michele Mehaffey [États-Unis] ; Thomas Besnard [France] ; Emily Becraft [États-Unis] ; Alexandrea Wadley [États-Unis] ; Anya Revah Politi [États-Unis] ; Sophie Colombo [États-Unis] ; Xiaolin Zhu [États-Unis] ; Zhong Ren [États-Unis] ; Ian Andrews [Australie] ; Tracy Dudding-Byth [Australie] ; Amy L. Schneider [Australie] ; Geoffrey Wallace [Australie] ; Aaron B. I. Rosen [États-Unis] ; Susan Schelley [États-Unis] ; Gregory M. Enns [États-Unis] ; Pierre Corre [France] ; Joline Dalton [États-Unis] ; Sandra Mercier [France] ; Xénia Latypova [France] ; Sébastien Schmitt [France] ; Edwin Guzman [États-Unis] ; Christine Moore [États-Unis] ; Louise Bier [États-Unis] ; Erin L. Heinzen [États-Unis] ; Peter Karachunski [États-Unis] ; Natasha Shur [États-Unis] ; Theresa Grebe [États-Unis] ; Alice Basinger [États-Unis] ; Joanne M. Nguyen [États-Unis] ; Stéphane Bézieau [France] ; Klaas Wierenga [États-Unis] ; Jonathan A. Bernstein [États-Unis] ; Ingrid E. Scheffer [Australie] ; Jill A. Rosenfeld [États-Unis] ; Heather C. Mefford [États-Unis] ; Bertrand Isidor [France] ; David B. Goldstein [États-Unis]

Source :

American Journal of Human Genetics [ 0002-9297 ] ; 2016.

RBID : PMC:4863562

Descripteurs français

English descriptors

KwdEn :
- Adolescent, Adult, Child, Child, Preschool, Developmental Disabilities (etiology), Developmental Disabilities (pathology), Exome (genetics), Female, GTP-Binding Protein beta Subunits (chemistry), GTP-Binding Protein beta Subunits (genetics), Germ-Line Mutation (genetics), Humans, Infant, Intellectual Disability (etiology), Intellectual Disability (pathology), Male, Muscle Hypotonia (etiology), Muscle Hypotonia (pathology), Phenotype, Protein Conformation, Seizures (etiology), Seizures (pathology), Signal Transduction, Young Adult.
MESH :
- chemical , chemistry : GTP-Binding Protein beta Subunits.
- etiology : Developmental Disabilities, Intellectual Disability, Muscle Hypotonia, Seizures.
- genetics : Exome, GTP-Binding Protein beta Subunits, Germ-Line Mutation.
- pathology : Developmental Disabilities, Intellectual Disability, Muscle Hypotonia, Seizures.
- Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Male, Phenotype, Protein Conformation, Signal Transduction, Young Adult.

Abstract

Whole-exome sequencing of 13 individuals with developmental delay commonly accompanied by abnormal muscle tone and seizures identified de novo missense mutations enriched within a sub-region of GNB1, a gene encoding the guanine nucleotide-binding protein subunit beta-1, Gβ. These 13 individuals were identified among a base of 5,855 individuals recruited for various undiagnosed genetic disorders. The probability of observing 13 or more de novo mutations by chance among 5,855 individuals is very low (p = 7.1 × 10⁻²¹), implicating GNB1 as a genome-wide-significant disease-associated gene. The majority of these 13 mutations affect known Gβ binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for Gα-Gβγ interaction (resulting in a constitutively active Gβγ) or through the disruption of residues relevant for interaction between Gβγ and certain downstream effectors (resulting in reduced interaction with the effectors). Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo GNB1 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863562

DOI: 10.1016/j.ajhg.2016.03.011
PubMed: 27108799
PubMed Central: 4863562

Affiliations:

Le document en format XML

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<author><name sortKey="Xia, Fan" sort="Xia, Fan" uniqKey="Xia F" first="Fan" last="Xia">Fan Xia</name>
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<country xml:lang="fr">Australie</country>
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<author><name sortKey="Schneider, Amy L" sort="Schneider, Amy L" uniqKey="Schneider A" first="Amy L." last="Schneider">Amy L. Schneider</name>
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<country xml:lang="fr">Australie</country>
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<wicri:regionArea>Department of Neurosciences, Royal Children’s Hospital, Herston School of Medicine, University of Queensland, Brisbane, QLD 4072</wicri:regionArea>
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<author><name sortKey="Schelley, Susan" sort="Schelley, Susan" uniqKey="Schelley S" first="Susan" last="Schelley">Susan Schelley</name>
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<author><name sortKey="Enns, Gregory M" sort="Enns, Gregory M" uniqKey="Enns G" first="Gregory M." last="Enns">Gregory M. Enns</name>
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<author><name sortKey="Corre, Pierre" sort="Corre, Pierre" uniqKey="Corre P" first="Pierre" last="Corre">Pierre Corre</name>
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<author><name sortKey="Dalton, Joline" sort="Dalton, Joline" uniqKey="Dalton J" first="Joline" last="Dalton">Joline Dalton</name>
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<author><name sortKey="Mercier, Sandra" sort="Mercier, Sandra" uniqKey="Mercier S" first="Sandra" last="Mercier">Sandra Mercier</name>
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<author><name sortKey="Latypova, Xenia" sort="Latypova, Xenia" uniqKey="Latypova X" first="Xénia" last="Latypova">Xénia Latypova</name>
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<author><name sortKey="Schmitt, Sebastien" sort="Schmitt, Sebastien" uniqKey="Schmitt S" first="Sébastien" last="Schmitt">Sébastien Schmitt</name>
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<country xml:lang="fr">France</country>
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<author><name sortKey="Guzman, Edwin" sort="Guzman, Edwin" uniqKey="Guzman E" first="Edwin" last="Guzman">Edwin Guzman</name>
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<country xml:lang="fr">États-Unis</country>
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<author><name sortKey="Moore, Christine" sort="Moore, Christine" uniqKey="Moore C" first="Christine" last="Moore">Christine Moore</name>
<affiliation wicri:level="2"><nlm:aff id="aff6">Division of Medical Genetics, Northwell Health, Manhasset, NY 11030, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Medical Genetics, Northwell Health, Manhasset, NY 11030</wicri:regionArea>
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</placeName>
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</author>
<author><name sortKey="Bier, Louise" sort="Bier, Louise" uniqKey="Bier L" first="Louise" last="Bier">Louise Bier</name>
<affiliation wicri:level="4"><nlm:aff id="aff1">Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Institute for Genomic Medicine, Columbia University, New York, NY 10032</wicri:regionArea>
<placeName><region type="state">État de New York</region>
<settlement type="city">New York</settlement>
</placeName>
<orgName type="university">Université Columbia</orgName>
</affiliation>
</author>
<author><name sortKey="Heinzen, Erin L" sort="Heinzen, Erin L" uniqKey="Heinzen E" first="Erin L." last="Heinzen">Erin L. Heinzen</name>
<affiliation wicri:level="4"><nlm:aff id="aff1">Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Institute for Genomic Medicine, Columbia University, New York, NY 10032</wicri:regionArea>
<placeName><region type="state">État de New York</region>
<settlement type="city">New York</settlement>
</placeName>
<orgName type="university">Université Columbia</orgName>
</affiliation>
</author>
<author><name sortKey="Karachunski, Peter" sort="Karachunski, Peter" uniqKey="Karachunski P" first="Peter" last="Karachunski">Peter Karachunski</name>
<affiliation wicri:level="2"><nlm:aff id="aff16">Department of Neurology, University of Minnesota, Minneapolis, MN 55454, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurology, University of Minnesota, Minneapolis, MN 55454</wicri:regionArea>
<placeName><region type="state">Minnesota</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Shur, Natasha" sort="Shur, Natasha" uniqKey="Shur N" first="Natasha" last="Shur">Natasha Shur</name>
<affiliation wicri:level="2"><nlm:aff id="aff17">Division of Genetics, Department of Pediatrics, Albany Medical Center, Albany, NY 12208, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Genetics, Department of Pediatrics, Albany Medical Center, Albany, NY 12208</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Grebe, Theresa" sort="Grebe, Theresa" uniqKey="Grebe T" first="Theresa" last="Grebe">Theresa Grebe</name>
<affiliation wicri:level="2"><nlm:aff id="aff18">Phoenix Children’s Hospital and Department of Child Health, University of Arizona College of Medicine, Phoenix, AZ 85724, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Phoenix Children’s Hospital and Department of Child Health, University of Arizona College of Medicine, Phoenix, AZ 85724</wicri:regionArea>
<placeName><region type="state">Arizona</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Basinger, Alice" sort="Basinger, Alice" uniqKey="Basinger A" first="Alice" last="Basinger">Alice Basinger</name>
<affiliation wicri:level="2"><nlm:aff id="aff19">Cook Children’s Physician Network, Fort Worth, TX 76102, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Cook Children’s Physician Network, Fort Worth, TX 76102</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Nguyen, Joanne M" sort="Nguyen, Joanne M" uniqKey="Nguyen J" first="Joanne M." last="Nguyen">Joanne M. Nguyen</name>
<affiliation wicri:level="2"><nlm:aff id="aff20">Division of Medical Genetics, Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Medical Genetics, Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX 77030</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bezieau, Stephane" sort="Bezieau, Stephane" uniqKey="Bezieau S" first="Stéphane" last="Bézieau">Stéphane Bézieau</name>
<affiliation wicri:level="3"><nlm:aff id="aff3">Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093</wicri:regionArea>
<placeName><region type="region" nuts="2">Pays de la Loire</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Wierenga, Klaas" sort="Wierenga, Klaas" uniqKey="Wierenga K" first="Klaas" last="Wierenga">Klaas Wierenga</name>
<affiliation wicri:level="2"><nlm:aff id="aff9">Section of Genetics, Department of Pediatrics, University of Oklahoma, Oklahoma City, OK 73019, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Section of Genetics, Department of Pediatrics, University of Oklahoma, Oklahoma City, OK 73019</wicri:regionArea>
<placeName><region type="state">Oklahoma</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bernstein, Jonathan A" sort="Bernstein, Jonathan A" uniqKey="Bernstein J" first="Jonathan A." last="Bernstein">Jonathan A. Bernstein</name>
<affiliation wicri:level="2"><nlm:aff id="aff8">Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Scheffer, Ingrid E" sort="Scheffer, Ingrid E" uniqKey="Scheffer I" first="Ingrid E." last="Scheffer">Ingrid E. Scheffer</name>
<affiliation wicri:level="4"><nlm:aff id="aff13">Department of Medicine, Austin Health, University of Melbourne, Heidelberg, VIC 3081, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Medicine, Austin Health, University of Melbourne, Heidelberg, VIC 3081</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
</placeName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff21">Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3050, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3050</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
</placeName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff22">Department of Paediatrics, Royal Children’s Hospital, University of Melbourne, Melbourne, VIC 3050, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Paediatrics, Royal Children’s Hospital, University of Melbourne, Melbourne, VIC 3050</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Rosenfeld, Jill A" sort="Rosenfeld, Jill A" uniqKey="Rosenfeld J" first="Jill A." last="Rosenfeld">Jill A. Rosenfeld</name>
<affiliation wicri:level="2"><nlm:aff id="aff7">Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mefford, Heather C" sort="Mefford, Heather C" uniqKey="Mefford H" first="Heather C." last="Mefford">Heather C. Mefford</name>
<affiliation wicri:level="4"><nlm:aff id="aff4">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle WA, 98195, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle WA, 98195</wicri:regionArea>
<orgName type="university">Université de Washington</orgName>
<placeName><settlement type="city">Seattle</settlement>
<region type="state">Washington (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Isidor, Bertrand" sort="Isidor, Bertrand" uniqKey="Isidor B" first="Bertrand" last="Isidor">Bertrand Isidor</name>
<affiliation wicri:level="1"><nlm:aff id="aff3">Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093</wicri:regionArea>
<wicri:noRegion>44093</wicri:noRegion>
<wicri:noRegion>44093</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Goldstein, David B" sort="Goldstein, David B" uniqKey="Goldstein D" first="David B." last="Goldstein">David B. Goldstein</name>
<affiliation wicri:level="4"><nlm:aff id="aff1">Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Institute for Genomic Medicine, Columbia University, New York, NY 10032</wicri:regionArea>
<placeName><region type="state">État de New York</region>
<settlement type="city">New York</settlement>
</placeName>
<orgName type="university">Université Columbia</orgName>
</affiliation>
</author>
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<idno type="pmc">4863562</idno>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Germline De Novo Mutations in <italic>GNB1</italic>
 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures</title>
<author><name sortKey="Petrovski, Slave" sort="Petrovski, Slave" uniqKey="Petrovski S" first="Slavé" last="Petrovski">Slavé Petrovski</name>
<affiliation wicri:level="4"><nlm:aff id="aff1">Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Institute for Genomic Medicine, Columbia University, New York, NY 10032</wicri:regionArea>
<placeName><region type="state">État de New York</region>
<settlement type="city">New York</settlement>
</placeName>
<orgName type="university">Université Columbia</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff2">Department of Medicine, Austin Health and Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC 3050, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Medicine, Austin Health and Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC 3050</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kury, Sebastien" sort="Kury, Sebastien" uniqKey="Kury S" first="Sébastien" last="Küry">Sébastien Küry</name>
<affiliation wicri:level="1"><nlm:aff id="aff3">Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093</wicri:regionArea>
<wicri:noRegion>44093</wicri:noRegion>
<wicri:noRegion>44093</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Myers, Candace T" sort="Myers, Candace T" uniqKey="Myers C" first="Candace T." last="Myers">Candace T. Myers</name>
<affiliation wicri:level="4"><nlm:aff id="aff4">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle WA, 98195, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle WA, 98195</wicri:regionArea>
<orgName type="university">Université de Washington</orgName>
<placeName><settlement type="city">Seattle</settlement>
<region type="state">Washington (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Anyane Yeboa, Kwame" sort="Anyane Yeboa, Kwame" uniqKey="Anyane Yeboa K" first="Kwame" last="Anyane-Yeboa">Kwame Anyane-Yeboa</name>
<affiliation wicri:level="2"><nlm:aff id="aff5">Division of Clinical Genetics, Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Clinical Genetics, Department of Pediatrics, Columbia University Medical Center, New York, NY 10032</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Cogne, Benjamin" sort="Cogne, Benjamin" uniqKey="Cogne B" first="Benjamin" last="Cogné">Benjamin Cogné</name>
<affiliation wicri:level="3"><nlm:aff id="aff3">Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093</wicri:regionArea>
<placeName><region type="region" nuts="2">Pays de la Loire</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bialer, Martin" sort="Bialer, Martin" uniqKey="Bialer M" first="Martin" last="Bialer">Martin Bialer</name>
<affiliation wicri:level="2"><nlm:aff id="aff6">Division of Medical Genetics, Northwell Health, Manhasset, NY 11030, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Medical Genetics, Northwell Health, Manhasset, NY 11030</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Xia, Fan" sort="Xia, Fan" uniqKey="Xia F" first="Fan" last="Xia">Fan Xia</name>
<affiliation wicri:level="2"><nlm:aff id="aff7">Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Hemati, Parisa" sort="Hemati, Parisa" uniqKey="Hemati P" first="Parisa" last="Hemati">Parisa Hemati</name>
<affiliation wicri:level="4"><nlm:aff id="aff1">Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Institute for Genomic Medicine, Columbia University, New York, NY 10032</wicri:regionArea>
<placeName><region type="state">État de New York</region>
<settlement type="city">New York</settlement>
</placeName>
<orgName type="university">Université Columbia</orgName>
</affiliation>
</author>
<author><name sortKey="Riviello, James" sort="Riviello, James" uniqKey="Riviello J" first="James" last="Riviello">James Riviello</name>
<affiliation wicri:level="4"><nlm:aff id="aff1">Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Institute for Genomic Medicine, Columbia University, New York, NY 10032</wicri:regionArea>
<placeName><region type="state">État de New York</region>
<settlement type="city">New York</settlement>
</placeName>
<orgName type="university">Université Columbia</orgName>
</affiliation>
</author>
<author><name sortKey="Mehaffey, Michele" sort="Mehaffey, Michele" uniqKey="Mehaffey M" first="Michele" last="Mehaffey">Michele Mehaffey</name>
<affiliation wicri:level="4"><nlm:aff id="aff4">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle WA, 98195, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle WA, 98195</wicri:regionArea>
<orgName type="university">Université de Washington</orgName>
<placeName><settlement type="city">Seattle</settlement>
<region type="state">Washington (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Besnard, Thomas" sort="Besnard, Thomas" uniqKey="Besnard T" first="Thomas" last="Besnard">Thomas Besnard</name>
<affiliation wicri:level="1"><nlm:aff id="aff3">Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093</wicri:regionArea>
<wicri:noRegion>44093</wicri:noRegion>
<wicri:noRegion>44093</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Becraft, Emily" sort="Becraft, Emily" uniqKey="Becraft E" first="Emily" last="Becraft">Emily Becraft</name>
<affiliation wicri:level="2"><nlm:aff id="aff8">Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Wadley, Alexandrea" sort="Wadley, Alexandrea" uniqKey="Wadley A" first="Alexandrea" last="Wadley">Alexandrea Wadley</name>
<affiliation wicri:level="2"><nlm:aff id="aff9">Section of Genetics, Department of Pediatrics, University of Oklahoma, Oklahoma City, OK 73019, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Section of Genetics, Department of Pediatrics, University of Oklahoma, Oklahoma City, OK 73019</wicri:regionArea>
<placeName><region type="state">Oklahoma</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Politi, Anya Revah" sort="Politi, Anya Revah" uniqKey="Politi A" first="Anya Revah" last="Politi">Anya Revah Politi</name>
<affiliation wicri:level="4"><nlm:aff id="aff1">Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Institute for Genomic Medicine, Columbia University, New York, NY 10032</wicri:regionArea>
<placeName><region type="state">État de New York</region>
<settlement type="city">New York</settlement>
</placeName>
<orgName type="university">Université Columbia</orgName>
</affiliation>
</author>
<author><name sortKey="Colombo, Sophie" sort="Colombo, Sophie" uniqKey="Colombo S" first="Sophie" last="Colombo">Sophie Colombo</name>
<affiliation wicri:level="4"><nlm:aff id="aff1">Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Institute for Genomic Medicine, Columbia University, New York, NY 10032</wicri:regionArea>
<placeName><region type="state">État de New York</region>
<settlement type="city">New York</settlement>
</placeName>
<orgName type="university">Université Columbia</orgName>
</affiliation>
</author>
<author><name sortKey="Zhu, Xiaolin" sort="Zhu, Xiaolin" uniqKey="Zhu X" first="Xiaolin" last="Zhu">Xiaolin Zhu</name>
<affiliation wicri:level="4"><nlm:aff id="aff1">Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Institute for Genomic Medicine, Columbia University, New York, NY 10032</wicri:regionArea>
<placeName><region type="state">État de New York</region>
<settlement type="city">New York</settlement>
</placeName>
<orgName type="university">Université Columbia</orgName>
</affiliation>
</author>
<author><name sortKey="Ren, Zhong" sort="Ren, Zhong" uniqKey="Ren Z" first="Zhong" last="Ren">Zhong Ren</name>
<affiliation wicri:level="4"><nlm:aff id="aff1">Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Institute for Genomic Medicine, Columbia University, New York, NY 10032</wicri:regionArea>
<placeName><region type="state">État de New York</region>
<settlement type="city">New York</settlement>
</placeName>
<orgName type="university">Université Columbia</orgName>
</affiliation>
</author>
<author><name sortKey="Andrews, Ian" sort="Andrews, Ian" uniqKey="Andrews I" first="Ian" last="Andrews">Ian Andrews</name>
<affiliation wicri:level="1"><nlm:aff id="aff10">School of Women’s and Children’s Health, University of New South Wales, Kensington, NSW 2052, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>School of Women’s and Children’s Health, University of New South Wales, Kensington, NSW 2052</wicri:regionArea>
<wicri:noRegion>NSW 2052</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Dudding Byth, Tracy" sort="Dudding Byth, Tracy" uniqKey="Dudding Byth T" first="Tracy" last="Dudding-Byth">Tracy Dudding-Byth</name>
<affiliation wicri:level="1"><nlm:aff id="aff11">Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298</wicri:regionArea>
<wicri:noRegion>NSW 2298</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff12">Priority Research Centre GrowUpWell, University of Newcastle, Callaghan, NSW 2308, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Priority Research Centre GrowUpWell, University of Newcastle, Callaghan, NSW 2308</wicri:regionArea>
<wicri:noRegion>NSW 2308</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Schneider, Amy L" sort="Schneider, Amy L" uniqKey="Schneider A" first="Amy L." last="Schneider">Amy L. Schneider</name>
<affiliation wicri:level="4"><nlm:aff id="aff13">Department of Medicine, Austin Health, University of Melbourne, Heidelberg, VIC 3081, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Medicine, Austin Health, University of Melbourne, Heidelberg, VIC 3081</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Wallace, Geoffrey" sort="Wallace, Geoffrey" uniqKey="Wallace G" first="Geoffrey" last="Wallace">Geoffrey Wallace</name>
<affiliation wicri:level="1"><nlm:aff id="aff14">Department of Neurosciences, Royal Children’s Hospital, Herston School of Medicine, University of Queensland, Brisbane, QLD 4072, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Neurosciences, Royal Children’s Hospital, Herston School of Medicine, University of Queensland, Brisbane, QLD 4072</wicri:regionArea>
<wicri:noRegion>QLD 4072</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Rosen, Aaron B I" sort="Rosen, Aaron B I" uniqKey="Rosen A" first="Aaron B. I." last="Rosen">Aaron B. I. Rosen</name>
<affiliation wicri:level="4"><nlm:aff id="aff4">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle WA, 98195, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle WA, 98195</wicri:regionArea>
<orgName type="university">Université de Washington</orgName>
<placeName><settlement type="city">Seattle</settlement>
<region type="state">Washington (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Schelley, Susan" sort="Schelley, Susan" uniqKey="Schelley S" first="Susan" last="Schelley">Susan Schelley</name>
<affiliation wicri:level="2"><nlm:aff id="aff8">Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Enns, Gregory M" sort="Enns, Gregory M" uniqKey="Enns G" first="Gregory M." last="Enns">Gregory M. Enns</name>
<affiliation wicri:level="2"><nlm:aff id="aff8">Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Corre, Pierre" sort="Corre, Pierre" uniqKey="Corre P" first="Pierre" last="Corre">Pierre Corre</name>
<affiliation wicri:level="3"><nlm:aff id="aff15">Service de Stomatologie, Centre Hospitalier Universitaire Nantes, Nantes 44093, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Service de Stomatologie, Centre Hospitalier Universitaire Nantes, Nantes 44093</wicri:regionArea>
<placeName><region type="region" nuts="2">Pays de la Loire</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Dalton, Joline" sort="Dalton, Joline" uniqKey="Dalton J" first="Joline" last="Dalton">Joline Dalton</name>
<affiliation wicri:level="2"><nlm:aff id="aff16">Department of Neurology, University of Minnesota, Minneapolis, MN 55454, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurology, University of Minnesota, Minneapolis, MN 55454</wicri:regionArea>
<placeName><region type="state">Minnesota</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mercier, Sandra" sort="Mercier, Sandra" uniqKey="Mercier S" first="Sandra" last="Mercier">Sandra Mercier</name>
<affiliation wicri:level="3"><nlm:aff id="aff3">Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093</wicri:regionArea>
<placeName><region type="region" nuts="2">Pays de la Loire</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Latypova, Xenia" sort="Latypova, Xenia" uniqKey="Latypova X" first="Xénia" last="Latypova">Xénia Latypova</name>
<affiliation wicri:level="3"><nlm:aff id="aff3">Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093</wicri:regionArea>
<placeName><region type="region" nuts="2">Pays de la Loire</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Schmitt, Sebastien" sort="Schmitt, Sebastien" uniqKey="Schmitt S" first="Sébastien" last="Schmitt">Sébastien Schmitt</name>
<affiliation wicri:level="3"><nlm:aff id="aff3">Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093</wicri:regionArea>
<placeName><region type="region" nuts="2">Pays de la Loire</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Guzman, Edwin" sort="Guzman, Edwin" uniqKey="Guzman E" first="Edwin" last="Guzman">Edwin Guzman</name>
<affiliation wicri:level="4"><nlm:aff id="aff1">Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Institute for Genomic Medicine, Columbia University, New York, NY 10032</wicri:regionArea>
<placeName><region type="state">État de New York</region>
<settlement type="city">New York</settlement>
</placeName>
<orgName type="university">Université Columbia</orgName>
</affiliation>
</author>
<author><name sortKey="Moore, Christine" sort="Moore, Christine" uniqKey="Moore C" first="Christine" last="Moore">Christine Moore</name>
<affiliation wicri:level="2"><nlm:aff id="aff6">Division of Medical Genetics, Northwell Health, Manhasset, NY 11030, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Medical Genetics, Northwell Health, Manhasset, NY 11030</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bier, Louise" sort="Bier, Louise" uniqKey="Bier L" first="Louise" last="Bier">Louise Bier</name>
<affiliation wicri:level="4"><nlm:aff id="aff1">Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Institute for Genomic Medicine, Columbia University, New York, NY 10032</wicri:regionArea>
<placeName><region type="state">État de New York</region>
<settlement type="city">New York</settlement>
</placeName>
<orgName type="university">Université Columbia</orgName>
</affiliation>
</author>
<author><name sortKey="Heinzen, Erin L" sort="Heinzen, Erin L" uniqKey="Heinzen E" first="Erin L." last="Heinzen">Erin L. Heinzen</name>
<affiliation wicri:level="4"><nlm:aff id="aff1">Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Institute for Genomic Medicine, Columbia University, New York, NY 10032</wicri:regionArea>
<placeName><region type="state">État de New York</region>
<settlement type="city">New York</settlement>
</placeName>
<orgName type="university">Université Columbia</orgName>
</affiliation>
</author>
<author><name sortKey="Karachunski, Peter" sort="Karachunski, Peter" uniqKey="Karachunski P" first="Peter" last="Karachunski">Peter Karachunski</name>
<affiliation wicri:level="2"><nlm:aff id="aff16">Department of Neurology, University of Minnesota, Minneapolis, MN 55454, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurology, University of Minnesota, Minneapolis, MN 55454</wicri:regionArea>
<placeName><region type="state">Minnesota</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Shur, Natasha" sort="Shur, Natasha" uniqKey="Shur N" first="Natasha" last="Shur">Natasha Shur</name>
<affiliation wicri:level="2"><nlm:aff id="aff17">Division of Genetics, Department of Pediatrics, Albany Medical Center, Albany, NY 12208, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Genetics, Department of Pediatrics, Albany Medical Center, Albany, NY 12208</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Grebe, Theresa" sort="Grebe, Theresa" uniqKey="Grebe T" first="Theresa" last="Grebe">Theresa Grebe</name>
<affiliation wicri:level="2"><nlm:aff id="aff18">Phoenix Children’s Hospital and Department of Child Health, University of Arizona College of Medicine, Phoenix, AZ 85724, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Phoenix Children’s Hospital and Department of Child Health, University of Arizona College of Medicine, Phoenix, AZ 85724</wicri:regionArea>
<placeName><region type="state">Arizona</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Basinger, Alice" sort="Basinger, Alice" uniqKey="Basinger A" first="Alice" last="Basinger">Alice Basinger</name>
<affiliation wicri:level="2"><nlm:aff id="aff19">Cook Children’s Physician Network, Fort Worth, TX 76102, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Cook Children’s Physician Network, Fort Worth, TX 76102</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Nguyen, Joanne M" sort="Nguyen, Joanne M" uniqKey="Nguyen J" first="Joanne M." last="Nguyen">Joanne M. Nguyen</name>
<affiliation wicri:level="2"><nlm:aff id="aff20">Division of Medical Genetics, Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Medical Genetics, Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX 77030</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bezieau, Stephane" sort="Bezieau, Stephane" uniqKey="Bezieau S" first="Stéphane" last="Bézieau">Stéphane Bézieau</name>
<affiliation wicri:level="3"><nlm:aff id="aff3">Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093</wicri:regionArea>
<placeName><region type="region" nuts="2">Pays de la Loire</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Wierenga, Klaas" sort="Wierenga, Klaas" uniqKey="Wierenga K" first="Klaas" last="Wierenga">Klaas Wierenga</name>
<affiliation wicri:level="2"><nlm:aff id="aff9">Section of Genetics, Department of Pediatrics, University of Oklahoma, Oklahoma City, OK 73019, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Section of Genetics, Department of Pediatrics, University of Oklahoma, Oklahoma City, OK 73019</wicri:regionArea>
<placeName><region type="state">Oklahoma</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bernstein, Jonathan A" sort="Bernstein, Jonathan A" uniqKey="Bernstein J" first="Jonathan A." last="Bernstein">Jonathan A. Bernstein</name>
<affiliation wicri:level="2"><nlm:aff id="aff8">Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Scheffer, Ingrid E" sort="Scheffer, Ingrid E" uniqKey="Scheffer I" first="Ingrid E." last="Scheffer">Ingrid E. Scheffer</name>
<affiliation wicri:level="4"><nlm:aff id="aff13">Department of Medicine, Austin Health, University of Melbourne, Heidelberg, VIC 3081, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Medicine, Austin Health, University of Melbourne, Heidelberg, VIC 3081</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
</placeName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff21">Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3050, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3050</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
</placeName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff22">Department of Paediatrics, Royal Children’s Hospital, University of Melbourne, Melbourne, VIC 3050, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Paediatrics, Royal Children’s Hospital, University of Melbourne, Melbourne, VIC 3050</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Rosenfeld, Jill A" sort="Rosenfeld, Jill A" uniqKey="Rosenfeld J" first="Jill A." last="Rosenfeld">Jill A. Rosenfeld</name>
<affiliation wicri:level="2"><nlm:aff id="aff7">Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mefford, Heather C" sort="Mefford, Heather C" uniqKey="Mefford H" first="Heather C." last="Mefford">Heather C. Mefford</name>
<affiliation wicri:level="4"><nlm:aff id="aff4">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle WA, 98195, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle WA, 98195</wicri:regionArea>
<orgName type="university">Université de Washington</orgName>
<placeName><settlement type="city">Seattle</settlement>
<region type="state">Washington (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Isidor, Bertrand" sort="Isidor, Bertrand" uniqKey="Isidor B" first="Bertrand" last="Isidor">Bertrand Isidor</name>
<affiliation wicri:level="1"><nlm:aff id="aff3">Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093</wicri:regionArea>
<wicri:noRegion>44093</wicri:noRegion>
<wicri:noRegion>44093</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Goldstein, David B" sort="Goldstein, David B" uniqKey="Goldstein D" first="David B." last="Goldstein">David B. Goldstein</name>
<affiliation wicri:level="4"><nlm:aff id="aff1">Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Institute for Genomic Medicine, Columbia University, New York, NY 10032</wicri:regionArea>
<placeName><region type="state">État de New York</region>
<settlement type="city">New York</settlement>
</placeName>
<orgName type="university">Université Columbia</orgName>
</affiliation>
</author>
</analytic>
<series><title level="j">American Journal of Human Genetics</title>
<idno type="ISSN">0002-9297</idno>
<idno type="eISSN">1537-6605</idno>
<imprint><date when="2016">2016</date>
</imprint>
</series>
</biblStruct>
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</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adolescent</term>
<term>Adult</term>
<term>Child</term>
<term>Child, Preschool</term>
<term>Developmental Disabilities (etiology)</term>
<term>Developmental Disabilities (pathology)</term>
<term>Exome (genetics)</term>
<term>Female</term>
<term>GTP-Binding Protein beta Subunits (chemistry)</term>
<term>GTP-Binding Protein beta Subunits (genetics)</term>
<term>Germ-Line Mutation (genetics)</term>
<term>Humans</term>
<term>Infant</term>
<term>Intellectual Disability (etiology)</term>
<term>Intellectual Disability (pathology)</term>
<term>Male</term>
<term>Muscle Hypotonia (etiology)</term>
<term>Muscle Hypotonia (pathology)</term>
<term>Phenotype</term>
<term>Protein Conformation</term>
<term>Seizures (etiology)</term>
<term>Seizures (pathology)</term>
<term>Signal Transduction</term>
<term>Young Adult</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Adolescent</term>
<term>Adulte</term>
<term>Conformation des protéines</term>
<term>Crises épileptiques (anatomopathologie)</term>
<term>Crises épileptiques (étiologie)</term>
<term>Déficience intellectuelle (anatomopathologie)</term>
<term>Déficience intellectuelle (étiologie)</term>
<term>Enfant</term>
<term>Enfant d'âge préscolaire</term>
<term>Exome (génétique)</term>
<term>Femelle</term>
<term>Humains</term>
<term>Hypotonie musculaire (anatomopathologie)</term>
<term>Hypotonie musculaire (étiologie)</term>
<term>Incapacités de développement (anatomopathologie)</term>
<term>Incapacités de développement (étiologie)</term>
<term>Jeune adulte</term>
<term>Mutation germinale (génétique)</term>
<term>Mâle</term>
<term>Nourrisson</term>
<term>Phénotype</term>
<term>Sous-unités bêta des protéines G ()</term>
<term>Sous-unités bêta des protéines G (génétique)</term>
<term>Transduction du signal</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>GTP-Binding Protein beta Subunits</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Crises épileptiques</term>
<term>Déficience intellectuelle</term>
<term>Hypotonie musculaire</term>
<term>Incapacités de développement</term>
</keywords>
<keywords scheme="MESH" qualifier="etiology" xml:lang="en"><term>Developmental Disabilities</term>
<term>Intellectual Disability</term>
<term>Muscle Hypotonia</term>
<term>Seizures</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Exome</term>
<term>GTP-Binding Protein beta Subunits</term>
<term>Germ-Line Mutation</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Exome</term>
<term>Mutation germinale</term>
<term>Sous-unités bêta des protéines G</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Developmental Disabilities</term>
<term>Intellectual Disability</term>
<term>Muscle Hypotonia</term>
<term>Seizures</term>
</keywords>
<keywords scheme="MESH" qualifier="étiologie" xml:lang="fr"><term>Crises épileptiques</term>
<term>Déficience intellectuelle</term>
<term>Hypotonie musculaire</term>
<term>Incapacités de développement</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Adolescent</term>
<term>Adult</term>
<term>Child</term>
<term>Child, Preschool</term>
<term>Female</term>
<term>Humans</term>
<term>Infant</term>
<term>Male</term>
<term>Phenotype</term>
<term>Protein Conformation</term>
<term>Signal Transduction</term>
<term>Young Adult</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Adolescent</term>
<term>Adulte</term>
<term>Conformation des protéines</term>
<term>Enfant</term>
<term>Enfant d'âge préscolaire</term>
<term>Femelle</term>
<term>Humains</term>
<term>Jeune adulte</term>
<term>Mâle</term>
<term>Nourrisson</term>
<term>Phénotype</term>
<term>Sous-unités bêta des protéines G</term>
<term>Transduction du signal</term>
</keywords>
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<front><div type="abstract" xml:lang="en"><p>Whole-exome sequencing of 13 individuals with developmental delay commonly accompanied by abnormal muscle tone and seizures identified de novo missense mutations enriched within a sub-region of <italic>GNB1</italic>
, a gene encoding the guanine nucleotide-binding protein subunit beta-1, Gβ. These 13 individuals were identified among a base of 5,855 individuals recruited for various undiagnosed genetic disorders. The probability of observing 13 or more de novo mutations by chance among 5,855 individuals is very low (p = 7.1 × 10<sup>−21</sup>
), implicating <italic>GNB1</italic>
 as a genome-wide-significant disease-associated gene. The majority of these 13 mutations affect known Gβ binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for Gα-Gβγ interaction (resulting in a constitutively active Gβγ) or through the disruption of residues relevant for interaction between Gβγ and certain downstream effectors (resulting in reduced interaction with the effectors). Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo <italic>GNB1</italic>
 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>Australie</li>
<li>France</li>
<li>États-Unis</li>
</country>
<region><li>Arizona</li>
<li>Californie</li>
<li>Minnesota</li>
<li>Oklahoma</li>
<li>Pays de la Loire</li>
<li>Texas</li>
<li>Victoria (État)</li>
<li>Washington (État)</li>
<li>État de New York</li>
</region>
<settlement><li>Melbourne</li>
<li>New York</li>
<li>Seattle</li>
</settlement>
<orgName><li>Université Columbia</li>
<li>Université de Melbourne</li>
<li>Université de Washington</li>
</orgName>
</list>
<tree><country name="États-Unis"><region name="État de New York"><name sortKey="Petrovski, Slave" sort="Petrovski, Slave" uniqKey="Petrovski S" first="Slavé" last="Petrovski">Slavé Petrovski</name>
</region>
<name sortKey="Anyane Yeboa, Kwame" sort="Anyane Yeboa, Kwame" uniqKey="Anyane Yeboa K" first="Kwame" last="Anyane-Yeboa">Kwame Anyane-Yeboa</name>
<name sortKey="Basinger, Alice" sort="Basinger, Alice" uniqKey="Basinger A" first="Alice" last="Basinger">Alice Basinger</name>
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   |texte=   Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures
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Serveur d'exploration sur les relations entre la France et l'Australie

Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures

Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures

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	Serveur d'exploration sur les relations entre la France et l'Australie
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