PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution
Identifieur interne : 004156 ( Pmc/Curation ); précédent : 004155; suivant : 004157PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution
Auteurs : Ghayda Mirzaa [États-Unis] ; Andrew E. Timms [États-Unis] ; Valerio Conti [Italie] ; Evan August Boyle [États-Unis] ; Katta M. Girisha [Inde] ; Beth Martin [États-Unis] ; Martin Kircher [États-Unis] ; Carissa Olds ; Jane Juusola [États-Unis] ; Sarah Collins ; Kaylee Park ; Melissa Carter [Canada] ; Ian Glass [États-Unis] ; Inge Kr Geloh-Mann [Allemagne] ; David Chitayat [Canada] ; Aditi Shah Parikh [États-Unis] ; Rachael Bradshaw [États-Unis] ; Erin Torti [États-Unis] ; Stephen Braddock [États-Unis] ; Leah Burke [États-Unis] ; Sondhya Ghedia [Australie] ; Mark Stephan [États-Unis] ; Fiona Stewart [Royaume-Uni] ; Chitra Prasad [Canada] ; Melanie Napier [Canada] ; Sulagna Saitta [États-Unis] ; Rachel Straussberg [Israël] ; Michael Gabbett [Australie] ; Bridget C. O Onnor [États-Unis] ; Catherine E. Keegan [États-Unis] ; Lim Jiin Yin [Singapour] ; Angeline Hwei Meeng Lai [Singapour] ; Nicole Martin [Canada] ; Margaret Mckinnon [Canada] ; Marie-Claude Addor [Suisse] ; Luigi Boccuto [États-Unis] ; Charles E. Schwartz [États-Unis] ; Agustina Lanoel [Argentine] ; Robert L. Conway [États-Unis] ; Koenraad Devriendt [Belgique] ; Katrina Tatton-Brown [Royaume-Uni] ; Mary Ella Pierpont [États-Unis] ; Michael Painter [États-Unis] ; Lisa Worgan [Australie] ; James Reggin [États-Unis] ; Raoul Hennekam [Pays-Bas] ; Karen Tsuchiya [États-Unis] ; Colin C. Pritchard [États-Unis] ; Mariana Aracena [Chili] ; Karen W. Gripp [États-Unis] ; Maria Cordisco [États-Unis] ; Hilde Van Esch [Belgique] ; Livia Garavelli [Italie] ; Cynthia Curry [États-Unis] ; Anne Goriely [Royaume-Uni] ; Hulya Kayserilli [Turquie] ; Jay Shendure [États-Unis] ; John Graham [États-Unis] ; Renzo Guerrini [Italie] ; William B. Dobyns [États-Unis]Source :
- JCI Insight [ 2379-3708 ] ; ????.
Abstract
Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of
Url:
DOI: 10.1172/jci.insight.87623
PubMed: 27631024
PubMed Central: 5019182
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David Chitayat<affiliation><nlm:aff wicri:cut=", and" id="A11">Mount Sinai Hospital, The Prenatal Diagnosis and Medical Genetics Division, Department of Obstetrics and Gynecology</nlm:aff>
<wicri:noCountry code="subfield">Department of Obstetrics and Gynecology</wicri:noCountry>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A12">Department of Pediatrics, Division of Clinical and Metabolic Genetics, University of Toronto, Toronto, Ontario, Canada.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Canada</country>
<wicri:regionArea>Department of Pediatrics, Division of Clinical and Metabolic Genetics, University of Toronto, Toronto, Ontario</wicri:regionArea>
</affiliation>
<affiliation><nlm:aff wicri:cut=", and" id="A22">Division of Genetics, Department of Pediatrics</nlm:aff>
<wicri:noCountry code="subfield">Department of Pediatrics</wicri:noCountry>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A23">Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Human Genetics, University of Michigan, Ann Arbor, Michigan</wicri:regionArea>
</affiliation>
<affiliation><nlm:aff wicri:cut=", and" id="A22">Division of Genetics, Department of Pediatrics</nlm:aff>
<wicri:noCountry code="subfield">Department of Pediatrics</wicri:noCountry>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A23">Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Human Genetics, University of Michigan, Ann Arbor, Michigan</wicri:regionArea>
</affiliation>
<affiliation><nlm:aff wicri:cut=" and" id="A38">Department of Laboratories, Seattle Children’s Hospital</nlm:aff>
<wicri:noCountry code="subfield">Seattle Children’s Hospital</wicri:noCountry>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A39">Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Laboratory Medicine, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en"><italic>PIK3CA</italic>
-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution</title>
<author><name sortKey="Mirzaa, Ghayda" sort="Mirzaa, Ghayda" uniqKey="Mirzaa G" first="Ghayda" last="Mirzaa">Ghayda Mirzaa</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
<affiliation><nlm:aff wicri:cut=" and" id="A2">Center for Integrative Brain Research</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Timms, Andrew E" sort="Timms, Andrew E" uniqKey="Timms A" first="Andrew E." last="Timms">Andrew E. Timms</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, Seattle, Washington</wicri:regionArea>
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<author><name sortKey="Conti, Valerio" sort="Conti, Valerio" uniqKey="Conti V" first="Valerio" last="Conti">Valerio Conti</name>
<affiliation wicri:level="1"><nlm:aff id="A4">Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A. Meyer Children’s Hospital, University of Florence, Florence, Italy.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Italie</country>
<wicri:regionArea>Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A. Meyer Children’s Hospital, University of Florence, Florence</wicri:regionArea>
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<author><name sortKey="Boyle, Evan August" sort="Boyle, Evan August" uniqKey="Boyle E" first="Evan August" last="Boyle">Evan August Boyle</name>
<affiliation wicri:level="1"><nlm:aff id="A5">Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Genetics, Stanford University School of Medicine, Stanford, California</wicri:regionArea>
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<author><name sortKey="Girisha, Katta M" sort="Girisha, Katta M" uniqKey="Girisha K" first="Katta M." last="Girisha">Katta M. Girisha</name>
<affiliation wicri:level="1"><nlm:aff id="A6">Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Inde</country>
<wicri:regionArea>Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka</wicri:regionArea>
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</author>
<author><name sortKey="Martin, Beth" sort="Martin, Beth" uniqKey="Martin B" first="Beth" last="Martin">Beth Martin</name>
<affiliation wicri:level="1"><nlm:aff id="A7">Department of Genome Sciences, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Genome Sciences, University of Washington, Seattle, Washington</wicri:regionArea>
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<author><name sortKey="Kircher, Martin" sort="Kircher, Martin" uniqKey="Kircher M" first="Martin" last="Kircher">Martin Kircher</name>
<affiliation wicri:level="1"><nlm:aff id="A7">Department of Genome Sciences, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Genome Sciences, University of Washington, Seattle, Washington</wicri:regionArea>
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<author><name sortKey="Olds, Carissa" sort="Olds, Carissa" uniqKey="Olds C" first="Carissa" last="Olds">Carissa Olds</name>
<affiliation><nlm:aff wicri:cut=" and" id="A2">Center for Integrative Brain Research</nlm:aff>
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<author><name sortKey="Juusola, Jane" sort="Juusola, Jane" uniqKey="Juusola J" first="Jane" last="Juusola">Jane Juusola</name>
<affiliation wicri:level="1"><nlm:aff id="A8">Whole Exome Sequencing Program, GeneDx, Gaithersburg, Maryland, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Whole Exome Sequencing Program, GeneDx, Gaithersburg, Maryland</wicri:regionArea>
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<author><name sortKey="Collins, Sarah" sort="Collins, Sarah" uniqKey="Collins S" first="Sarah" last="Collins">Sarah Collins</name>
<affiliation><nlm:aff wicri:cut=" and" id="A2">Center for Integrative Brain Research</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Park, Kaylee" sort="Park, Kaylee" uniqKey="Park K" first="Kaylee" last="Park">Kaylee Park</name>
<affiliation><nlm:aff wicri:cut=" and" id="A2">Center for Integrative Brain Research</nlm:aff>
</affiliation>
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<author><name sortKey="Carter, Melissa" sort="Carter, Melissa" uniqKey="Carter M" first="Melissa" last="Carter">Melissa Carter</name>
<affiliation wicri:level="1"><nlm:aff id="A9">Regional Genetics Program, The Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Canada</country>
<wicri:regionArea>Regional Genetics Program, The Children’s Hospital of Eastern Ontario, Ottawa, Ontario</wicri:regionArea>
</affiliation>
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<author><name sortKey="Glass, Ian" sort="Glass, Ian" uniqKey="Glass I" first="Ian" last="Glass">Ian Glass</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington</wicri:regionArea>
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<affiliation><nlm:aff wicri:cut=" and" id="A2">Center for Integrative Brain Research</nlm:aff>
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<author><name sortKey="Kr Geloh Mann, Inge" sort="Kr Geloh Mann, Inge" uniqKey="Kr Geloh Mann I" first="Inge" last="Kr Geloh-Mann">Inge Kr Geloh-Mann</name>
<affiliation wicri:level="1"><nlm:aff id="A10">Department of Pediatrics, and Pediatric Neurology and Developmental Medicine, University Children’s Hospital, Tübingen, Germany.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Allemagne</country>
<wicri:regionArea>Department of Pediatrics, and Pediatric Neurology and Developmental Medicine, University Children’s Hospital, Tübingen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Chitayat, David" sort="Chitayat, David" uniqKey="Chitayat D" first="David" last="Chitayat">David Chitayat</name>
<affiliation><nlm:aff wicri:cut=", and" id="A11">Mount Sinai Hospital, The Prenatal Diagnosis and Medical Genetics Division, Department of Obstetrics and Gynecology</nlm:aff>
<wicri:noCountry code="subfield">Department of Obstetrics and Gynecology</wicri:noCountry>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A12">Department of Pediatrics, Division of Clinical and Metabolic Genetics, University of Toronto, Toronto, Ontario, Canada.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Canada</country>
<wicri:regionArea>Department of Pediatrics, Division of Clinical and Metabolic Genetics, University of Toronto, Toronto, Ontario</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Parikh, Aditi Shah" sort="Parikh, Aditi Shah" uniqKey="Parikh A" first="Aditi Shah" last="Parikh">Aditi Shah Parikh</name>
<affiliation wicri:level="1"><nlm:aff id="A13">Center for Human Genetics, University Hospitals Case Medical Center, Cleveland, Ohio, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Center for Human Genetics, University Hospitals Case Medical Center, Cleveland, Ohio</wicri:regionArea>
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<author><name sortKey="Bradshaw, Rachael" sort="Bradshaw, Rachael" uniqKey="Bradshaw R" first="Rachael" last="Bradshaw">Rachael Bradshaw</name>
<affiliation wicri:level="1"><nlm:aff id="A14">Department of Pediatrics, Division of Medical Genetics, Saint Louis University, St. Louis, Missouri, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Division of Medical Genetics, Saint Louis University, St. Louis, Missouri</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Torti, Erin" sort="Torti, Erin" uniqKey="Torti E" first="Erin" last="Torti">Erin Torti</name>
<affiliation wicri:level="1"><nlm:aff id="A14">Department of Pediatrics, Division of Medical Genetics, Saint Louis University, St. Louis, Missouri, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Division of Medical Genetics, Saint Louis University, St. Louis, Missouri</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Braddock, Stephen" sort="Braddock, Stephen" uniqKey="Braddock S" first="Stephen" last="Braddock">Stephen Braddock</name>
<affiliation wicri:level="1"><nlm:aff id="A14">Department of Pediatrics, Division of Medical Genetics, Saint Louis University, St. Louis, Missouri, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Division of Medical Genetics, Saint Louis University, St. Louis, Missouri</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Burke, Leah" sort="Burke, Leah" uniqKey="Burke L" first="Leah" last="Burke">Leah Burke</name>
<affiliation wicri:level="1"><nlm:aff id="A15">Department of Pediatrics, University of Vermont College of Medicine, Burlington, Vermont, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, University of Vermont College of Medicine, Burlington, Vermont</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ghedia, Sondhya" sort="Ghedia, Sondhya" uniqKey="Ghedia S" first="Sondhya" last="Ghedia">Sondhya Ghedia</name>
<affiliation wicri:level="1"><nlm:aff id="A16">Department of Clinical Genetics, Royal North Shore Hospital, St Leonards, New South Wales, Australia.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Australie</country>
<wicri:regionArea>Department of Clinical Genetics, Royal North Shore Hospital, St Leonards, New South Wales</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Stephan, Mark" sort="Stephan, Mark" uniqKey="Stephan M" first="Mark" last="Stephan">Mark Stephan</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Stewart, Fiona" sort="Stewart, Fiona" uniqKey="Stewart F" first="Fiona" last="Stewart">Fiona Stewart</name>
<affiliation wicri:level="1"><nlm:aff id="A17">Belfast Health and Social Care Trust, Belfast, United Kingdom.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Royaume-Uni</country>
<wicri:regionArea>Belfast Health and Social Care Trust, Belfast</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Prasad, Chitra" sort="Prasad, Chitra" uniqKey="Prasad C" first="Chitra" last="Prasad">Chitra Prasad</name>
<affiliation wicri:level="1"><nlm:aff id="A18">Genetics, Metabolism and Pediatrics, London, Ontario, Canada.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Canada</country>
<wicri:regionArea>Genetics, Metabolism and Pediatrics, London, Ontario</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Napier, Melanie" sort="Napier, Melanie" uniqKey="Napier M" first="Melanie" last="Napier">Melanie Napier</name>
<affiliation wicri:level="1"><nlm:aff id="A18">Genetics, Metabolism and Pediatrics, London, Ontario, Canada.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Canada</country>
<wicri:regionArea>Genetics, Metabolism and Pediatrics, London, Ontario</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Saitta, Sulagna" sort="Saitta, Sulagna" uniqKey="Saitta S" first="Sulagna" last="Saitta">Sulagna Saitta</name>
<affiliation wicri:level="1"><nlm:aff id="A19">Clinical Genetics, Center for Personalized Medicine, Children’s Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Clinical Genetics, Center for Personalized Medicine, Children’s Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Straussberg, Rachel" sort="Straussberg, Rachel" uniqKey="Straussberg R" first="Rachel" last="Straussberg">Rachel Straussberg</name>
<affiliation wicri:level="1"><nlm:aff id="A20">Neurology Unit, Schneider Children’s Medical Center of Israel, Petach Tikva, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Israël</country>
<wicri:regionArea>Neurology Unit, Schneider Children’s Medical Center of Israel, Petach Tikva, and Sackler School of Medicine, Tel Aviv University, Tel Aviv</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Gabbett, Michael" sort="Gabbett, Michael" uniqKey="Gabbett M" first="Michael" last="Gabbett">Michael Gabbett</name>
<affiliation wicri:level="1"><nlm:aff id="A21">School of Medicine, Griffith University, Brisbane, Queensland, Australia.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Australie</country>
<wicri:regionArea>School of Medicine, Griffith University, Brisbane, Queensland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="O Onnor, Bridget C" sort="O Onnor, Bridget C" uniqKey="O Onnor B" first="Bridget C." last="O Onnor">Bridget C. O Onnor</name>
<affiliation><nlm:aff wicri:cut=", and" id="A22">Division of Genetics, Department of Pediatrics</nlm:aff>
<wicri:noCountry code="subfield">Department of Pediatrics</wicri:noCountry>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A23">Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Human Genetics, University of Michigan, Ann Arbor, Michigan</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Keegan, Catherine E" sort="Keegan, Catherine E" uniqKey="Keegan C" first="Catherine E." last="Keegan">Catherine E. Keegan</name>
<affiliation><nlm:aff wicri:cut=", and" id="A22">Division of Genetics, Department of Pediatrics</nlm:aff>
<wicri:noCountry code="subfield">Department of Pediatrics</wicri:noCountry>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A23">Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Human Genetics, University of Michigan, Ann Arbor, Michigan</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Yin, Lim Jiin" sort="Yin, Lim Jiin" uniqKey="Yin L" first="Lim Jiin" last="Yin">Lim Jiin Yin</name>
<affiliation wicri:level="1"><nlm:aff id="A24">Genetics Service, Department of Pediatric Medicine, KK Women’s and Children’s Hospital, Singapore.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Singapour</country>
<wicri:regionArea>Genetics Service, Department of Pediatric Medicine, KK Women’s and Children’s Hospital</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Lai, Angeline Hwei Meeng" sort="Lai, Angeline Hwei Meeng" uniqKey="Lai A" first="Angeline Hwei Meeng" last="Lai">Angeline Hwei Meeng Lai</name>
<affiliation wicri:level="1"><nlm:aff id="A24">Genetics Service, Department of Pediatric Medicine, KK Women’s and Children’s Hospital, Singapore.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Singapour</country>
<wicri:regionArea>Genetics Service, Department of Pediatric Medicine, KK Women’s and Children’s Hospital</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Martin, Nicole" sort="Martin, Nicole" uniqKey="Martin N" first="Nicole" last="Martin">Nicole Martin</name>
<affiliation wicri:level="1"><nlm:aff id="A12">Department of Pediatrics, Division of Clinical and Metabolic Genetics, University of Toronto, Toronto, Ontario, Canada.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Canada</country>
<wicri:regionArea>Department of Pediatrics, Division of Clinical and Metabolic Genetics, University of Toronto, Toronto, Ontario</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mckinnon, Margaret" sort="Mckinnon, Margaret" uniqKey="Mckinnon M" first="Margaret" last="Mckinnon">Margaret Mckinnon</name>
<affiliation wicri:level="1"><nlm:aff id="A25">British Columbia Medical Genetics Provincial Program, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Canada</country>
<wicri:regionArea>British Columbia Medical Genetics Provincial Program, University of British Columbia, Vancouver, British Columbia</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Addor, Marie Claude" sort="Addor, Marie Claude" uniqKey="Addor M" first="Marie-Claude" last="Addor">Marie-Claude Addor</name>
<affiliation wicri:level="1"><nlm:aff id="A26">Service de génétique médicale, Centre Hospitalier Universitaire Vaudois CHUV, Switzerland.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Suisse</country>
<wicri:regionArea>Service de génétique médicale, Centre Hospitalier Universitaire Vaudois CHUV</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Boccuto, Luigi" sort="Boccuto, Luigi" uniqKey="Boccuto L" first="Luigi" last="Boccuto">Luigi Boccuto</name>
<affiliation wicri:level="1"><nlm:aff id="A27">Greenwood Genetic Center, Greenwood, South Carolina, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Greenwood Genetic Center, Greenwood, South Carolina</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Schwartz, Charles E" sort="Schwartz, Charles E" uniqKey="Schwartz C" first="Charles E." last="Schwartz">Charles E. Schwartz</name>
<affiliation wicri:level="1"><nlm:aff id="A27">Greenwood Genetic Center, Greenwood, South Carolina, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Greenwood Genetic Center, Greenwood, South Carolina</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Lanoel, Agustina" sort="Lanoel, Agustina" uniqKey="Lanoel A" first="Agustina" last="Lanoel">Agustina Lanoel</name>
<affiliation wicri:level="1"><nlm:aff id="A28">Department of Dermatology, Children Hospital Prof. Dr. J. P. Garrahan, Buenos Aires, Argentina.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Argentine</country>
<wicri:regionArea>Department of Dermatology, Children Hospital Prof. Dr. J. P. Garrahan, Buenos Aires</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Conway, Robert L" sort="Conway, Robert L" uniqKey="Conway R" first="Robert L." last="Conway">Robert L. Conway</name>
<affiliation wicri:level="1"><nlm:aff id="A29">Children’s Hospital of Michigan, Wayne State University, Detroit, Michigan, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Children’s Hospital of Michigan, Wayne State University, Detroit, Michigan</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Devriendt, Koenraad" sort="Devriendt, Koenraad" uniqKey="Devriendt K" first="Koenraad" last="Devriendt">Koenraad Devriendt</name>
<affiliation wicri:level="1"><nlm:aff id="A30">Center for Human Genetics, University Hospitals Leuven and KU Leuven, Leuven, Belgium.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Belgique</country>
<wicri:regionArea>Center for Human Genetics, University Hospitals Leuven and KU Leuven, Leuven</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Tatton Brown, Katrina" sort="Tatton Brown, Katrina" uniqKey="Tatton Brown K" first="Katrina" last="Tatton-Brown">Katrina Tatton-Brown</name>
<affiliation wicri:level="1"><nlm:aff id="A31">South West Thames Regional Genetics Service, St George’s University NHS Foundation Trust, London, and Section of Cancer Genetics, Institute of Cancer Research, Sutton, United Kingdom.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Royaume-Uni</country>
<wicri:regionArea>South West Thames Regional Genetics Service, St George’s University NHS Foundation Trust, London, and Section of Cancer Genetics, Institute of Cancer Research, Sutton</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Pierpont, Mary Ella" sort="Pierpont, Mary Ella" uniqKey="Pierpont M" first="Mary Ella" last="Pierpont">Mary Ella Pierpont</name>
<affiliation wicri:level="1"><nlm:aff id="A32">Department of Pediatrics and Ophthalmology, University of Minnesota, Minneapolis, Minnesota, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pediatrics and Ophthalmology, University of Minnesota, Minneapolis, Minnesota</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Painter, Michael" sort="Painter, Michael" uniqKey="Painter M" first="Michael" last="Painter">Michael Painter</name>
<affiliation wicri:level="1"><nlm:aff id="A33">Department of Child Neurology, University of Florida, Jacksonville, Florida, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Child Neurology, University of Florida, Jacksonville, Florida</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Worgan, Lisa" sort="Worgan, Lisa" uniqKey="Worgan L" first="Lisa" last="Worgan">Lisa Worgan</name>
<affiliation wicri:level="1"><nlm:aff id="A34">Department of Genetics, Liverpool Hospital, Liverpool, New South Wales, Australia.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Australie</country>
<wicri:regionArea>Department of Genetics, Liverpool Hospital, Liverpool, New South Wales</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Reggin, James" sort="Reggin, James" uniqKey="Reggin J" first="James" last="Reggin">James Reggin</name>
<affiliation wicri:level="1"><nlm:aff id="A35">Department of Neurology, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Neurology, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A36">Providence Child Neurology, Providence Sacred Heart Medical Center and Children’s Hospital, Spokane, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Providence Child Neurology, Providence Sacred Heart Medical Center and Children’s Hospital, Spokane, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Hennekam, Raoul" sort="Hennekam, Raoul" uniqKey="Hennekam R" first="Raoul" last="Hennekam">Raoul Hennekam</name>
<affiliation wicri:level="1"><nlm:aff id="A37">Department of Pediatrics and Translational Genetics, Department of Pediatrics, Academic Medical Center, University of Amsterdam Medical Center, Amsterdam, The Netherlands.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department of Pediatrics and Translational Genetics, Department of Pediatrics, Academic Medical Center, University of Amsterdam Medical Center, Amsterdam</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Tsuchiya, Karen" sort="Tsuchiya, Karen" uniqKey="Tsuchiya K" first="Karen" last="Tsuchiya">Karen Tsuchiya</name>
<affiliation><nlm:aff wicri:cut=" and" id="A38">Department of Laboratories, Seattle Children’s Hospital</nlm:aff>
<wicri:noCountry code="subfield">Seattle Children’s Hospital</wicri:noCountry>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A39">Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Laboratory Medicine, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Pritchard, Colin C" sort="Pritchard, Colin C" uniqKey="Pritchard C" first="Colin C." last="Pritchard">Colin C. Pritchard</name>
<affiliation wicri:level="1"><nlm:aff id="A39">Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Laboratory Medicine, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Aracena, Mariana" sort="Aracena, Mariana" uniqKey="Aracena M" first="Mariana" last="Aracena">Mariana Aracena</name>
<affiliation wicri:level="1"><nlm:aff id="A40">División de Pediatría, Pontificia Universidad Católica de Chile, Pediatra-Genetista, Unidad de Genética, Hospital Dr. Luis Calvo Mackenna, Santiago, Chile.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Chili</country>
<wicri:regionArea>División de Pediatría, Pontificia Universidad Católica de Chile, Pediatra-Genetista, Unidad de Genética, Hospital Dr. Luis Calvo Mackenna, Santiago</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Gripp, Karen W" sort="Gripp, Karen W" uniqKey="Gripp K" first="Karen W." last="Gripp">Karen W. Gripp</name>
<affiliation wicri:level="1"><nlm:aff id="A41">Department of Pediatrics, Sidney Kimmel Medical School at T. Jefferson University, Chief of Division of Medical Genetics, A.I. duPont Hospital for Children, Wilmington, Delaware, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Sidney Kimmel Medical School at T. Jefferson University, Chief of Division of Medical Genetics, A.I. duPont Hospital for Children, Wilmington, Delaware</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Cordisco, Maria" sort="Cordisco, Maria" uniqKey="Cordisco M" first="Maria" last="Cordisco">Maria Cordisco</name>
<affiliation wicri:level="1"><nlm:aff id="A42">Departments of Dermatology and Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Departments of Dermatology and Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Van Esch, Hilde" sort="Van Esch, Hilde" uniqKey="Van Esch H" first="Hilde" last="Van Esch">Hilde Van Esch</name>
<affiliation wicri:level="1"><nlm:aff id="A43">Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Belgique</country>
<wicri:regionArea>Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Garavelli, Livia" sort="Garavelli, Livia" uniqKey="Garavelli L" first="Livia" last="Garavelli">Livia Garavelli</name>
<affiliation wicri:level="1"><nlm:aff id="A44">Clinical Genetics Unit, IRCCS Santa Maria Nuova Hospital, Reggio Emilia, Italy.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Italie</country>
<wicri:regionArea>Clinical Genetics Unit, IRCCS Santa Maria Nuova Hospital, Reggio Emilia</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Curry, Cynthia" sort="Curry, Cynthia" uniqKey="Curry C" first="Cynthia" last="Curry">Cynthia Curry</name>
<affiliation wicri:level="1"><nlm:aff id="A45">University of California, San Francisco, San Francisco/Genetic Medicine Central California, San Francisco, California, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>University of California, San Francisco, San Francisco/Genetic Medicine Central California, San Francisco, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Goriely, Anne" sort="Goriely, Anne" uniqKey="Goriely A" first="Anne" last="Goriely">Anne Goriely</name>
<affiliation wicri:level="1"><nlm:aff id="A46">Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Royaume-Uni</country>
<wicri:regionArea>Weatherall Institute of Molecular Medicine, University of Oxford, Oxford</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kayserilli, Hulya" sort="Kayserilli, Hulya" uniqKey="Kayserilli H" first="Hulya" last="Kayserilli">Hulya Kayserilli</name>
<affiliation wicri:level="1"><nlm:aff id="A47">Koç University, School of Medicine, Medical Genetics Department, Koç University Hospital, Istanbul, Turkey.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Turquie</country>
<wicri:regionArea>Koç University, School of Medicine, Medical Genetics Department, Koç University Hospital, Istanbul</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Shendure, Jay" sort="Shendure, Jay" uniqKey="Shendure J" first="Jay" last="Shendure">Jay Shendure</name>
<affiliation wicri:level="1"><nlm:aff id="A7">Department of Genome Sciences, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Genome Sciences, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A48">Howard Hughes Medical Institute, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Howard Hughes Medical Institute, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Graham, John" sort="Graham, John" uniqKey="Graham J" first="John" last="Graham">John Graham</name>
<affiliation wicri:level="1"><nlm:aff id="A49">Department of Pediatrics, Cedars-Sinai Medical Center, Harbor-UCLA Medical Center, David Geffen School of Medicine Los Angeles, California, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Cedars-Sinai Medical Center, Harbor-UCLA Medical Center, David Geffen School of Medicine Los Angeles, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Guerrini, Renzo" sort="Guerrini, Renzo" uniqKey="Guerrini R" first="Renzo" last="Guerrini">Renzo Guerrini</name>
<affiliation wicri:level="1"><nlm:aff id="A4">Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A. Meyer Children’s Hospital, University of Florence, Florence, Italy.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Italie</country>
<wicri:regionArea>Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A. Meyer Children’s Hospital, University of Florence, Florence</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Dobyns, William B" sort="Dobyns, William B" uniqKey="Dobyns W" first="William B." last="Dobyns">William B. Dobyns</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
<affiliation><nlm:aff wicri:cut=" and" id="A2">Center for Integrative Brain Research</nlm:aff>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A35">Department of Neurology, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Neurology, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">27631024</idno>
<idno type="pmc">5019182</idno>
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<idno type="RBID">PMC:5019182</idno>
<idno type="doi">10.1172/jci.insight.87623</idno>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"><italic>PIK3CA</italic>
-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution</title>
<author><name sortKey="Mirzaa, Ghayda" sort="Mirzaa, Ghayda" uniqKey="Mirzaa G" first="Ghayda" last="Mirzaa">Ghayda Mirzaa</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
<affiliation><nlm:aff wicri:cut=" and" id="A2">Center for Integrative Brain Research</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Timms, Andrew E" sort="Timms, Andrew E" uniqKey="Timms A" first="Andrew E." last="Timms">Andrew E. Timms</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Conti, Valerio" sort="Conti, Valerio" uniqKey="Conti V" first="Valerio" last="Conti">Valerio Conti</name>
<affiliation wicri:level="1"><nlm:aff id="A4">Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A. Meyer Children’s Hospital, University of Florence, Florence, Italy.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Italie</country>
<wicri:regionArea>Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A. Meyer Children’s Hospital, University of Florence, Florence</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Boyle, Evan August" sort="Boyle, Evan August" uniqKey="Boyle E" first="Evan August" last="Boyle">Evan August Boyle</name>
<affiliation wicri:level="1"><nlm:aff id="A5">Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Genetics, Stanford University School of Medicine, Stanford, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Girisha, Katta M" sort="Girisha, Katta M" uniqKey="Girisha K" first="Katta M." last="Girisha">Katta M. Girisha</name>
<affiliation wicri:level="1"><nlm:aff id="A6">Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Inde</country>
<wicri:regionArea>Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Martin, Beth" sort="Martin, Beth" uniqKey="Martin B" first="Beth" last="Martin">Beth Martin</name>
<affiliation wicri:level="1"><nlm:aff id="A7">Department of Genome Sciences, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Genome Sciences, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kircher, Martin" sort="Kircher, Martin" uniqKey="Kircher M" first="Martin" last="Kircher">Martin Kircher</name>
<affiliation wicri:level="1"><nlm:aff id="A7">Department of Genome Sciences, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Genome Sciences, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Olds, Carissa" sort="Olds, Carissa" uniqKey="Olds C" first="Carissa" last="Olds">Carissa Olds</name>
<affiliation><nlm:aff wicri:cut=" and" id="A2">Center for Integrative Brain Research</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Juusola, Jane" sort="Juusola, Jane" uniqKey="Juusola J" first="Jane" last="Juusola">Jane Juusola</name>
<affiliation wicri:level="1"><nlm:aff id="A8">Whole Exome Sequencing Program, GeneDx, Gaithersburg, Maryland, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Whole Exome Sequencing Program, GeneDx, Gaithersburg, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Collins, Sarah" sort="Collins, Sarah" uniqKey="Collins S" first="Sarah" last="Collins">Sarah Collins</name>
<affiliation><nlm:aff wicri:cut=" and" id="A2">Center for Integrative Brain Research</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Park, Kaylee" sort="Park, Kaylee" uniqKey="Park K" first="Kaylee" last="Park">Kaylee Park</name>
<affiliation><nlm:aff wicri:cut=" and" id="A2">Center for Integrative Brain Research</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Carter, Melissa" sort="Carter, Melissa" uniqKey="Carter M" first="Melissa" last="Carter">Melissa Carter</name>
<affiliation wicri:level="1"><nlm:aff id="A9">Regional Genetics Program, The Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Canada</country>
<wicri:regionArea>Regional Genetics Program, The Children’s Hospital of Eastern Ontario, Ottawa, Ontario</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Glass, Ian" sort="Glass, Ian" uniqKey="Glass I" first="Ian" last="Glass">Ian Glass</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
<affiliation><nlm:aff wicri:cut=" and" id="A2">Center for Integrative Brain Research</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kr Geloh Mann, Inge" sort="Kr Geloh Mann, Inge" uniqKey="Kr Geloh Mann I" first="Inge" last="Kr Geloh-Mann">Inge Kr Geloh-Mann</name>
<affiliation wicri:level="1"><nlm:aff id="A10">Department of Pediatrics, and Pediatric Neurology and Developmental Medicine, University Children’s Hospital, Tübingen, Germany.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Allemagne</country>
<wicri:regionArea>Department of Pediatrics, and Pediatric Neurology and Developmental Medicine, University Children’s Hospital, Tübingen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Chitayat, David" sort="Chitayat, David" uniqKey="Chitayat D" first="David" last="Chitayat">David Chitayat</name>
<affiliation><nlm:aff wicri:cut=", and" id="A11">Mount Sinai Hospital, The Prenatal Diagnosis and Medical Genetics Division, Department of Obstetrics and Gynecology</nlm:aff>
<wicri:noCountry code="subfield">Department of Obstetrics and Gynecology</wicri:noCountry>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A12">Department of Pediatrics, Division of Clinical and Metabolic Genetics, University of Toronto, Toronto, Ontario, Canada.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Canada</country>
<wicri:regionArea>Department of Pediatrics, Division of Clinical and Metabolic Genetics, University of Toronto, Toronto, Ontario</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Parikh, Aditi Shah" sort="Parikh, Aditi Shah" uniqKey="Parikh A" first="Aditi Shah" last="Parikh">Aditi Shah Parikh</name>
<affiliation wicri:level="1"><nlm:aff id="A13">Center for Human Genetics, University Hospitals Case Medical Center, Cleveland, Ohio, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Center for Human Genetics, University Hospitals Case Medical Center, Cleveland, Ohio</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Bradshaw, Rachael" sort="Bradshaw, Rachael" uniqKey="Bradshaw R" first="Rachael" last="Bradshaw">Rachael Bradshaw</name>
<affiliation wicri:level="1"><nlm:aff id="A14">Department of Pediatrics, Division of Medical Genetics, Saint Louis University, St. Louis, Missouri, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Division of Medical Genetics, Saint Louis University, St. Louis, Missouri</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Torti, Erin" sort="Torti, Erin" uniqKey="Torti E" first="Erin" last="Torti">Erin Torti</name>
<affiliation wicri:level="1"><nlm:aff id="A14">Department of Pediatrics, Division of Medical Genetics, Saint Louis University, St. Louis, Missouri, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Division of Medical Genetics, Saint Louis University, St. Louis, Missouri</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Braddock, Stephen" sort="Braddock, Stephen" uniqKey="Braddock S" first="Stephen" last="Braddock">Stephen Braddock</name>
<affiliation wicri:level="1"><nlm:aff id="A14">Department of Pediatrics, Division of Medical Genetics, Saint Louis University, St. Louis, Missouri, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Division of Medical Genetics, Saint Louis University, St. Louis, Missouri</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Burke, Leah" sort="Burke, Leah" uniqKey="Burke L" first="Leah" last="Burke">Leah Burke</name>
<affiliation wicri:level="1"><nlm:aff id="A15">Department of Pediatrics, University of Vermont College of Medicine, Burlington, Vermont, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, University of Vermont College of Medicine, Burlington, Vermont</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ghedia, Sondhya" sort="Ghedia, Sondhya" uniqKey="Ghedia S" first="Sondhya" last="Ghedia">Sondhya Ghedia</name>
<affiliation wicri:level="1"><nlm:aff id="A16">Department of Clinical Genetics, Royal North Shore Hospital, St Leonards, New South Wales, Australia.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Australie</country>
<wicri:regionArea>Department of Clinical Genetics, Royal North Shore Hospital, St Leonards, New South Wales</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Stephan, Mark" sort="Stephan, Mark" uniqKey="Stephan M" first="Mark" last="Stephan">Mark Stephan</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Stewart, Fiona" sort="Stewart, Fiona" uniqKey="Stewart F" first="Fiona" last="Stewart">Fiona Stewart</name>
<affiliation wicri:level="1"><nlm:aff id="A17">Belfast Health and Social Care Trust, Belfast, United Kingdom.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Royaume-Uni</country>
<wicri:regionArea>Belfast Health and Social Care Trust, Belfast</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Prasad, Chitra" sort="Prasad, Chitra" uniqKey="Prasad C" first="Chitra" last="Prasad">Chitra Prasad</name>
<affiliation wicri:level="1"><nlm:aff id="A18">Genetics, Metabolism and Pediatrics, London, Ontario, Canada.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Canada</country>
<wicri:regionArea>Genetics, Metabolism and Pediatrics, London, Ontario</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Napier, Melanie" sort="Napier, Melanie" uniqKey="Napier M" first="Melanie" last="Napier">Melanie Napier</name>
<affiliation wicri:level="1"><nlm:aff id="A18">Genetics, Metabolism and Pediatrics, London, Ontario, Canada.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Canada</country>
<wicri:regionArea>Genetics, Metabolism and Pediatrics, London, Ontario</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Saitta, Sulagna" sort="Saitta, Sulagna" uniqKey="Saitta S" first="Sulagna" last="Saitta">Sulagna Saitta</name>
<affiliation wicri:level="1"><nlm:aff id="A19">Clinical Genetics, Center for Personalized Medicine, Children’s Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Clinical Genetics, Center for Personalized Medicine, Children’s Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Straussberg, Rachel" sort="Straussberg, Rachel" uniqKey="Straussberg R" first="Rachel" last="Straussberg">Rachel Straussberg</name>
<affiliation wicri:level="1"><nlm:aff id="A20">Neurology Unit, Schneider Children’s Medical Center of Israel, Petach Tikva, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Israël</country>
<wicri:regionArea>Neurology Unit, Schneider Children’s Medical Center of Israel, Petach Tikva, and Sackler School of Medicine, Tel Aviv University, Tel Aviv</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Gabbett, Michael" sort="Gabbett, Michael" uniqKey="Gabbett M" first="Michael" last="Gabbett">Michael Gabbett</name>
<affiliation wicri:level="1"><nlm:aff id="A21">School of Medicine, Griffith University, Brisbane, Queensland, Australia.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Australie</country>
<wicri:regionArea>School of Medicine, Griffith University, Brisbane, Queensland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="O Onnor, Bridget C" sort="O Onnor, Bridget C" uniqKey="O Onnor B" first="Bridget C." last="O Onnor">Bridget C. O Onnor</name>
<affiliation><nlm:aff wicri:cut=", and" id="A22">Division of Genetics, Department of Pediatrics</nlm:aff>
<wicri:noCountry code="subfield">Department of Pediatrics</wicri:noCountry>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A23">Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Human Genetics, University of Michigan, Ann Arbor, Michigan</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Keegan, Catherine E" sort="Keegan, Catherine E" uniqKey="Keegan C" first="Catherine E." last="Keegan">Catherine E. Keegan</name>
<affiliation><nlm:aff wicri:cut=", and" id="A22">Division of Genetics, Department of Pediatrics</nlm:aff>
<wicri:noCountry code="subfield">Department of Pediatrics</wicri:noCountry>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A23">Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Human Genetics, University of Michigan, Ann Arbor, Michigan</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Yin, Lim Jiin" sort="Yin, Lim Jiin" uniqKey="Yin L" first="Lim Jiin" last="Yin">Lim Jiin Yin</name>
<affiliation wicri:level="1"><nlm:aff id="A24">Genetics Service, Department of Pediatric Medicine, KK Women’s and Children’s Hospital, Singapore.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Singapour</country>
<wicri:regionArea>Genetics Service, Department of Pediatric Medicine, KK Women’s and Children’s Hospital</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Lai, Angeline Hwei Meeng" sort="Lai, Angeline Hwei Meeng" uniqKey="Lai A" first="Angeline Hwei Meeng" last="Lai">Angeline Hwei Meeng Lai</name>
<affiliation wicri:level="1"><nlm:aff id="A24">Genetics Service, Department of Pediatric Medicine, KK Women’s and Children’s Hospital, Singapore.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Singapour</country>
<wicri:regionArea>Genetics Service, Department of Pediatric Medicine, KK Women’s and Children’s Hospital</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Martin, Nicole" sort="Martin, Nicole" uniqKey="Martin N" first="Nicole" last="Martin">Nicole Martin</name>
<affiliation wicri:level="1"><nlm:aff id="A12">Department of Pediatrics, Division of Clinical and Metabolic Genetics, University of Toronto, Toronto, Ontario, Canada.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Canada</country>
<wicri:regionArea>Department of Pediatrics, Division of Clinical and Metabolic Genetics, University of Toronto, Toronto, Ontario</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mckinnon, Margaret" sort="Mckinnon, Margaret" uniqKey="Mckinnon M" first="Margaret" last="Mckinnon">Margaret Mckinnon</name>
<affiliation wicri:level="1"><nlm:aff id="A25">British Columbia Medical Genetics Provincial Program, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Canada</country>
<wicri:regionArea>British Columbia Medical Genetics Provincial Program, University of British Columbia, Vancouver, British Columbia</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Addor, Marie Claude" sort="Addor, Marie Claude" uniqKey="Addor M" first="Marie-Claude" last="Addor">Marie-Claude Addor</name>
<affiliation wicri:level="1"><nlm:aff id="A26">Service de génétique médicale, Centre Hospitalier Universitaire Vaudois CHUV, Switzerland.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Suisse</country>
<wicri:regionArea>Service de génétique médicale, Centre Hospitalier Universitaire Vaudois CHUV</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Boccuto, Luigi" sort="Boccuto, Luigi" uniqKey="Boccuto L" first="Luigi" last="Boccuto">Luigi Boccuto</name>
<affiliation wicri:level="1"><nlm:aff id="A27">Greenwood Genetic Center, Greenwood, South Carolina, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Greenwood Genetic Center, Greenwood, South Carolina</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Schwartz, Charles E" sort="Schwartz, Charles E" uniqKey="Schwartz C" first="Charles E." last="Schwartz">Charles E. Schwartz</name>
<affiliation wicri:level="1"><nlm:aff id="A27">Greenwood Genetic Center, Greenwood, South Carolina, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Greenwood Genetic Center, Greenwood, South Carolina</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Lanoel, Agustina" sort="Lanoel, Agustina" uniqKey="Lanoel A" first="Agustina" last="Lanoel">Agustina Lanoel</name>
<affiliation wicri:level="1"><nlm:aff id="A28">Department of Dermatology, Children Hospital Prof. Dr. J. P. Garrahan, Buenos Aires, Argentina.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Argentine</country>
<wicri:regionArea>Department of Dermatology, Children Hospital Prof. Dr. J. P. Garrahan, Buenos Aires</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Conway, Robert L" sort="Conway, Robert L" uniqKey="Conway R" first="Robert L." last="Conway">Robert L. Conway</name>
<affiliation wicri:level="1"><nlm:aff id="A29">Children’s Hospital of Michigan, Wayne State University, Detroit, Michigan, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Children’s Hospital of Michigan, Wayne State University, Detroit, Michigan</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Devriendt, Koenraad" sort="Devriendt, Koenraad" uniqKey="Devriendt K" first="Koenraad" last="Devriendt">Koenraad Devriendt</name>
<affiliation wicri:level="1"><nlm:aff id="A30">Center for Human Genetics, University Hospitals Leuven and KU Leuven, Leuven, Belgium.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Belgique</country>
<wicri:regionArea>Center for Human Genetics, University Hospitals Leuven and KU Leuven, Leuven</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Tatton Brown, Katrina" sort="Tatton Brown, Katrina" uniqKey="Tatton Brown K" first="Katrina" last="Tatton-Brown">Katrina Tatton-Brown</name>
<affiliation wicri:level="1"><nlm:aff id="A31">South West Thames Regional Genetics Service, St George’s University NHS Foundation Trust, London, and Section of Cancer Genetics, Institute of Cancer Research, Sutton, United Kingdom.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Royaume-Uni</country>
<wicri:regionArea>South West Thames Regional Genetics Service, St George’s University NHS Foundation Trust, London, and Section of Cancer Genetics, Institute of Cancer Research, Sutton</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Pierpont, Mary Ella" sort="Pierpont, Mary Ella" uniqKey="Pierpont M" first="Mary Ella" last="Pierpont">Mary Ella Pierpont</name>
<affiliation wicri:level="1"><nlm:aff id="A32">Department of Pediatrics and Ophthalmology, University of Minnesota, Minneapolis, Minnesota, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pediatrics and Ophthalmology, University of Minnesota, Minneapolis, Minnesota</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Painter, Michael" sort="Painter, Michael" uniqKey="Painter M" first="Michael" last="Painter">Michael Painter</name>
<affiliation wicri:level="1"><nlm:aff id="A33">Department of Child Neurology, University of Florida, Jacksonville, Florida, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Child Neurology, University of Florida, Jacksonville, Florida</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Worgan, Lisa" sort="Worgan, Lisa" uniqKey="Worgan L" first="Lisa" last="Worgan">Lisa Worgan</name>
<affiliation wicri:level="1"><nlm:aff id="A34">Department of Genetics, Liverpool Hospital, Liverpool, New South Wales, Australia.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Australie</country>
<wicri:regionArea>Department of Genetics, Liverpool Hospital, Liverpool, New South Wales</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Reggin, James" sort="Reggin, James" uniqKey="Reggin J" first="James" last="Reggin">James Reggin</name>
<affiliation wicri:level="1"><nlm:aff id="A35">Department of Neurology, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Neurology, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A36">Providence Child Neurology, Providence Sacred Heart Medical Center and Children’s Hospital, Spokane, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Providence Child Neurology, Providence Sacred Heart Medical Center and Children’s Hospital, Spokane, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Hennekam, Raoul" sort="Hennekam, Raoul" uniqKey="Hennekam R" first="Raoul" last="Hennekam">Raoul Hennekam</name>
<affiliation wicri:level="1"><nlm:aff id="A37">Department of Pediatrics and Translational Genetics, Department of Pediatrics, Academic Medical Center, University of Amsterdam Medical Center, Amsterdam, The Netherlands.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department of Pediatrics and Translational Genetics, Department of Pediatrics, Academic Medical Center, University of Amsterdam Medical Center, Amsterdam</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Tsuchiya, Karen" sort="Tsuchiya, Karen" uniqKey="Tsuchiya K" first="Karen" last="Tsuchiya">Karen Tsuchiya</name>
<affiliation><nlm:aff wicri:cut=" and" id="A38">Department of Laboratories, Seattle Children’s Hospital</nlm:aff>
<wicri:noCountry code="subfield">Seattle Children’s Hospital</wicri:noCountry>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A39">Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Laboratory Medicine, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Pritchard, Colin C" sort="Pritchard, Colin C" uniqKey="Pritchard C" first="Colin C." last="Pritchard">Colin C. Pritchard</name>
<affiliation wicri:level="1"><nlm:aff id="A39">Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Laboratory Medicine, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Aracena, Mariana" sort="Aracena, Mariana" uniqKey="Aracena M" first="Mariana" last="Aracena">Mariana Aracena</name>
<affiliation wicri:level="1"><nlm:aff id="A40">División de Pediatría, Pontificia Universidad Católica de Chile, Pediatra-Genetista, Unidad de Genética, Hospital Dr. Luis Calvo Mackenna, Santiago, Chile.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Chili</country>
<wicri:regionArea>División de Pediatría, Pontificia Universidad Católica de Chile, Pediatra-Genetista, Unidad de Genética, Hospital Dr. Luis Calvo Mackenna, Santiago</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Gripp, Karen W" sort="Gripp, Karen W" uniqKey="Gripp K" first="Karen W." last="Gripp">Karen W. Gripp</name>
<affiliation wicri:level="1"><nlm:aff id="A41">Department of Pediatrics, Sidney Kimmel Medical School at T. Jefferson University, Chief of Division of Medical Genetics, A.I. duPont Hospital for Children, Wilmington, Delaware, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Sidney Kimmel Medical School at T. Jefferson University, Chief of Division of Medical Genetics, A.I. duPont Hospital for Children, Wilmington, Delaware</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Cordisco, Maria" sort="Cordisco, Maria" uniqKey="Cordisco M" first="Maria" last="Cordisco">Maria Cordisco</name>
<affiliation wicri:level="1"><nlm:aff id="A42">Departments of Dermatology and Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Departments of Dermatology and Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Van Esch, Hilde" sort="Van Esch, Hilde" uniqKey="Van Esch H" first="Hilde" last="Van Esch">Hilde Van Esch</name>
<affiliation wicri:level="1"><nlm:aff id="A43">Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Belgique</country>
<wicri:regionArea>Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Garavelli, Livia" sort="Garavelli, Livia" uniqKey="Garavelli L" first="Livia" last="Garavelli">Livia Garavelli</name>
<affiliation wicri:level="1"><nlm:aff id="A44">Clinical Genetics Unit, IRCCS Santa Maria Nuova Hospital, Reggio Emilia, Italy.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Italie</country>
<wicri:regionArea>Clinical Genetics Unit, IRCCS Santa Maria Nuova Hospital, Reggio Emilia</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Curry, Cynthia" sort="Curry, Cynthia" uniqKey="Curry C" first="Cynthia" last="Curry">Cynthia Curry</name>
<affiliation wicri:level="1"><nlm:aff id="A45">University of California, San Francisco, San Francisco/Genetic Medicine Central California, San Francisco, California, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>University of California, San Francisco, San Francisco/Genetic Medicine Central California, San Francisco, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Goriely, Anne" sort="Goriely, Anne" uniqKey="Goriely A" first="Anne" last="Goriely">Anne Goriely</name>
<affiliation wicri:level="1"><nlm:aff id="A46">Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Royaume-Uni</country>
<wicri:regionArea>Weatherall Institute of Molecular Medicine, University of Oxford, Oxford</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kayserilli, Hulya" sort="Kayserilli, Hulya" uniqKey="Kayserilli H" first="Hulya" last="Kayserilli">Hulya Kayserilli</name>
<affiliation wicri:level="1"><nlm:aff id="A47">Koç University, School of Medicine, Medical Genetics Department, Koç University Hospital, Istanbul, Turkey.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Turquie</country>
<wicri:regionArea>Koç University, School of Medicine, Medical Genetics Department, Koç University Hospital, Istanbul</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Shendure, Jay" sort="Shendure, Jay" uniqKey="Shendure J" first="Jay" last="Shendure">Jay Shendure</name>
<affiliation wicri:level="1"><nlm:aff id="A7">Department of Genome Sciences, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Genome Sciences, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A48">Howard Hughes Medical Institute, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Howard Hughes Medical Institute, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Graham, John" sort="Graham, John" uniqKey="Graham J" first="John" last="Graham">John Graham</name>
<affiliation wicri:level="1"><nlm:aff id="A49">Department of Pediatrics, Cedars-Sinai Medical Center, Harbor-UCLA Medical Center, David Geffen School of Medicine Los Angeles, California, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Cedars-Sinai Medical Center, Harbor-UCLA Medical Center, David Geffen School of Medicine Los Angeles, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Guerrini, Renzo" sort="Guerrini, Renzo" uniqKey="Guerrini R" first="Renzo" last="Guerrini">Renzo Guerrini</name>
<affiliation wicri:level="1"><nlm:aff id="A4">Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A. Meyer Children’s Hospital, University of Florence, Florence, Italy.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Italie</country>
<wicri:regionArea>Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A. Meyer Children’s Hospital, University of Florence, Florence</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Dobyns, William B" sort="Dobyns, William B" uniqKey="Dobyns W" first="William B." last="Dobyns">William B. Dobyns</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
<affiliation><nlm:aff wicri:cut=" and" id="A2">Center for Integrative Brain Research</nlm:aff>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A35">Department of Neurology, University of Washington, Seattle, Washington, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Neurology, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">JCI Insight</title>
<idno type="eISSN">2379-3708</idno>
<imprint><date when="????">????</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
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<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of <italic>PIK3CA</italic>
have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified <italic>PIK3CA</italic>
mutations in 60 individuals. Several other individuals (<italic>n</italic>
= 12) were identified separately to have mutations in <italic>PIK3CA</italic>
by clinical targeted-panel testing (<italic>n</italic>
= 6), whole-exome sequencing (<italic>n</italic>
= 5), or Sanger sequencing (<italic>n</italic>
= 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 <italic>PIK3CA</italic>
mutations were novel. We also identified constitutional <italic>PIK3CA</italic>
mutations in 10 patients. Our molecular data, combined with review of the literature, show that <italic>PIK3CA</italic>
-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations.</p>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Vattathil, S" uniqKey="Vattathil S">S Vattathil</name>
</author>
<author><name sortKey="Scheet, P" uniqKey="Scheet P">P Scheet</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Biesecker, Lg" uniqKey="Biesecker L">LG Biesecker</name>
</author>
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<journal-id journal-id-type="iso-abbrev">JCI Insight</journal-id>
<journal-id journal-id-type="publisher-id">JCI Insight</journal-id>
<journal-title-group><journal-title>JCI Insight</journal-title>
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<issn pub-type="epub">2379-3708</issn>
<publisher><publisher-name>American Society for Clinical Investigation</publisher-name>
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<article-meta><article-id pub-id-type="pmid">27631024</article-id>
<article-id pub-id-type="pmc">5019182</article-id>
<article-id pub-id-type="publisher-id">87623</article-id>
<article-id pub-id-type="doi">10.1172/jci.insight.87623</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
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<title-group><article-title><italic>PIK3CA</italic>
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<xref ref-type="aff" rid="A22">22</xref>
<xref ref-type="aff" rid="A23">23</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0002-7780-6542</contrib-id>
<name><surname>Keegan</surname>
<given-names>Catherine E.</given-names>
</name>
<email>keeganc@med.umich.edu</email>
<xref ref-type="aff" rid="A22">22</xref>
<xref ref-type="aff" rid="A23">23</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Yin</surname>
<given-names>Lim Jiin</given-names>
</name>
<xref ref-type="aff" rid="A24">24</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lai</surname>
<given-names>Angeline Hwei Meeng</given-names>
</name>
<email>angeline.lai.h.m@singhealth.com.sg</email>
<xref ref-type="aff" rid="A24">24</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Martin</surname>
<given-names>Nicole</given-names>
</name>
<email>NMartin@mtsinai.on.ca</email>
<xref ref-type="aff" rid="A12">12</xref>
</contrib>
<contrib contrib-type="author"><name><surname>McKinnon</surname>
<given-names>Margaret</given-names>
</name>
<xref ref-type="aff" rid="A25">25</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Addor</surname>
<given-names>Marie-Claude</given-names>
</name>
<xref ref-type="aff" rid="A26">26</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0003-2017-4270</contrib-id>
<name><surname>Boccuto</surname>
<given-names>Luigi</given-names>
</name>
<email>lboccuto@ggc.org</email>
<xref ref-type="aff" rid="A27">27</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Schwartz</surname>
<given-names>Charles E.</given-names>
</name>
<email>ceschwartz@ggc.org</email>
<xref ref-type="aff" rid="A27">27</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lanoel</surname>
<given-names>Agustina</given-names>
</name>
<email>agustinalanoel@hotmail.com</email>
<xref ref-type="aff" rid="A28">28</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Conway</surname>
<given-names>Robert L.</given-names>
</name>
<email>rconway@med.wayne.edu</email>
<xref ref-type="aff" rid="A29">29</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Devriendt</surname>
<given-names>Koenraad</given-names>
</name>
<email>koenraad.devriendt@uzleuven.be</email>
<xref ref-type="aff" rid="A30">30</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tatton-Brown</surname>
<given-names>Katrina</given-names>
</name>
<email>Kate.Tatton-Brown@icr.ac.uk</email>
<xref ref-type="aff" rid="A31">31</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Pierpont</surname>
<given-names>Mary Ella</given-names>
</name>
<email>pierp001@umn.edu</email>
<xref ref-type="aff" rid="A32">32</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Painter</surname>
<given-names>Michael</given-names>
</name>
<email>mjp24@pitt.edu</email>
<xref ref-type="aff" rid="A33">33</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Worgan</surname>
<given-names>Lisa</given-names>
</name>
<email>Lisa.Worgan@sswahs.nsw.gov.au</email>
<xref ref-type="aff" rid="A34">34</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Reggin</surname>
<given-names>James</given-names>
</name>
<email>James.Reggin@providence.org</email>
<xref ref-type="aff" rid="A35">35</xref>
<xref ref-type="aff" rid="A36">36</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hennekam</surname>
<given-names>Raoul</given-names>
</name>
<email>r.c.hennekam@amc.uva.nl</email>
<xref ref-type="aff" rid="A37">37</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0003-1406-5000</contrib-id>
<name><surname>Tsuchiya</surname>
<given-names>Karen</given-names>
</name>
<email>karen.tsuchiya@seattlechildrens.org</email>
<xref ref-type="aff" rid="A38">38</xref>
<xref ref-type="aff" rid="A39">39</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Pritchard</surname>
<given-names>Colin C.</given-names>
</name>
<email>cpritch@uw.edu</email>
<xref ref-type="aff" rid="A39">39</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Aracena</surname>
<given-names>Mariana</given-names>
</name>
<email>maracen@gmail.com</email>
<xref ref-type="aff" rid="A40">40</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gripp</surname>
<given-names>Karen W.</given-names>
</name>
<email>Karen.Gripp@nemours.org</email>
<xref ref-type="aff" rid="A41">41</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cordisco</surname>
<given-names>Maria</given-names>
</name>
<email>Maria_Cordisco@URMC.Rochester.edu</email>
<xref ref-type="aff" rid="A42">42</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Van Esch</surname>
<given-names>Hilde</given-names>
</name>
<email>hilde.vanesch@uz.kuleuven.ac.be</email>
<xref ref-type="aff" rid="A43">43</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Garavelli</surname>
<given-names>Livia</given-names>
</name>
<email>Livia.Garavelli@asmn.re.it</email>
<xref ref-type="aff" rid="A44">44</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Curry</surname>
<given-names>Cynthia</given-names>
</name>
<email>cynthia.curry@gmail.com</email>
<xref ref-type="aff" rid="A45">45</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Goriely</surname>
<given-names>Anne</given-names>
</name>
<email>anne.goriely@imm.ox.ac.uk</email>
<xref ref-type="aff" rid="A46">46</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kayserilli</surname>
<given-names>Hulya</given-names>
</name>
<xref ref-type="aff" rid="A47">47</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Shendure</surname>
<given-names>Jay</given-names>
</name>
<email>shendure@u.washington.edu</email>
<xref ref-type="aff" rid="A7">7</xref>
<xref ref-type="aff" rid="A48">48</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Graham</surname>
<given-names>John</given-names>
<suffix>Jr.</suffix>
</name>
<xref ref-type="aff" rid="A49">49</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Guerrini</surname>
<given-names>Renzo</given-names>
</name>
<email>r.guerrini@meyer.it</email>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dobyns</surname>
<given-names>William B.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A35">35</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.</aff>
<aff id="A2"><label>2</label>
Center for Integrative Brain Research and</aff>
<aff id="A3"><label>3</label>
Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, Seattle, Washington, USA.</aff>
<aff id="A4"><label>4</label>
Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A. Meyer Children’s Hospital, University of Florence, Florence, Italy.</aff>
<aff id="A5"><label>5</label>
Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.</aff>
<aff id="A6"><label>6</label>
Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.</aff>
<aff id="A7"><label>7</label>
Department of Genome Sciences, University of Washington, Seattle, Washington, USA.</aff>
<aff id="A8"><label>8</label>
Whole Exome Sequencing Program, GeneDx, Gaithersburg, Maryland, USA.</aff>
<aff id="A9"><label>9</label>
Regional Genetics Program, The Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada.</aff>
<aff id="A10"><label>10</label>
Department of Pediatrics, and Pediatric Neurology and Developmental Medicine, University Children’s Hospital, Tübingen, Germany.</aff>
<aff id="A11"><label>11</label>
Mount Sinai Hospital, The Prenatal Diagnosis and Medical Genetics Division, Department of Obstetrics and Gynecology, and</aff>
<aff id="A12"><label>12</label>
Department of Pediatrics, Division of Clinical and Metabolic Genetics, University of Toronto, Toronto, Ontario, Canada.</aff>
<aff id="A13"><label>13</label>
Center for Human Genetics, University Hospitals Case Medical Center, Cleveland, Ohio, USA.</aff>
<aff id="A14"><label>14</label>
Department of Pediatrics, Division of Medical Genetics, Saint Louis University, St. Louis, Missouri, USA.</aff>
<aff id="A15"><label>15</label>
Department of Pediatrics, University of Vermont College of Medicine, Burlington, Vermont, USA.</aff>
<aff id="A16"><label>16</label>
Department of Clinical Genetics, Royal North Shore Hospital, St Leonards, New South Wales, Australia.</aff>
<aff id="A17"><label>17</label>
Belfast Health and Social Care Trust, Belfast, United Kingdom.</aff>
<aff id="A18"><label>18</label>
Genetics, Metabolism and Pediatrics, London, Ontario, Canada.</aff>
<aff id="A19"><label>19</label>
Clinical Genetics, Center for Personalized Medicine, Children’s Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California, USA.</aff>
<aff id="A20"><label>20</label>
Neurology Unit, Schneider Children’s Medical Center of Israel, Petach Tikva, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.</aff>
<aff id="A21"><label>21</label>
School of Medicine, Griffith University, Brisbane, Queensland, Australia.</aff>
<aff id="A22"><label>22</label>
Division of Genetics, Department of Pediatrics, and</aff>
<aff id="A23"><label>23</label>
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.</aff>
<aff id="A24"><label>24</label>
Genetics Service, Department of Pediatric Medicine, KK Women’s and Children’s Hospital, Singapore.</aff>
<aff id="A25"><label>25</label>
British Columbia Medical Genetics Provincial Program, University of British Columbia, Vancouver, British Columbia, Canada.</aff>
<aff id="A26"><label>26</label>
Service de génétique médicale, Centre Hospitalier Universitaire Vaudois CHUV, Switzerland.</aff>
<aff id="A27"><label>27</label>
Greenwood Genetic Center, Greenwood, South Carolina, USA.</aff>
<aff id="A28"><label>28</label>
Department of Dermatology, Children Hospital Prof. Dr. J. P. Garrahan, Buenos Aires, Argentina.</aff>
<aff id="A29"><label>29</label>
Children’s Hospital of Michigan, Wayne State University, Detroit, Michigan, USA.</aff>
<aff id="A30"><label>30</label>
Center for Human Genetics, University Hospitals Leuven and KU Leuven, Leuven, Belgium.</aff>
<aff id="A31"><label>31</label>
South West Thames Regional Genetics Service, St George’s University NHS Foundation Trust, London, and Section of Cancer Genetics, Institute of Cancer Research, Sutton, United Kingdom.</aff>
<aff id="A32"><label>32</label>
Department of Pediatrics and Ophthalmology, University of Minnesota, Minneapolis, Minnesota, USA.</aff>
<aff id="A33"><label>33</label>
Department of Child Neurology, University of Florida, Jacksonville, Florida, USA.</aff>
<aff id="A34"><label>34</label>
Department of Genetics, Liverpool Hospital, Liverpool, New South Wales, Australia.</aff>
<aff id="A35"><label>35</label>
Department of Neurology, University of Washington, Seattle, Washington, USA.</aff>
<aff id="A36"><label>36</label>
Providence Child Neurology, Providence Sacred Heart Medical Center and Children’s Hospital, Spokane, Washington, USA.</aff>
<aff id="A37"><label>37</label>
Department of Pediatrics and Translational Genetics, Department of Pediatrics, Academic Medical Center, University of Amsterdam Medical Center, Amsterdam, The Netherlands.</aff>
<aff id="A38"><label>38</label>
Department of Laboratories, Seattle Children’s Hospital and</aff>
<aff id="A39"><label>39</label>
Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.</aff>
<aff id="A40"><label>40</label>
División de Pediatría, Pontificia Universidad Católica de Chile, Pediatra-Genetista, Unidad de Genética, Hospital Dr. Luis Calvo Mackenna, Santiago, Chile.</aff>
<aff id="A41"><label>41</label>
Department of Pediatrics, Sidney Kimmel Medical School at T. Jefferson University, Chief of Division of Medical Genetics, A.I. duPont Hospital for Children, Wilmington, Delaware, USA.</aff>
<aff id="A42"><label>42</label>
Departments of Dermatology and Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.</aff>
<aff id="A43"><label>43</label>
Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.</aff>
<aff id="A44"><label>44</label>
Clinical Genetics Unit, IRCCS Santa Maria Nuova Hospital, Reggio Emilia, Italy.</aff>
<aff id="A45"><label>45</label>
University of California, San Francisco, San Francisco/Genetic Medicine Central California, San Francisco, California, USA.</aff>
<aff id="A46"><label>46</label>
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.</aff>
<aff id="A47"><label>47</label>
Koç University, School of Medicine, Medical Genetics Department, Koç University Hospital, Istanbul, Turkey.</aff>
<aff id="A48"><label>48</label>
Howard Hughes Medical Institute, Seattle, Washington, USA.</aff>
<aff id="A49"><label>49</label>
Department of Pediatrics, Cedars-Sinai Medical Center, Harbor-UCLA Medical Center, David Geffen School of Medicine Los Angeles, California, USA.</aff>
<author-notes><corresp>Address correspondence to: Ghayda Mirzaa, Center for Integrative Brain Research, Seattle Children’s Research Institute, 1900 9th Avenue, Mailstop C9S-10, Seattle, Washington 98101, USA. Phone: 206.884.1276; E-mail: <email>gmirzaa@uw.edu</email>
.</corresp>
</author-notes>
<pub-date date-type="pub" publication-format="electronic" iso-8601-date="2016-06-16"><day>16</day>
<month>6</month>
<year>2016</year>
</pub-date>
<pub-date date-type="collection" publication-format="electronic" iso-8601-date="2016-06-16"><day>16</day>
<month>6</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>16</day>
<month>6</month>
<year>2016</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and
0 days and was based on the . </pmc-comment>
<volume>1</volume>
<issue>9</issue>
<elocation-id>e87623</elocation-id>
<history><date date-type="received"><day>23</day>
<month>3</month>
<year>2016</year>
</date>
<date date-type="accepted"><day>17</day>
<month>5</month>
<year>2016</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2016 Mirzaa et al.</copyright-statement>
<copyright-year>2016</copyright-year>
<copyright-holder>Mirzaa et al.</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p><pmc-comment>CREATIVE COMMONS</pmc-comment>
This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
.</license-p>
</license>
</permissions>
<self-uri xlink:href="https://insight.jci.org/articles/view/87623">This article is available online at https://insight.jci.org/articles/view/87623</self-uri>
<abstract><p>Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of <italic>PIK3CA</italic>
have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified <italic>PIK3CA</italic>
mutations in 60 individuals. Several other individuals (<italic>n</italic>
= 12) were identified separately to have mutations in <italic>PIK3CA</italic>
by clinical targeted-panel testing (<italic>n</italic>
= 6), whole-exome sequencing (<italic>n</italic>
= 5), or Sanger sequencing (<italic>n</italic>
= 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 <italic>PIK3CA</italic>
mutations were novel. We also identified constitutional <italic>PIK3CA</italic>
mutations in 10 patients. Our molecular data, combined with review of the literature, show that <italic>PIK3CA</italic>
-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations.</p>
</abstract>
<abstract abstract-type="toc"><p>The clinical and molecular spectrum of PIK3CA-related developmental disorders are correlated with types of mutations, tissue distributions, and levels of mosaicism with the clinical phenotype.</p>
</abstract>
</article-meta>
</front>
<floats-group><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label>
<caption><title>Levels of mosaicism in <italic>PIK3CA</italic>
by sample type.</title>
<p>Dot blot graph showing alternative allele percentages (AAPs) clustered by type of tissue in all mutation-positive individuals (<italic>n</italic>
= 72). Horizontal bars indicate the mean AAP within each sample type: red = blood (<italic>n</italic>
= 44); blue = saliva (<italic>n</italic>
= 38); orange = skin fibroblasts (<italic>n</italic>
= 26). Two-tailed <italic>t</italic>
test (<italic>P</italic>
values): blood-saliva: <italic>P</italic>
= 0.035; blood-skin: <italic>P</italic>
= 0.036; saliva-skin, <italic>P</italic>
= 0.65.</p>
</caption>
<graphic xlink:href="jciinsight-1-87623-g001"></graphic>
</fig>
<fig id="F2" orientation="portrait" position="float"><label>Figure 2</label>
<caption><title>Distribution of <italic>PIK3CA</italic>
mutations by functional domain in cancer and developmental (pediatric) disorders.</title>
<p>Graph showing the number of published <italic>PIK3CA</italic>
mutations by amino acid location in the Catalogue of Somatic Mutations in Cancer (COSMIC) database of somatic variation in cancer (shown in green; last accessed May 2016) and in children with developmental disorders comparing the megalencephaly-capillary malformation syndrome (MCAP; shown in blue) and all other developmental disorders (shown in orange). Mutations shown include those reported in this study as well as published mutations. Notes: (a) The 2-tailed <italic>P</italic>
value by Fisher’s exact test was less than 0.0001, supporting that the association between MCAP and non-hotspot mutations and non-MCAP and hotspot associations is extremely statistically significant. (b) “Hotspot” mutations in this analysis are the most activating mutations in somatic tissues in cancer (p.Glu542Lys, p.Glu545Lys, p.His1047Arg) (<xref rid="B13" ref-type="bibr">13</xref>
).</p>
</caption>
<graphic xlink:href="jciinsight-1-87623-g002"></graphic>
</fig>
<fig id="F3" orientation="portrait" position="float"><label>Figure 3</label>
<caption><title>Clinical photographs of MCAP patients.</title>
<p>(<bold>A</bold>
) Facial photograph of patient LR14-323 (p.Arg83Gln). (<bold>B</bold>
–<bold>D</bold>
) Photograph of the face (<bold>B</bold>
), occipital region (<bold>C</bold>
), and left foot (<bold>D</bold>
) of LR13-359 (p.Pro104Leu) showing MEG, occipital capillary malformation, and syndactyly of the second, third, and fourth toes. (<bold>E</bold>
) Computed tomography (CT) image of LR01-060 (p.Pro104Leu) showing the subcutaneous hemangioma (arrowheads). (<bold>F</bold>
) Photograph of the trunk of LR12-080 (p.Arg115Pro) showing cutaneous capillary malformation with midline delineation. (<bold>G</bold>
) Photograph of LR12-365 (p.Asn345Thr) showing diffuse capillary malformations, MEG with a prominent forehead, and postaxial polydactyly of the left hand. (<bold>H</bold>
) Photograph of LR13-036 (p.Glu365Lys) showing MEG, a disproportionately small body, and short extremities (clinically diagnosed with rhizomelic shortening of the extremities). (<bold>I</bold>
) Photograph of LR11-418 (p.Cys378Tyr) showing diffuse capillary malformations and apparent megalencephaly (MEG). (<bold>J</bold>
and <bold>K</bold>
) Photograph of the face (<bold>J</bold>
) and left foot (<bold>K</bold>
) of LR12-330 (p.Glu545Asp) showing clear MEG, capillary malformation of the philtrum, skin laxity of the forehead, and syndactyly of the second, third, and fourth toes. (<bold>L</bold>
and <bold>M</bold>
) Photographs of the face (<bold>L</bold>
) and body (<bold>M</bold>
) of LR13-038 (p.Gly914Arg) showing MEG, reticulated capillary malformations, pigmented nevus of the right arm, and asymmetry of the legs. (<bold>N</bold>
and <bold>O</bold>
) Photographs of the chest (<bold>N</bold>
) and lower extremity (<bold>O</bold>
) of LR12-383 (p.Gly914Arg) showing clear asymmetry of the trunk involving the right breast and overgrowth of the right leg with prominent venous network. (<bold>P</bold>
and <bold>Q</bold>
) photographs of the left (<bold>P</bold>
) and right (<bold>Q</bold>
) feet of LR11-081 (p.Thr1025Ala) showing bilateral asymmetric macrodactyly, sandal-gap toes, and capillary malformations. (<bold>R</bold>
) Photograph of the feet of LR13-169 (p.Ala1035Thr) showing syndactyly of the second, third, and fourth toes on the right, and second and third toes on the left. (<bold>S</bold>
and <bold>T</bold>
) photographs of the face (<bold>S</bold>
) and lower extremities (<bold>T</bold>
) of LR12-328 (p.Met1043Ile) showing facial and body asymmetry, MEG with a prominent forehead, and capillary malformations on the face and body.</p>
</caption>
<graphic xlink:href="jciinsight-1-87623-g003"></graphic>
</fig>
<fig id="F4" orientation="portrait" position="float"><label>Figure 4</label>
<caption><title>Clinical photographs of <italic>PIK3CA</italic>
mutation–positive patients with segmental overgrowth.</title>
<p>(<bold>A</bold>
–<bold>D</bold>
) Photographs at 1 year (<bold>A</bold>
), birth (<bold>B</bold>
), right foot (<bold>C</bold>
), and left foot (<bold>D</bold>
) of LR11-082 (p.Gly106Val) showing diffuse and asymmetric body overgrowth, diffuse capillary malformations, bilateral syndactyly of second, third, and fourth toes, and joint hypermobility. (<bold>E</bold>
–<bold>G</bold>
) Photograph of the body (<bold>E</bold>
and <bold>F</bold>
) and left foot (<bold>G</bold>
) of LR12-070 (Glu453Lys) showing asymmetric overgrowth, capillary malformations with midline delineation, and postsurgical changes after resection of the second toe due to severe macrodactyly. (<bold>H</bold>
and <bold>I</bold>
) Facial photographs of patient LR12-183 (p.Glu542Lys) showing multiple epidermal nevi. (<bold>J</bold>
and <bold>K</bold>
) Photographs of LR12-172 (p.His1047Arg) showing macrodactyly of the left hand.</p>
</caption>
<graphic xlink:href="jciinsight-1-87623-g004"></graphic>
</fig>
<fig id="F5" orientation="portrait" position="float"><label>Figure 5</label>
<caption><title>Brain MRI images of <italic>PIK3CA</italic>
mutation–positive patients.</title>
<p>(<bold>A</bold>
and <bold>B</bold>
) LR11-082. T1-weighted mid-sagittal (<bold>A</bold>
) and T2-weighted axial (<bold>B</bold>
) image at age 6 months showing a large cerebellum, crowded posterior fossa with cerebellar tonsillar ectopia, and a relatively normal cortical gyral pattern (arrowhead). (<bold>C</bold>
) LR12-184. T1-weighted mid-sagittal image showing marked cerebellar tonsillar ectopia (arrowhead). (<bold>D</bold>
–<bold>H</bold>
) LR12-183. T1-weighted mid-sagittal (<bold>D</bold>
), T2-weighted axial (<bold>E</bold>
and <bold>G</bold>
), and coronal (<bold>F</bold>
) images showing diffuse cortical dysplasia, partial agenesis of the corpus callosum, dysplasia/hypoplasia of the cerebellar vermis and hemispheres, diffuse dysmyelination, abnormal high T2 signal intensities in the red nuclei and thalami bilaterally (red arrows in <bold>E</bold>
and <bold>F</bold>
), and a very large tectum (red arrow in <bold>D</bold>
). (<bold>H</bold>
and <bold>I</bold>
) LR13-197. T1-weighted mid-sagittal (<bold>H</bold>
) and T2-weighted axial (<bold>I</bold>
) images showing bilateral cortical dysplasia, hippocampal dysplasia, white matter dysmyelination, and bilaterally dysplastic ventricles. There is mild cerebellar tonsillar ectopia (arrow in <bold>H</bold>
).</p>
</caption>
<graphic xlink:href="jciinsight-1-87623-g005"></graphic>
</fig>
<fig id="F6" orientation="portrait" position="float"><label>Figure 6</label>
<caption><title>The PI3K-AKT-MTOR–related developmental brain disorders spectrum.</title>
<p>Diagram showing the PI3K-AKT-MTOR pathway highlighting genes associated with developmental brain disorders including <italic>PIK3CA</italic>
, <italic>PIK3R2</italic>
, <italic>PTEN</italic>
, <italic>AKT3</italic>
, <italic>MTOR</italic>
, <italic>CCND2</italic>
, <italic>DEPDC5</italic>
, <italic>NPRL2</italic>
, and <italic>NPRL3</italic>
(shown in blue), as well as <italic>TSC1</italic>
and <italic>TSC2</italic>
genes (shown in red).</p>
</caption>
<graphic xlink:href="jciinsight-1-87623-g006"></graphic>
</fig>
<table-wrap id="T5" orientation="portrait" position="float"><label>Table 5</label>
<caption><title>Comparison of intermediate and hotspot <italic>PIK3CA</italic>
gain-of-function phenotypes</title>
</caption>
<graphic xlink:href="jciinsight-1-87623-g011"></graphic>
</table-wrap>
<table-wrap id="T4" orientation="portrait" position="float"><label>Table 4</label>
<caption><title><italic>PIK3CA</italic>
mutations and levels of mosaicism — part 3 (<italic>n</italic>
= 31 patients) [<italic>PIK3CA</italic>
: NM_006218.2]</title>
</caption>
<graphic xlink:href="jciinsight-1-87623-g010"></graphic>
</table-wrap>
<table-wrap id="T3" orientation="portrait" position="float"><label>Table 3</label>
<caption><title><italic>PIK3CA</italic>
mutations and levels of mosaicism — part 2 (<italic>n</italic>
= 19 patients) [<italic>PIK3CA</italic>
: NM_006218.2]</title>
</caption>
<graphic xlink:href="jciinsight-1-87623-g009"></graphic>
</table-wrap>
<table-wrap id="T2" orientation="portrait" position="float"><label>Table 2</label>
<caption><title><italic>PIK3CA</italic>
mutations and levels of mosaicism — part 1 (<italic>n</italic>
= 22 patients) [<italic>PIK3CA</italic>
: NM_006218.2]</title>
</caption>
<graphic xlink:href="jciinsight-1-87623-g008"></graphic>
</table-wrap>
<table-wrap id="T1" orientation="portrait" position="float"><label>Table 1</label>
<caption><title>Cohort of children with brain and/or body overgrowth screened for <italic>PIK3CA</italic>
mutations</title>
</caption>
<graphic xlink:href="jciinsight-1-87623-g007"></graphic>
</table-wrap>
</floats-group>
</pmc>
</record>
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