Characterization of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next generation sequencing study
Identifieur interne : 002C32 ( Pmc/Curation ); précédent : 002C31; suivant : 002C33Characterization of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next generation sequencing study
Auteurs : Ghayda Mirzaa [États-Unis] ; Valerio Conti [Italie] ; Andrew E. Timms [États-Unis] ; Christopher D. Smyser [États-Unis] ; Sarah Ahmed [États-Unis] ; Melissa Carter [Canada] ; Sarah Barnett [États-Unis] ; Robert B. Hufnagel [États-Unis] ; Amy Goldstein [États-Unis] ; Yoko Narumi-Kishimoto [Japon] ; Carissa Olds [États-Unis] ; Sarah Collins [États-Unis] ; Kathreen Johnston [États-Unis] ; Jean-François Deleuze [France] ; Patrick Nitschké [France] ; Kathryn Friend [Australie] ; Catharine Harris [États-Unis] ; Allison Goetsch [États-Unis] ; Beth Martin [États-Unis] ; Evan August Boyle [États-Unis] ; Elena Parrini [Italie] ; Davide Mei [Italie] ; Lorenzo Tattini [Italie] ; Anne Slavotinek [États-Unis] ; Ed Blair [Royaume-Uni] ; Christopher Barnett [Australie] ; Jay Shendure [États-Unis] ; Jamel Chelly [France] ; William B. Dobyns [États-Unis] ; Renzo Guerrini [Italie]Source :
- The Lancet. Neurology [ 1474-4422 ] ; 2015.
Abstract
Bilateral perisylvian polymicrogyria (BPP), the most common form of regional polymicrogyria, causes the congenital bilateral perisylvian syndrome, featuring oromotor dysfunction, cognitive impairment and epilepsy. BPP is etiologically heterogeneous, but only a few genetic causes have been reported. The aim of this study was to identify additional genetic etiologies of BPP and delineate their frequency in this patient population.
We performed child-parent (trio)-based whole exome sequencing (WES)
on eight children with BPP. Following the identification of mosaic
Using WES, we identified a mosaic mutation (p.Gly373Arg) in the
regulatory subunit of the PI3K-AKT-MTOR pathway,
Constitutional and mosaic mutations in the
Url:
DOI: 10.1016/S1474-4422(15)00278-1
PubMed: 26520804
PubMed Central: 4672724
Links toward previous steps (curation, corpus...)
- to stream Pmc, to step Corpus: Pour aller vers cette notice dans l'étape Curation :002D82
Links to Exploration step
PMC:4672724Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Characterization of mutations of the phosphoinositide-3-kinase
regulatory subunit, <italic>PIK3R2</italic>
, in perisylvian polymicrogyria: a
next generation sequencing study</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">États-Unis</country>
<wicri:regionArea>Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Integrative Brain Research, 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="A3">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">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="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="A4">Center for Developmental Biology and Regenerative, Medicine, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
<country xml:lang="fr">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="Smyser, Christopher D" sort="Smyser, Christopher D" uniqKey="Smyser C" first="Christopher D." last="Smyser">Christopher D. Smyser</name>
<affiliation wicri:level="1"><nlm:aff id="A5">Departments of Neurology and Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departments of Neurology and Pediatrics, Washington University School of Medicine, St. Louis, Missouri</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ahmed, Sarah" sort="Ahmed, Sarah" uniqKey="Ahmed S" first="Sarah" last="Ahmed">Sarah Ahmed</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington</wicri:regionArea>
</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="A6">Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Barnett, Sarah" sort="Barnett, Sarah" uniqKey="Barnett S" first="Sarah" last="Barnett">Sarah Barnett</name>
<affiliation wicri:level="1"><nlm:aff id="A7">Division of Medical Genetics, University of Missouri, Missouri, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Medical Genetics, University of Missouri, Missouri</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Hufnagel, Robert B" sort="Hufnagel, Robert B" uniqKey="Hufnagel R" first="Robert B." last="Hufnagel">Robert B. Hufnagel</name>
<affiliation wicri:level="1"><nlm:aff id="A8">Division of Human Genetics, Cincinnati Children’s Hospital, Cincinnati, Ohio, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Human Genetics, Cincinnati Children’s Hospital, Cincinnati, Ohio</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Goldstein, Amy" sort="Goldstein, Amy" uniqKey="Goldstein A" first="Amy" last="Goldstein">Amy Goldstein</name>
<affiliation wicri:level="1"><nlm:aff id="A9">Division of Child Neurology, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Child Neurology, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Narumi Kishimoto, Yoko" sort="Narumi Kishimoto, Yoko" uniqKey="Narumi Kishimoto Y" first="Yoko" last="Narumi-Kishimoto">Yoko Narumi-Kishimoto</name>
<affiliation wicri:level="1"><nlm:aff id="A10">Department of Pediatrics, Shimada Ryoiku Center Hachiouji, Tokyo, Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Pediatrics, Shimada Ryoiku Center Hachiouji, Tokyo</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Olds, Carissa" sort="Olds, Carissa" uniqKey="Olds C" first="Carissa" last="Olds">Carissa Olds</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Collins, Sarah" sort="Collins, Sarah" uniqKey="Collins S" first="Sarah" last="Collins">Sarah Collins</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Johnston, Kathreen" sort="Johnston, Kathreen" uniqKey="Johnston K" first="Kathreen" last="Johnston">Kathreen Johnston</name>
<affiliation wicri:level="1"><nlm:aff id="A11">Genetics Department, The Permanente Medical Group, San Francisco, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Genetics Department, The Permanente Medical Group, San Francisco, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Deleuze, Jean Francois" sort="Deleuze, Jean Francois" uniqKey="Deleuze J" first="Jean-François" last="Deleuze">Jean-François Deleuze</name>
<affiliation wicri:level="1"><nlm:aff id="A12">Centre National de Génotypage, Evry, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Centre National de Génotypage, Evry</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Nitschke, Patrick" sort="Nitschke, Patrick" uniqKey="Nitschke P" first="Patrick" last="Nitschké">Patrick Nitschké</name>
<affiliation wicri:level="1"><nlm:aff id="A13">Plateforme de Bioinformatique Paris-Descartes, Institut Imagine, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Plateforme de Bioinformatique Paris-Descartes, Institut Imagine, Paris</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Friend, Kathryn" sort="Friend, Kathryn" uniqKey="Friend K" first="Kathryn" last="Friend">Kathryn Friend</name>
<affiliation wicri:level="1"><nlm:aff id="A14">Genetics and Molecular Pathology, Women’s and Children’s Hospital, North Adelaide, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Genetics and Molecular Pathology, Women’s and Children’s Hospital, North Adelaide</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Harris, Catharine" sort="Harris, Catharine" uniqKey="Harris C" first="Catharine" last="Harris">Catharine Harris</name>
<affiliation wicri:level="1"><nlm:aff id="A7">Division of Medical Genetics, University of Missouri, Missouri, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Medical Genetics, University of Missouri, Missouri</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Goetsch, Allison" sort="Goetsch, Allison" uniqKey="Goetsch A" first="Allison" last="Goetsch">Allison Goetsch</name>
<affiliation wicri:level="1"><nlm:aff id="A15">Division of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois</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="A16">Department of Genome Sciences, University of Washington, Seattle, Washington, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genome Sciences, University of Washington, Seattle, Washington</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="A17">Department of Genetics, Stanford University School of Medicine, Stanford, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics, Stanford University School of Medicine, Stanford, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Parrini, Elena" sort="Parrini, Elena" uniqKey="Parrini E" first="Elena" last="Parrini">Elena Parrini</name>
<affiliation wicri:level="1"><nlm:aff id="A3">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">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="Mei, Davide" sort="Mei, Davide" uniqKey="Mei D" first="Davide" last="Mei">Davide Mei</name>
<affiliation wicri:level="1"><nlm:aff id="A3">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">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="Tattini, Lorenzo" sort="Tattini, Lorenzo" uniqKey="Tattini L" first="Lorenzo" last="Tattini">Lorenzo Tattini</name>
<affiliation wicri:level="1"><nlm:aff id="A3">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">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="Slavotinek, Anne" sort="Slavotinek, Anne" uniqKey="Slavotinek A" first="Anne" last="Slavotinek">Anne Slavotinek</name>
<affiliation wicri:level="1"><nlm:aff id="A18">Department of Pediatrics, Division of Genetics, University of California, San Francisco, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Division of Genetics, University of California, San Francisco, CA</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Blair, Ed" sort="Blair, Ed" uniqKey="Blair E" first="Ed" last="Blair">Ed Blair</name>
<affiliation wicri:level="1"><nlm:aff id="A19">Department of Clinical Genetics, Churchill Hospital, Oxford University Hospitals, Headington, United Kingdom</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Department of Clinical Genetics, Churchill Hospital, Oxford University Hospitals, Headington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Barnett, Christopher" sort="Barnett, Christopher" uniqKey="Barnett C" first="Christopher" last="Barnett">Christopher Barnett</name>
<affiliation wicri:level="1"><nlm:aff id="A20">South Australian Clinical Genetics Service, Women’s and Children’s Hospital/SA Pathology, North Adelaide, Australia, Discipline of Pediatrics, University of Adelaide, Adelaide, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>South Australian Clinical Genetics Service, Women’s and Children’s Hospital/SA Pathology, North Adelaide, Australia, Discipline of Pediatrics, University of Adelaide, Adelaide</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="A16">Department of Genome Sciences, University of Washington, Seattle, Washington, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genome Sciences, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Chelly, Jamel" sort="Chelly, Jamel" uniqKey="Chelly J" first="Jamel" last="Chelly">Jamel Chelly</name>
<affiliation wicri:level="1"><nlm:aff id="A21">Pôle de biologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Pôle de biologie, Hôpitaux Universitaires de Strasbourg, Strasbourg</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A22">IGBMC, Translational Medicine and Neurogenetics Department. Illkirch, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>IGBMC, Translational Medicine and Neurogenetics Department. Illkirch</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">États-Unis</country>
<wicri:regionArea>Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington</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="A3">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">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>
<affiliation wicri:level="1"><nlm:aff id="A23">IRCCS Stella Maris Foundation, Pisa, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>IRCCS Stella Maris Foundation, Pisa</wicri:regionArea>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">26520804</idno>
<idno type="pmc">4672724</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4672724</idno>
<idno type="RBID">PMC:4672724</idno>
<idno type="doi">10.1016/S1474-4422(15)00278-1</idno>
<date when="2015">2015</date>
<idno type="wicri:Area/Pmc/Corpus">002D82</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002D82</idno>
<idno type="wicri:Area/Pmc/Curation">002C32</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">002C32</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Characterization of mutations of the phosphoinositide-3-kinase
regulatory subunit, <italic>PIK3R2</italic>
, in perisylvian polymicrogyria: a
next generation sequencing study</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">États-Unis</country>
<wicri:regionArea>Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Integrative Brain Research, 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="A3">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">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="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="A4">Center for Developmental Biology and Regenerative, Medicine, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
<country xml:lang="fr">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="Smyser, Christopher D" sort="Smyser, Christopher D" uniqKey="Smyser C" first="Christopher D." last="Smyser">Christopher D. Smyser</name>
<affiliation wicri:level="1"><nlm:aff id="A5">Departments of Neurology and Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departments of Neurology and Pediatrics, Washington University School of Medicine, St. Louis, Missouri</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ahmed, Sarah" sort="Ahmed, Sarah" uniqKey="Ahmed S" first="Sarah" last="Ahmed">Sarah Ahmed</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington</wicri:regionArea>
</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="A6">Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Barnett, Sarah" sort="Barnett, Sarah" uniqKey="Barnett S" first="Sarah" last="Barnett">Sarah Barnett</name>
<affiliation wicri:level="1"><nlm:aff id="A7">Division of Medical Genetics, University of Missouri, Missouri, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Medical Genetics, University of Missouri, Missouri</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Hufnagel, Robert B" sort="Hufnagel, Robert B" uniqKey="Hufnagel R" first="Robert B." last="Hufnagel">Robert B. Hufnagel</name>
<affiliation wicri:level="1"><nlm:aff id="A8">Division of Human Genetics, Cincinnati Children’s Hospital, Cincinnati, Ohio, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Human Genetics, Cincinnati Children’s Hospital, Cincinnati, Ohio</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Goldstein, Amy" sort="Goldstein, Amy" uniqKey="Goldstein A" first="Amy" last="Goldstein">Amy Goldstein</name>
<affiliation wicri:level="1"><nlm:aff id="A9">Division of Child Neurology, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Child Neurology, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Narumi Kishimoto, Yoko" sort="Narumi Kishimoto, Yoko" uniqKey="Narumi Kishimoto Y" first="Yoko" last="Narumi-Kishimoto">Yoko Narumi-Kishimoto</name>
<affiliation wicri:level="1"><nlm:aff id="A10">Department of Pediatrics, Shimada Ryoiku Center Hachiouji, Tokyo, Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Pediatrics, Shimada Ryoiku Center Hachiouji, Tokyo</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Olds, Carissa" sort="Olds, Carissa" uniqKey="Olds C" first="Carissa" last="Olds">Carissa Olds</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Collins, Sarah" sort="Collins, Sarah" uniqKey="Collins S" first="Sarah" last="Collins">Sarah Collins</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Johnston, Kathreen" sort="Johnston, Kathreen" uniqKey="Johnston K" first="Kathreen" last="Johnston">Kathreen Johnston</name>
<affiliation wicri:level="1"><nlm:aff id="A11">Genetics Department, The Permanente Medical Group, San Francisco, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Genetics Department, The Permanente Medical Group, San Francisco, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Deleuze, Jean Francois" sort="Deleuze, Jean Francois" uniqKey="Deleuze J" first="Jean-François" last="Deleuze">Jean-François Deleuze</name>
<affiliation wicri:level="1"><nlm:aff id="A12">Centre National de Génotypage, Evry, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Centre National de Génotypage, Evry</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Nitschke, Patrick" sort="Nitschke, Patrick" uniqKey="Nitschke P" first="Patrick" last="Nitschké">Patrick Nitschké</name>
<affiliation wicri:level="1"><nlm:aff id="A13">Plateforme de Bioinformatique Paris-Descartes, Institut Imagine, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Plateforme de Bioinformatique Paris-Descartes, Institut Imagine, Paris</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Friend, Kathryn" sort="Friend, Kathryn" uniqKey="Friend K" first="Kathryn" last="Friend">Kathryn Friend</name>
<affiliation wicri:level="1"><nlm:aff id="A14">Genetics and Molecular Pathology, Women’s and Children’s Hospital, North Adelaide, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Genetics and Molecular Pathology, Women’s and Children’s Hospital, North Adelaide</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Harris, Catharine" sort="Harris, Catharine" uniqKey="Harris C" first="Catharine" last="Harris">Catharine Harris</name>
<affiliation wicri:level="1"><nlm:aff id="A7">Division of Medical Genetics, University of Missouri, Missouri, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Medical Genetics, University of Missouri, Missouri</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Goetsch, Allison" sort="Goetsch, Allison" uniqKey="Goetsch A" first="Allison" last="Goetsch">Allison Goetsch</name>
<affiliation wicri:level="1"><nlm:aff id="A15">Division of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois</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="A16">Department of Genome Sciences, University of Washington, Seattle, Washington, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genome Sciences, University of Washington, Seattle, Washington</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="A17">Department of Genetics, Stanford University School of Medicine, Stanford, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics, Stanford University School of Medicine, Stanford, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Parrini, Elena" sort="Parrini, Elena" uniqKey="Parrini E" first="Elena" last="Parrini">Elena Parrini</name>
<affiliation wicri:level="1"><nlm:aff id="A3">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">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="Mei, Davide" sort="Mei, Davide" uniqKey="Mei D" first="Davide" last="Mei">Davide Mei</name>
<affiliation wicri:level="1"><nlm:aff id="A3">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">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="Tattini, Lorenzo" sort="Tattini, Lorenzo" uniqKey="Tattini L" first="Lorenzo" last="Tattini">Lorenzo Tattini</name>
<affiliation wicri:level="1"><nlm:aff id="A3">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">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="Slavotinek, Anne" sort="Slavotinek, Anne" uniqKey="Slavotinek A" first="Anne" last="Slavotinek">Anne Slavotinek</name>
<affiliation wicri:level="1"><nlm:aff id="A18">Department of Pediatrics, Division of Genetics, University of California, San Francisco, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Division of Genetics, University of California, San Francisco, CA</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Blair, Ed" sort="Blair, Ed" uniqKey="Blair E" first="Ed" last="Blair">Ed Blair</name>
<affiliation wicri:level="1"><nlm:aff id="A19">Department of Clinical Genetics, Churchill Hospital, Oxford University Hospitals, Headington, United Kingdom</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Department of Clinical Genetics, Churchill Hospital, Oxford University Hospitals, Headington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Barnett, Christopher" sort="Barnett, Christopher" uniqKey="Barnett C" first="Christopher" last="Barnett">Christopher Barnett</name>
<affiliation wicri:level="1"><nlm:aff id="A20">South Australian Clinical Genetics Service, Women’s and Children’s Hospital/SA Pathology, North Adelaide, Australia, Discipline of Pediatrics, University of Adelaide, Adelaide, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>South Australian Clinical Genetics Service, Women’s and Children’s Hospital/SA Pathology, North Adelaide, Australia, Discipline of Pediatrics, University of Adelaide, Adelaide</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="A16">Department of Genome Sciences, University of Washington, Seattle, Washington, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genome Sciences, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Chelly, Jamel" sort="Chelly, Jamel" uniqKey="Chelly J" first="Jamel" last="Chelly">Jamel Chelly</name>
<affiliation wicri:level="1"><nlm:aff id="A21">Pôle de biologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Pôle de biologie, Hôpitaux Universitaires de Strasbourg, Strasbourg</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A22">IGBMC, Translational Medicine and Neurogenetics Department. Illkirch, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>IGBMC, Translational Medicine and Neurogenetics Department. Illkirch</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">États-Unis</country>
<wicri:regionArea>Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington</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="A3">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">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>
<affiliation wicri:level="1"><nlm:aff id="A23">IRCCS Stella Maris Foundation, Pisa, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>IRCCS Stella Maris Foundation, Pisa</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">The Lancet. Neurology</title>
<idno type="ISSN">1474-4422</idno>
<idno type="eISSN">1474-4465</idno>
<imprint><date when="2015">2015</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><title>SUMMARY</title>
<sec id="S1"><title>Background</title>
<p id="P3">Bilateral perisylvian polymicrogyria (BPP), the most common form of
regional polymicrogyria, causes the congenital bilateral perisylvian
syndrome, featuring oromotor dysfunction, cognitive impairment and epilepsy.
BPP is etiologically heterogeneous, but only a few genetic causes have been
reported. The aim of this study was to identify additional genetic
etiologies of BPP and delineate their frequency in this patient
population.</p>
</sec>
<sec id="S2"><title>Methods</title>
<p id="P4">We performed child-parent (trio)-based whole exome sequencing (WES)
on eight children with BPP. Following the identification of mosaic
<italic>PIK3R2</italic>
mutations in two of these eight children, we
performed targeted screening of <italic>PIK3R2</italic>
in a cohort of 118
children with BPP who were ascertained from 1980 until 2015 using two
methods. First, we performed targeted sequencing of the entire
<italic>PIK3R2</italic>
gene by single molecule molecular inversion
probes (smMIPs) on 38 patients with BPP with normal-large head size. Second,
we performed amplicon sequencing of the recurrent <italic>PIK3R2</italic>
mutation (p.Gly373Arg) on 80 children with various types of polymicrogyria
including BPP. One additional patient underwent clinical WES independently,
and was included in this study given the phenotypic similarity to our
cohort. All patients included in this study were children (< 18 years of
age) with polymicrogyria enrolled in our research program.</p>
</sec>
<sec id="S3"><title>Findings</title>
<p id="P5">Using WES, we identified a mosaic mutation (p.Gly373Arg) in the
regulatory subunit of the PI3K-AKT-MTOR pathway, <italic>PIK3R2</italic>
, in
two children with BPP. Of the 38 patients with BPP and normal-large head
size who underwent targeted next generation sequencing by smMIPs, we
identified constitutional and mosaic <italic>PIK3R2</italic>
mutations in 17
additional children. In parallel, one patient was found to have the
recurrent <italic>PIK3R2</italic>
mutation by clinical WES. Seven patients
had BPP alone, and 13 had BPP in association with features of the
megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH).
Nineteen patients had the same mutation (Gly373Arg), and one had a nearby
missense mutation (p.Lys376Glu). Across the entire cohort, mutations were
constitutional in 12 and mosaic in eight patients. Among mosaic patients, we
observed substantial variation in alternate (mutant) allele levels ranging
from 2·5% (10/377) to 36·7% (39/106) of
reads, equivalent to 5–73·4% of cells analyzed.
Levels of mosaicism varied from undetectable to 17·1%
(37/216) of reads in blood-derived compared to 29·4%
(2030/6889) to 43·3% (275/634) in saliva-derived DNA.</p>
</sec>
<sec id="S4"><title>Interpretation</title>
<p id="P6">Constitutional and mosaic mutations in the <italic>PIK3R2</italic>
gene are associated with a spectrum of developmental brain disorders ranging
from BPP with a normal head size to the
megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. The
phenotypic variability and low-level mosaicism challenging conventional
molecular methods have important implications for genetic testing and
counseling.</p>
</sec>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Guerrini, R" uniqKey="Guerrini R">R Guerrini</name>
</author>
<author><name sortKey="Dobyns, Wb" uniqKey="Dobyns W">WB Dobyns</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Leventer, Rj" uniqKey="Leventer R">RJ Leventer</name>
</author>
<author><name sortKey="Jansen, A" uniqKey="Jansen A">A Jansen</name>
</author>
<author><name sortKey="Pilz, Dt" uniqKey="Pilz D">DT Pilz</name>
</author>
<author><name sortKey="Stoodley, N" uniqKey="Stoodley N">N Stoodley</name>
</author>
<author><name sortKey="Marini, C" uniqKey="Marini C">C Marini</name>
</author>
<author><name sortKey="Dubeau, F" uniqKey="Dubeau F">F Dubeau</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kuzniecky, Ri" uniqKey="Kuzniecky R">RI Kuzniecky</name>
</author>
<author><name sortKey="Andermann, F" uniqKey="Andermann F">F Andermann</name>
</author>
<author><name sortKey="Guerrini, R" uniqKey="Guerrini R">R Guerrini</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Stutterd, Ca" uniqKey="Stutterd C">CA Stutterd</name>
</author>
<author><name sortKey="Leventer, Rj" uniqKey="Leventer R">RJ Leventer</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kheradmand Kia, S" uniqKey="Kheradmand Kia S">S Kheradmand Kia</name>
</author>
<author><name sortKey="Verbeek, E" uniqKey="Verbeek E">E Verbeek</name>
</author>
<author><name sortKey="Engelen, E" uniqKey="Engelen E">E Engelen</name>
</author>
<author><name sortKey="Schot, R" uniqKey="Schot R">R Schot</name>
</author>
<author><name sortKey="Poot, Ra" uniqKey="Poot R">RA Poot</name>
</author>
<author><name sortKey="De Coo, Ifm" uniqKey="De Coo I">IFM de Coo</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Nellhaus, G" uniqKey="Nellhaus G">G Nellhaus</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Hiatt, Jb" uniqKey="Hiatt J">JB Hiatt</name>
</author>
<author><name sortKey="Pritchard, Cc" uniqKey="Pritchard C">CC Pritchard</name>
</author>
<author><name sortKey="Salipante, Sj" uniqKey="Salipante S">SJ Salipante</name>
</author>
<author><name sortKey="O Oak, Bj" uniqKey="O Oak B">BJ O’Roak</name>
</author>
<author><name sortKey="Shendure, J" uniqKey="Shendure J">J Shendure</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Boyle, Ea" uniqKey="Boyle E">EA Boyle</name>
</author>
<author><name sortKey="O Oak, Bj" uniqKey="O Oak B">BJ O’Roak</name>
</author>
<author><name sortKey="Martin, Bk" uniqKey="Martin B">BK Martin</name>
</author>
<author><name sortKey="Kumar, A" uniqKey="Kumar A">A Kumar</name>
</author>
<author><name sortKey="Shendure, J" uniqKey="Shendure J">J Shendure</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Newcombe" uniqKey="Newcombe">Newcombe</name>
</author>
<author><name sortKey="Robert, G" uniqKey="Robert G">G Robert</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Poirier, K" uniqKey="Poirier K">K Poirier</name>
</author>
<author><name sortKey="Lebrun, N" uniqKey="Lebrun N">N Lebrun</name>
</author>
<author><name sortKey="Broix, L" uniqKey="Broix L">L Broix</name>
</author>
<author><name sortKey="Tian, G" uniqKey="Tian G">G Tian</name>
</author>
<author><name sortKey="Saillour, Y" uniqKey="Saillour Y">Y Saillour</name>
</author>
<author><name sortKey="Boscheron, C" uniqKey="Boscheron C">C Boscheron</name>
</author>
<author><name sortKey="Parrini, E" uniqKey="Parrini E">E Parrini</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Poirier, K" uniqKey="Poirier K">K Poirier</name>
</author>
<author><name sortKey="Martinovic, J" uniqKey="Martinovic J">J Martinovic</name>
</author>
<author><name sortKey="Laquerriere, A" uniqKey="Laquerriere A">A Laquerrière</name>
</author>
<author><name sortKey="Cavallin, M" uniqKey="Cavallin M">M Cavallin</name>
</author>
<author><name sortKey="Fallet Bianco, C" uniqKey="Fallet Bianco C">C Fallet-Bianco</name>
</author>
<author><name sortKey="Desguerre, I" uniqKey="Desguerre I">I Desguerre</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Vissers, Le" uniqKey="Vissers L">LE Vissers</name>
</author>
<author><name sortKey="De Ligt, J" uniqKey="De Ligt J">J de Ligt</name>
</author>
<author><name sortKey="Gilissen, C" uniqKey="Gilissen C">C Gilissen</name>
</author>
<author><name sortKey="Janssen, I" uniqKey="Janssen I">I Janssen</name>
</author>
<author><name sortKey="Steehouwer, M" uniqKey="Steehouwer M">M Steehouwer</name>
</author>
<author><name sortKey="De Vries, P" uniqKey="De Vries P">P de Vries</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Li, Y" uniqKey="Li Y">Y Li</name>
</author>
<author><name sortKey="Vinckenbosch, N" uniqKey="Vinckenbosch N">N Vinckenbosch</name>
</author>
<author><name sortKey="Tian, G" uniqKey="Tian G">G Tian</name>
</author>
<author><name sortKey="Huerta Sanchez, E" uniqKey="Huerta Sanchez E">E Huerta-Sanchez</name>
</author>
<author><name sortKey="Jiang, T" uniqKey="Jiang T">T Jiang</name>
</author>
<author><name sortKey="Jiang, H" uniqKey="Jiang H">H Jiang</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Riviere, J B" uniqKey="Riviere J">J-B Rivière</name>
</author>
<author><name sortKey="Mirzaa, Gm" uniqKey="Mirzaa G">GM Mirzaa</name>
</author>
<author><name sortKey="O Oak, Bj" uniqKey="O Oak B">BJ O’Roak</name>
</author>
<author><name sortKey="Beddaoui, M" uniqKey="Beddaoui M">M Beddaoui</name>
</author>
<author><name sortKey="Alcantara, D" uniqKey="Alcantara D">D Alcantara</name>
</author>
<author><name sortKey="Conway, Rl" uniqKey="Conway R">RL Conway</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Richards, S" uniqKey="Richards S">S Richards</name>
</author>
<author><name sortKey="Aziz, N" uniqKey="Aziz N">N Aziz</name>
</author>
<author><name sortKey="Bale, S" uniqKey="Bale S">S Bale</name>
</author>
<author><name sortKey="Bick, D" uniqKey="Bick D">D Bick</name>
</author>
<author><name sortKey="Das, S" uniqKey="Das S">S Das</name>
</author>
<author><name sortKey="Gastier Foster, J" uniqKey="Gastier Foster J">J Gastier-Foster</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Leventer, Rj" uniqKey="Leventer R">RJ Leventer</name>
</author>
<author><name sortKey="Jansen, A" uniqKey="Jansen A">A Jansen</name>
</author>
<author><name sortKey="Pilz, Dt" uniqKey="Pilz D">DT Pilz</name>
</author>
<author><name sortKey="Stoodley, N" uniqKey="Stoodley N">N Stoodley</name>
</author>
<author><name sortKey="Marini, C" uniqKey="Marini C">C Marini</name>
</author>
<author><name sortKey="Dubeau, F" uniqKey="Dubeau F">F Dubeau</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mirzaa, G" uniqKey="Mirzaa G">G Mirzaa</name>
</author>
<author><name sortKey="Dodge, Nn" uniqKey="Dodge N">NN Dodge</name>
</author>
<author><name sortKey="Glass, I" uniqKey="Glass I">I Glass</name>
</author>
<author><name sortKey="Day, C" uniqKey="Day C">C Day</name>
</author>
<author><name sortKey="Gripp, K" uniqKey="Gripp K">K Gripp</name>
</author>
<author><name sortKey="Nicholson, L" uniqKey="Nicholson L">L Nicholson</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Barkovich, Aj" uniqKey="Barkovich A">AJ Barkovich</name>
</author>
<author><name sortKey="Hevner, R" uniqKey="Hevner R">R Hevner</name>
</author>
<author><name sortKey="Guerrini, R" uniqKey="Guerrini R">R Guerrini</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Guerreiro, Mm" uniqKey="Guerreiro M">MM Guerreiro</name>
</author>
<author><name sortKey="Andermann, E" uniqKey="Andermann E">E Andermann</name>
</author>
<author><name sortKey="Guerrini, R" uniqKey="Guerrini R">R Guerrini</name>
</author>
<author><name sortKey="Dobyns, Wb" uniqKey="Dobyns W">WB Dobyns</name>
</author>
<author><name sortKey="Kuzniecky, R" uniqKey="Kuzniecky R">R Kuzniecky</name>
</author>
<author><name sortKey="Silver, K" uniqKey="Silver K">K Silver</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Dobyns, Wb" uniqKey="Dobyns W">WB Dobyns</name>
</author>
<author><name sortKey="Mirzaa, G" uniqKey="Mirzaa G">G Mirzaa</name>
</author>
<author><name sortKey="Christian, Sl" uniqKey="Christian S">SL Christian</name>
</author>
<author><name sortKey="Petras, K" uniqKey="Petras K">K Petras</name>
</author>
<author><name sortKey="Roseberry, J" uniqKey="Roseberry J">J Roseberry</name>
</author>
<author><name sortKey="Clark, Gd" uniqKey="Clark G">GD Clark</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Robin, Nh" uniqKey="Robin N">NH Robin</name>
</author>
<author><name sortKey="Taylor, Cj" uniqKey="Taylor C">CJ Taylor</name>
</author>
<author><name sortKey="Mcdonald Mcginn, Dm" uniqKey="Mcdonald Mcginn D">DM McDonald-McGinn</name>
</author>
<author><name sortKey="Zackai, Eh" uniqKey="Zackai E">EH Zackai</name>
</author>
<author><name sortKey="Bingham, P" uniqKey="Bingham P">P Bingham</name>
</author>
<author><name sortKey="Collins, Kj" uniqKey="Collins K">KJ Collins</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Borgatti, R" uniqKey="Borgatti R">R Borgatti</name>
</author>
<author><name sortKey="Triulzi, F" uniqKey="Triulzi F">F Triulzi</name>
</author>
<author><name sortKey="Zucca, C" uniqKey="Zucca C">C Zucca</name>
</author>
<author><name sortKey="Piccinelli, P" uniqKey="Piccinelli P">P Piccinelli</name>
</author>
<author><name sortKey="Balottin, U" uniqKey="Balottin U">U Balottin</name>
</author>
<author><name sortKey="Carrozzo, R" uniqKey="Carrozzo R">R Carrozzo</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Jaglin, Xh" uniqKey="Jaglin X">XH Jaglin</name>
</author>
<author><name sortKey="Poirier, K" uniqKey="Poirier K">K Poirier</name>
</author>
<author><name sortKey="Saillour, Y" uniqKey="Saillour Y">Y Saillour</name>
</author>
<author><name sortKey="Buhler, E" uniqKey="Buhler E">E Buhler</name>
</author>
<author><name sortKey="Tian, G" uniqKey="Tian G">G Tian</name>
</author>
<author><name sortKey="Bahi Buisson, N" uniqKey="Bahi Buisson N">N Bahi-Buisson</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Fallet Bianco, C" uniqKey="Fallet Bianco C">C Fallet-Bianco</name>
</author>
<author><name sortKey="Laquerriere, A" uniqKey="Laquerriere A">A Laquerrière</name>
</author>
<author><name sortKey="Poirier, K" uniqKey="Poirier K">K Poirier</name>
</author>
<author><name sortKey="Razavi, F" uniqKey="Razavi F">F Razavi</name>
</author>
<author><name sortKey="Guimiot, F" uniqKey="Guimiot F">F Guimiot</name>
</author>
<author><name sortKey="Dias, P" uniqKey="Dias P">P Dias</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="O Riscoll, Mc" uniqKey="O Riscoll M">MC O’Driscoll</name>
</author>
<author><name sortKey="Daly, Sb" uniqKey="Daly S">SB Daly</name>
</author>
<author><name sortKey="Urquhart, Je" uniqKey="Urquhart J">JE Urquhart</name>
</author>
<author><name sortKey="Black, Gc" uniqKey="Black G">GC Black</name>
</author>
<author><name sortKey="Pilz, Dt" uniqKey="Pilz D">DT Pilz</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Poduri, A" uniqKey="Poduri A">A Poduri</name>
</author>
<author><name sortKey="Evrony, Gd" uniqKey="Evrony G">GD Evrony</name>
</author>
<author><name sortKey="Cai, X" uniqKey="Cai X">X Cai</name>
</author>
<author><name sortKey="Elhosary, Pc" uniqKey="Elhosary P">PC Elhosary</name>
</author>
<author><name sortKey="Beroukhim, R" uniqKey="Beroukhim R">R Beroukhim</name>
</author>
<author><name sortKey="Lehtinen, Mk" uniqKey="Lehtinen M">MK Lehtinen</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lee, Jh" uniqKey="Lee J">JH Lee</name>
</author>
<author><name sortKey="Huynh, M" uniqKey="Huynh M">M Huynh</name>
</author>
<author><name sortKey="Silhavy, Jl" uniqKey="Silhavy J">JL Silhavy</name>
</author>
<author><name sortKey="Kim, S" uniqKey="Kim S">S Kim</name>
</author>
<author><name sortKey="Dixon Salazar, T" uniqKey="Dixon Salazar T">T Dixon-Salazar</name>
</author>
<author><name sortKey="Heiberg, A" uniqKey="Heiberg A">A Heiberg</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mirzaa, Gm" uniqKey="Mirzaa G">GM Mirzaa</name>
</author>
<author><name sortKey="Parry, Da" uniqKey="Parry D">DA Parry</name>
</author>
<author><name sortKey="Fry, Ae" uniqKey="Fry A">AE Fry</name>
</author>
<author><name sortKey="Giamanco, Ka" uniqKey="Giamanco K">KA Giamanco</name>
</author>
<author><name sortKey="Schwartzentruber, J" uniqKey="Schwartzentruber J">J Schwartzentruber</name>
</author>
<author><name sortKey="Vanstone, M" uniqKey="Vanstone M">M Vanstone</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Colombani, M" uniqKey="Colombani M">M Colombani</name>
</author>
<author><name sortKey="Chouchane, M" uniqKey="Chouchane M">M Chouchane</name>
</author>
<author><name sortKey="Pitelet, G" uniqKey="Pitelet G">G Pitelet</name>
</author>
<author><name sortKey="Morales, L" uniqKey="Morales L">L Morales</name>
</author>
<author><name sortKey="Callier, P" uniqKey="Callier P">P Callier</name>
</author>
<author><name sortKey="Pinard, Jp" uniqKey="Pinard J">JP Pinard</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Garavelli, L" uniqKey="Garavelli L">L Garavelli</name>
</author>
<author><name sortKey="Guareschi, E" uniqKey="Guareschi E">E Guareschi</name>
</author>
<author><name sortKey="Errico, S" uniqKey="Errico S">S Errico</name>
</author>
<author><name sortKey="Simoni, A" uniqKey="Simoni A">A Simoni</name>
</author>
<author><name sortKey="Bergonzini, P" uniqKey="Bergonzini P">P Bergonzini</name>
</author>
<author><name sortKey="Zollino, M" uniqKey="Zollino M">M Zollino</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Osterling, Wl" uniqKey="Osterling W">WL Osterling</name>
</author>
<author><name sortKey="Boyer, Rs" uniqKey="Boyer R">RS Boyer</name>
</author>
<author><name sortKey="Hedlund, Gl" uniqKey="Hedlund G">GL Hedlund</name>
</author>
<author><name sortKey="Bale, Jf" uniqKey="Bale J">JF Bale</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Pisano, T" uniqKey="Pisano T">T Pisano</name>
</author>
<author><name sortKey="Meloni, M" uniqKey="Meloni M">M Meloni</name>
</author>
<author><name sortKey="Cianchetti, C" uniqKey="Cianchetti C">C Cianchetti</name>
</author>
<author><name sortKey="Falchi, M" uniqKey="Falchi M">M Falchi</name>
</author>
<author><name sortKey="Nucaro, A" uniqKey="Nucaro A">A Nucaro</name>
</author>
<author><name sortKey="Pruna, D" uniqKey="Pruna D">D Pruna</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Nakamura, K" uniqKey="Nakamura K">K Nakamura</name>
</author>
<author><name sortKey="Kato, M" uniqKey="Kato M">M Kato</name>
</author>
<author><name sortKey="Tohyama, J" uniqKey="Tohyama J">J Tohyama</name>
</author>
<author><name sortKey="Shiohama, T" uniqKey="Shiohama T">T Shiohama</name>
</author>
<author><name sortKey="Hayasaka, K" uniqKey="Hayasaka K">K Hayasaka</name>
</author>
<author><name sortKey="Nishiyama, K" uniqKey="Nishiyama K">K Nishiyama</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Tapper, Wj" uniqKey="Tapper W">WJ Tapper</name>
</author>
<author><name sortKey="Foulds, N" uniqKey="Foulds N">N Foulds</name>
</author>
<author><name sortKey="Cross, Ncp" uniqKey="Cross N">NCP Cross</name>
</author>
<author><name sortKey="Aranaz, P" uniqKey="Aranaz P">P Aranaz</name>
</author>
<author><name sortKey="Score, J" uniqKey="Score J">J Score</name>
</author>
<author><name sortKey="Hidalgo Curtis, C" uniqKey="Hidalgo Curtis C">C Hidalgo-Curtis</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Jamuar, Ss" uniqKey="Jamuar S">SS Jamuar</name>
</author>
<author><name sortKey="Lam, A Tn" uniqKey="Lam A">A-TN Lam</name>
</author>
<author><name sortKey="Kircher, M" uniqKey="Kircher M">M Kircher</name>
</author>
<author><name sortKey="D Ama, Am" uniqKey="D Ama A">AM D’Gama</name>
</author>
<author><name sortKey="Wang, J" uniqKey="Wang J">J Wang</name>
</author>
<author><name sortKey="Barry, Bj" uniqKey="Barry B">BJ Barry</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Cheung, Lwt" uniqKey="Cheung L">LWT Cheung</name>
</author>
<author><name sortKey="Hennessy, Bt" uniqKey="Hennessy B">BT Hennessy</name>
</author>
<author><name sortKey="Li, J" uniqKey="Li J">J Li</name>
</author>
<author><name sortKey="Yu, S" uniqKey="Yu S">S Yu</name>
</author>
<author><name sortKey="Myers, Ap" uniqKey="Myers A">AP Myers</name>
</author>
<author><name sortKey="Djordjevic, B" uniqKey="Djordjevic B">B Djordjevic</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="D Ama, Am" uniqKey="D Ama A">AM D’Gama</name>
</author>
<author><name sortKey="Geng, Y" uniqKey="Geng Y">Y Geng</name>
</author>
<author><name sortKey="Couto, Ja" uniqKey="Couto J">JA Couto</name>
</author>
<author><name sortKey="Martin, B" uniqKey="Martin B">B Martin</name>
</author>
<author><name sortKey="Boyle, Ea" uniqKey="Boyle E">EA Boyle</name>
</author>
<author><name sortKey="Lacoursiere, Cm" uniqKey="Lacoursiere C">CM LaCoursiere</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mirzaa, Gm" uniqKey="Mirzaa G">GM Mirzaa</name>
</author>
<author><name sortKey="Poduri, A" uniqKey="Poduri A">A Poduri</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ronan, L" uniqKey="Ronan L">L Ronan</name>
</author>
<author><name sortKey="Fletcher, Pc" uniqKey="Fletcher P">PC Fletcher</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="O Ahilly, R" uniqKey="O Ahilly R">R O’Rahilly</name>
</author>
<author><name sortKey="Muller, F" uniqKey="Muller F">F Müller</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Budday, S" uniqKey="Budday S">S Budday</name>
</author>
<author><name sortKey="Raybaud, C" uniqKey="Raybaud C">C Raybaud</name>
</author>
<author><name sortKey="Kuhl, E" uniqKey="Kuhl E">E Kuhl</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Campbell, Im" uniqKey="Campbell I">IM Campbell</name>
</author>
<author><name sortKey="Stewart, Jr" uniqKey="Stewart J">JR Stewart</name>
</author>
<author><name sortKey="James, Ra" uniqKey="James R">RA James</name>
</author>
<author><name sortKey="Lupski, Jr" uniqKey="Lupski J">JR Lupski</name>
</author>
<author><name sortKey="Stankiewicz, P" uniqKey="Stankiewicz P">P Stankiewicz</name>
</author>
<author><name sortKey="Olofsson, P" uniqKey="Olofsson P">P Olofsson</name>
</author>
<author><name sortKey="Shaw, Ca" uniqKey="Shaw C">CA Shaw</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Campbell, Im" uniqKey="Campbell I">IM Campbell</name>
</author>
<author><name sortKey="Yuan, B" uniqKey="Yuan B">B Yuan</name>
</author>
<author><name sortKey="Robberecht, C" uniqKey="Robberecht C">C Robberecht</name>
</author>
<author><name sortKey="Pfundt, R" uniqKey="Pfundt R">R Pfundt</name>
</author>
<author><name sortKey="Szafranski, P" uniqKey="Szafranski P">P Szafranski</name>
</author>
<author><name sortKey="Mcentagart, Me" uniqKey="Mcentagart M">ME McEntagart</name>
</author>
</analytic>
</biblStruct>
</listBibl>
</div1>
</back>
</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">101139309</journal-id>
<journal-id journal-id-type="pubmed-jr-id">30413</journal-id>
<journal-id journal-id-type="nlm-ta">Lancet Neurol</journal-id>
<journal-id journal-id-type="iso-abbrev">Lancet Neurol</journal-id>
<journal-title-group><journal-title>The Lancet. Neurology</journal-title>
</journal-title-group>
<issn pub-type="ppub">1474-4422</issn>
<issn pub-type="epub">1474-4465</issn>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">26520804</article-id>
<article-id pub-id-type="pmc">4672724</article-id>
<article-id pub-id-type="doi">10.1016/S1474-4422(15)00278-1</article-id>
<article-id pub-id-type="manuscript">NIHMS737729</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Characterization of mutations of the phosphoinositide-3-kinase
regulatory subunit, <italic>PIK3R2</italic>
, in perisylvian polymicrogyria: a
next generation sequencing study</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Mirzaa</surname>
<given-names>Ghayda</given-names>
</name>
<degrees>M.D.</degrees>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Conti</surname>
<given-names>Valerio</given-names>
</name>
<degrees>Ph.D.</degrees>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Timms</surname>
<given-names>Andrew E.</given-names>
</name>
<degrees>Ph.D.</degrees>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Smyser</surname>
<given-names>Christopher D.</given-names>
</name>
<degrees>M.D.</degrees>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ahmed</surname>
<given-names>Sarah</given-names>
</name>
<degrees>M.D.</degrees>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Carter</surname>
<given-names>Melissa</given-names>
</name>
<degrees>M.D.</degrees>
<xref ref-type="aff" rid="A6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Barnett</surname>
<given-names>Sarah</given-names>
</name>
<degrees>M.S.</degrees>
<xref ref-type="aff" rid="A7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hufnagel</surname>
<given-names>Robert B.</given-names>
</name>
<degrees>M.D.</degrees>
<xref ref-type="aff" rid="A8">8</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Goldstein</surname>
<given-names>Amy</given-names>
</name>
<degrees>M.D.</degrees>
<xref ref-type="aff" rid="A9">9</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Narumi-Kishimoto</surname>
<given-names>Yoko</given-names>
</name>
<degrees>M.D.</degrees>
<xref ref-type="aff" rid="A10">10</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Olds</surname>
<given-names>Carissa</given-names>
</name>
<degrees>M.Sc.</degrees>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Collins</surname>
<given-names>Sarah</given-names>
</name>
<degrees>M.S.</degrees>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Johnston</surname>
<given-names>Kathreen</given-names>
</name>
<degrees>M.D.</degrees>
<xref ref-type="aff" rid="A11">11</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Deleuze</surname>
<given-names>Jean-François</given-names>
</name>
<degrees>Ph.D.</degrees>
<xref ref-type="aff" rid="A12">12</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Nitschké</surname>
<given-names>Patrick</given-names>
</name>
<degrees>Ph.D.</degrees>
<xref ref-type="aff" rid="A13">13</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Friend</surname>
<given-names>Kathryn</given-names>
</name>
<degrees>Ph.D.</degrees>
<xref ref-type="aff" rid="A14">14</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Harris</surname>
<given-names>Catharine</given-names>
</name>
<degrees>M.D.</degrees>
<xref ref-type="aff" rid="A7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Goetsch</surname>
<given-names>Allison</given-names>
</name>
<degrees>M.S.</degrees>
<xref ref-type="aff" rid="A15">15</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Martin</surname>
<given-names>Beth</given-names>
</name>
<degrees>B.S.</degrees>
<xref ref-type="aff" rid="A16">16</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Boyle</surname>
<given-names>Evan August</given-names>
</name>
<degrees>B.S.</degrees>
<xref ref-type="aff" rid="A17">17</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Parrini</surname>
<given-names>Elena</given-names>
</name>
<degrees>M.D.</degrees>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mei</surname>
<given-names>Davide</given-names>
</name>
<degrees>M.S.L.T.</degrees>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tattini</surname>
<given-names>Lorenzo</given-names>
</name>
<degrees>Ph.D.</degrees>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Slavotinek</surname>
<given-names>Anne</given-names>
</name>
<degrees>M.B.B.S.</degrees>
<xref ref-type="aff" rid="A18">18</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Blair</surname>
<given-names>Ed</given-names>
</name>
<degrees>MRCP</degrees>
<xref ref-type="aff" rid="A19">19</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Barnett</surname>
<given-names>Christopher</given-names>
</name>
<degrees>M.B.B.S.</degrees>
<xref ref-type="aff" rid="A20">20</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Shendure</surname>
<given-names>Jay</given-names>
</name>
<degrees>M.D.</degrees>
<xref ref-type="aff" rid="A16">16</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chelly</surname>
<given-names>Jamel</given-names>
</name>
<degrees>M.D.</degrees>
<xref ref-type="aff" rid="A21">21</xref>
<xref ref-type="aff" rid="A22">22</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dobyns</surname>
<given-names>William B.</given-names>
</name>
<degrees>M.D.</degrees>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Guerrini</surname>
<given-names>Renzo</given-names>
</name>
<degrees>M.D.</degrees>
<xref ref-type="aff" rid="A3">3</xref>
<xref ref-type="aff" rid="A23">23</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, Seattle Children’s Research Institute, Seattle, Washington, USA</aff>
<aff id="A3"><label>3</label>
Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A. Meyer Children’s Hospital, University of Florence, Florence, Italy</aff>
<aff id="A4"><label>4</label>
Center for Developmental Biology and Regenerative, Medicine, Seattle Children’s Research Institute, Seattle, Washington, USA</aff>
<aff id="A5"><label>5</label>
Departments of Neurology and Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA</aff>
<aff id="A6"><label>6</label>
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Canada</aff>
<aff id="A7"><label>7</label>
Division of Medical Genetics, University of Missouri, Missouri, USA</aff>
<aff id="A8"><label>8</label>
Division of Human Genetics, Cincinnati Children’s Hospital, Cincinnati, Ohio, USA</aff>
<aff id="A9"><label>9</label>
Division of Child Neurology, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA</aff>
<aff id="A10"><label>10</label>
Department of Pediatrics, Shimada Ryoiku Center Hachiouji, Tokyo, Japan</aff>
<aff id="A11"><label>11</label>
Genetics Department, The Permanente Medical Group, San Francisco, California, USA</aff>
<aff id="A12"><label>12</label>
Centre National de Génotypage, Evry, France</aff>
<aff id="A13"><label>13</label>
Plateforme de Bioinformatique Paris-Descartes, Institut Imagine, Paris, France</aff>
<aff id="A14"><label>14</label>
Genetics and Molecular Pathology, Women’s and Children’s Hospital, North Adelaide, Australia</aff>
<aff id="A15"><label>15</label>
Division of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA</aff>
<aff id="A16"><label>16</label>
Department of Genome Sciences, University of Washington, Seattle, Washington, USA</aff>
<aff id="A17"><label>17</label>
Department of Genetics, Stanford University School of Medicine, Stanford, California, USA</aff>
<aff id="A18"><label>18</label>
Department of Pediatrics, Division of Genetics, University of California, San Francisco, CA, USA</aff>
<aff id="A19"><label>19</label>
Department of Clinical Genetics, Churchill Hospital, Oxford University Hospitals, Headington, United Kingdom</aff>
<aff id="A20"><label>20</label>
South Australian Clinical Genetics Service, Women’s and Children’s Hospital/SA Pathology, North Adelaide, Australia, Discipline of Pediatrics, University of Adelaide, Adelaide, Australia</aff>
<aff id="A21"><label>21</label>
Pôle de biologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France</aff>
<aff id="A22"><label>22</label>
IGBMC, Translational Medicine and Neurogenetics Department. Illkirch, France</aff>
<aff id="A23"><label>23</label>
IRCCS Stella Maris Foundation, Pisa, Italy</aff>
<author-notes><corresp id="FN1">Corresponding author: Ghayda M. Mirzaa, M.D., Division of Genetic
Medicine, Department of Pediatrics, University of Washington and Center for
Integrative Brain Research, Seattle Children’s Research Institute,
Seattle, WA 98101. <email>gmirzaa@uw.edu</email>
; or Renzo Guerrini, M.D.,
Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories,
Neuroscience Department, A. Meyer Children’s Hospital, University of
Florence, Viale Pieraccini 24, 50139, Florence, Italy.
<email>renzo.guerrini@meyer.it</email>
</corresp>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>19</day>
<month>11</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="epub"><day>29</day>
<month>10</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="ppub"><month>12</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>01</day>
<month>12</month>
<year>2016</year>
</pub-date>
<volume>14</volume>
<issue>12</issue>
<fpage>1182</fpage>
<lpage>1195</lpage>
<pmc-comment>elocation-id from pubmed: 10.1016/S1474-4422(15)00278-1</pmc-comment>
<permissions><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0/"><license-p>This manuscript version is made available under the CC BY-NC-ND 4.0
license.</license-p>
</license>
</permissions>
<abstract><title>SUMMARY</title>
<sec id="S1"><title>Background</title>
<p id="P3">Bilateral perisylvian polymicrogyria (BPP), the most common form of
regional polymicrogyria, causes the congenital bilateral perisylvian
syndrome, featuring oromotor dysfunction, cognitive impairment and epilepsy.
BPP is etiologically heterogeneous, but only a few genetic causes have been
reported. The aim of this study was to identify additional genetic
etiologies of BPP and delineate their frequency in this patient
population.</p>
</sec>
<sec id="S2"><title>Methods</title>
<p id="P4">We performed child-parent (trio)-based whole exome sequencing (WES)
on eight children with BPP. Following the identification of mosaic
<italic>PIK3R2</italic>
mutations in two of these eight children, we
performed targeted screening of <italic>PIK3R2</italic>
in a cohort of 118
children with BPP who were ascertained from 1980 until 2015 using two
methods. First, we performed targeted sequencing of the entire
<italic>PIK3R2</italic>
gene by single molecule molecular inversion
probes (smMIPs) on 38 patients with BPP with normal-large head size. Second,
we performed amplicon sequencing of the recurrent <italic>PIK3R2</italic>
mutation (p.Gly373Arg) on 80 children with various types of polymicrogyria
including BPP. One additional patient underwent clinical WES independently,
and was included in this study given the phenotypic similarity to our
cohort. All patients included in this study were children (< 18 years of
age) with polymicrogyria enrolled in our research program.</p>
</sec>
<sec id="S3"><title>Findings</title>
<p id="P5">Using WES, we identified a mosaic mutation (p.Gly373Arg) in the
regulatory subunit of the PI3K-AKT-MTOR pathway, <italic>PIK3R2</italic>
, in
two children with BPP. Of the 38 patients with BPP and normal-large head
size who underwent targeted next generation sequencing by smMIPs, we
identified constitutional and mosaic <italic>PIK3R2</italic>
mutations in 17
additional children. In parallel, one patient was found to have the
recurrent <italic>PIK3R2</italic>
mutation by clinical WES. Seven patients
had BPP alone, and 13 had BPP in association with features of the
megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH).
Nineteen patients had the same mutation (Gly373Arg), and one had a nearby
missense mutation (p.Lys376Glu). Across the entire cohort, mutations were
constitutional in 12 and mosaic in eight patients. Among mosaic patients, we
observed substantial variation in alternate (mutant) allele levels ranging
from 2·5% (10/377) to 36·7% (39/106) of
reads, equivalent to 5–73·4% of cells analyzed.
Levels of mosaicism varied from undetectable to 17·1%
(37/216) of reads in blood-derived compared to 29·4%
(2030/6889) to 43·3% (275/634) in saliva-derived DNA.</p>
</sec>
<sec id="S4"><title>Interpretation</title>
<p id="P6">Constitutional and mosaic mutations in the <italic>PIK3R2</italic>
gene are associated with a spectrum of developmental brain disorders ranging
from BPP with a normal head size to the
megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. The
phenotypic variability and low-level mosaicism challenging conventional
molecular methods have important implications for genetic testing and
counseling.</p>
</sec>
</abstract>
<kwd-group><kwd><italic>PIK3R2</italic>
</kwd>
<kwd>polymicrogyria</kwd>
<kwd>megalencephaly</kwd>
<kwd>MPPH syndrome</kwd>
<kwd>mosaicism</kwd>
</kwd-group>
</article-meta>
</front>
<floats-group><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label>
<caption><title>Experimental workflow of this study that allowed detection of the <italic>de
novo</italic>
sequence variation in <italic>PIK3R2</italic>
gene in
individuals with BPP</title>
<p>The entire exome sequencing methodology and workflow used in this study are
adaptations of those previously reported in Poirier et al (2013).<sup><xref rid="R10" ref-type="bibr">10</xref>
</sup>
</p>
</caption>
<graphic xlink:href="nihms737729f1"></graphic>
</fig>
<fig id="F2" orientation="portrait" position="float"><label>Figure 2</label>
<caption><title>Brain MRI images of patients with constitutional <italic>PIK3R2</italic>
mutations</title>
<p>Representative T1 and T2-weighted mid-sagittal, axial and coronal 3 Tesla (T)
brain MRI images in patients 2 (LR12-099) at age two years (A, B), 3 (LR12-415)
at age eight years (C, D), 5 (LR13-242) at age five years (E, F), 6 (LR13-398)
at age three years (G, H), 7 (LR08-305) at age two years (I, J), 9 (LR13-088) at
age one year and six months (K, L), 11 (LR13-157a2) at age 21 days (M, N) and 12
(LR08-308) at age five years (O, P). Note bilateral perisylvian polymicrogyria
(BPP) (arrows), and superiorly extended sylvian fissures (arrowheads). Other
notable features include moderate to severe ventriculomegaly (B, F, H, L, P),
and cavum septum pellucidum et vergae (F, J and M). White and black arrowheads
are used interchangeably to contrast with the background.</p>
</caption>
<graphic xlink:href="nihms737729f2"></graphic>
</fig>
<fig id="F3" orientation="portrait" position="float"><label>Figure 3</label>
<caption><title>Brain MRI images of patients with mosaic <italic>PIK3R2</italic>
mutations</title>
<p>Representative T1 and T2-weighted, SWAN, IR, 3T and 7T mid-sagittal, axial and
coronal brain MRI images in patients 13 (LR09-216) at age four years (A, B), 14
(LP99-083) at age 12 years (C, D), 15 (LR11-322) at age two years (E, F), 16
(LR13-409) at age three years (G, H), 17 (LR13-302) at age two years (I, J), 18
(1734P) at age 14 years (K, L), 19 (1317N) at age 22 years (M, N) and 20
(LR11-278) at age 3 years (O, P). Note bilateral perisylvian polymicrogyria
(BPP) (arrows), and extended sylvian fissures (arrowheads). Images K, L, M and N
are at 7T. Note in image N the different morphological pattern between the
normal mesial parieto –occipital cortex (square) and the undulated
packed and infolded microgyri in the lateral parietal cortex (asterisks). Other
notable features include mild-moderate ventriculomegaly (G, H, I, J, K, L, M,
O), cerebellar tonsillar ectopia (A, C) (white circles), thick corpus callosum
(C, E), and cavum septum pellucidum et vergae (G,H, O). White and black
arrowheads are used interchangeably to contrast with the background.</p>
</caption>
<graphic xlink:href="nihms737729f3"></graphic>
</fig>
<table-wrap id="T1" position="float" orientation="landscape"><label>Table 1</label>
<caption><p>Summary of the clinical and neuroimaging features of the cohort included in this
study (N=127)</p>
</caption>
<table frame="box" rules="cols"><thead><tr><th valign="top" align="left" rowspan="1" colspan="1"></th>
<th colspan="2" valign="top" align="center" rowspan="1">Mutation-positive patients</th>
<th colspan="3" valign="top" align="center" rowspan="1">Mutation-negative patients</th>
</tr>
<tr><th colspan="6" valign="bottom" align="left" rowspan="1"><hr></hr>
</th>
</tr>
<tr><th valign="middle" align="left" rowspan="1" colspan="1">Cohort/Feature</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Constitutional <italic>PIK3R2</italic>
mutations (N=12)</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Mosaic <italic>PIK3R2</italic>
mutations
(N=8)</th>
<th valign="middle" align="center" rowspan="1" colspan="1">BPP WES (N=6)</th>
<th valign="middle" align="center" rowspan="1" colspan="1">PMG-Amplicon Sequencing
(N=80<xref rid="TFN2" ref-type="table-fn">*</xref>
)</th>
<th valign="middle" align="center" rowspan="1" colspan="1">BPP smMIPs (N=21)</th>
</tr>
<tr><th colspan="6" valign="bottom" align="left" rowspan="1"><hr></hr>
</th>
</tr>
</thead>
<tbody><tr><td align="left" valign="top" rowspan="1" colspan="1"><bold>Gender</bold>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">8 F, 4 M</td>
<td align="center" valign="top" rowspan="1" colspan="1">4 F, 4 M</td>
<td align="center" valign="top" rowspan="1" colspan="1">4 F, 2 M</td>
<td align="center" valign="top" rowspan="1" colspan="1">30 F, 23 M</td>
<td align="center" valign="top" rowspan="1" colspan="1">8 F, 13 M</td>
</tr>
<tr><td colspan="6" valign="bottom" align="left" rowspan="1"><hr></hr>
</td>
</tr>
<tr><td align="left" valign="top" rowspan="1" colspan="1"><bold>Ethnicity</bold>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">11/12 Caucasian<break></break>
1/12
African-American</td>
<td align="center" valign="top" rowspan="1" colspan="1">8/8 Caucasian</td>
<td align="center" valign="top" rowspan="1" colspan="1">6/6 Caucasian</td>
<td align="center" valign="top" rowspan="1" colspan="1">53/53 Caucasian</td>
<td align="center" valign="top" rowspan="1" colspan="1">11/21 Caucasian, 2/21 African American, 2/21
Asian, 2/21 Hispanic, 4/21 Unknown</td>
</tr>
<tr><td colspan="6" valign="bottom" align="left" rowspan="1"><hr></hr>
</td>
</tr>
<tr><td align="left" valign="top" rowspan="1" colspan="1"><bold>OFC Measurements</bold>
</td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" valign="top" rowspan="1" colspan="1">Mean OFC (in SD) at birth for
females/males</td>
<td align="center" valign="top" rowspan="1" colspan="1">3·8/4·8</td>
<td align="center" valign="top" rowspan="1" colspan="1">4/3·1</td>
<td align="center" valign="top" rowspan="1" colspan="1">0/0</td>
<td align="center" valign="top" rowspan="1" colspan="1">1/0</td>
<td align="center" valign="top" rowspan="1" colspan="1">1·6/3·33</td>
</tr>
<tr><td align="left" valign="top" rowspan="1" colspan="1">Mean OFC (in SD) at last assessment for
females/males</td>
<td align="center" valign="top" rowspan="1" colspan="1">3·75/5·25</td>
<td align="center" valign="top" rowspan="1" colspan="1">2·8/4·7</td>
<td align="center" valign="top" rowspan="1" colspan="1">0/2</td>
<td align="center" valign="top" rowspan="1" colspan="1">1·2/0·7</td>
<td align="center" valign="top" rowspan="1" colspan="1">4·25/3·2</td>
</tr>
<tr><td align="left" valign="top" rowspan="1" colspan="1">Age range of last assessment</td>
<td align="center" valign="top" rowspan="1" colspan="1">14mo–8·5yrs/3mo–18yrs</td>
<td align="center" valign="top" rowspan="1" colspan="1">7mo–22yrs/4mo–14yrs</td>
<td align="center" valign="top" rowspan="1" colspan="1">4·5yrs–16yrs/3,7yrs</td>
<td align="center" valign="top" rowspan="1" colspan="1">3mo–13·5
yrs/1–15·5yrs</td>
<td align="center" valign="top" rowspan="1" colspan="1">5·5mo–7·5yrs/13mo–7·5yrs</td>
</tr>
<tr><td colspan="6" valign="bottom" align="left" rowspan="1"><hr></hr>
</td>
</tr>
<tr><td align="left" valign="top" rowspan="1" colspan="1"><bold>Megalencephaly (OFC >2
SD)</bold>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">9/12 (75%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">7/8 (88%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">0/6 (0%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">2/53 (4%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">19/21 (90%)</td>
</tr>
<tr><td colspan="6" valign="bottom" align="left" rowspan="1"><hr></hr>
</td>
</tr>
<tr><td align="left" valign="top" rowspan="1" colspan="1"><bold>Brain Imaging</bold>
</td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" valign="top" rowspan="1" colspan="1">Polymicrogyria (BPP) Grade 1–2</td>
<td align="center" valign="top" rowspan="1" colspan="1">10/12 (83%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">6/8 (75%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">3/6 (50%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">24/53 (45%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">5/21 (24%)</td>
</tr>
<tr><td align="left" valign="top" rowspan="1" colspan="1">Polymicrogyria (BPP) Grade 3–4</td>
<td align="center" valign="top" rowspan="1" colspan="1">2/12 (17%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">2/8 (25%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">3/6 (50%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">29/53 (55%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">16/21 (76%)</td>
</tr>
<tr><td align="left" valign="top" rowspan="1" colspan="1">Ventriculomegaly</td>
<td align="center" valign="top" rowspan="1" colspan="1">12/12 (100%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">5/8 (63%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">0/6 (0%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">6/53 (11%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">9/21 (43%)</td>
</tr>
<tr><td align="left" valign="top" rowspan="1" colspan="1">Hydrocephalus (s/p shunting)</td>
<td align="center" valign="top" rowspan="1" colspan="1">1/12 (8%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">0/8 (0%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">0/6 (0%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">0/53 (0%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">3/21 (14%)</td>
</tr>
<tr><td align="left" valign="top" rowspan="1" colspan="1">Thick corpus callosum</td>
<td align="center" valign="top" rowspan="1" colspan="1">5/12 (42%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">3/8 (38%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">0/6 (0%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">2/53 (4%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">4/21 (19%)</td>
</tr>
<tr><td colspan="6" valign="bottom" align="left" rowspan="1"><hr></hr>
</td>
</tr>
<tr><td align="left" valign="top" rowspan="1" colspan="1"><bold>Epilepsy</bold>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">7/12 (58%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">6/8 (75%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">1/6 (17%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">37/53 (70%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">13/21 (62%)</td>
</tr>
<tr><td align="left" valign="top" rowspan="1" colspan="1"><bold>Mean age of seizure onset</bold>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">11 mo</td>
<td align="center" valign="top" rowspan="1" colspan="1">3·89 yrs</td>
<td align="center" valign="top" rowspan="1" colspan="1">2·25 yrs</td>
<td align="center" valign="top" rowspan="1" colspan="1">3·35 yrs</td>
<td align="center" valign="top" rowspan="1" colspan="1">14 mo</td>
</tr>
<tr><td align="left" valign="top" rowspan="1" colspan="1"><bold>SD</bold>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">8·58 mo</td>
<td align="center" valign="top" rowspan="1" colspan="1">4·74 yrs</td>
<td align="center" valign="top" rowspan="1" colspan="1">NA</td>
<td align="center" valign="top" rowspan="1" colspan="1">3·85 yrs</td>
<td align="center" valign="top" rowspan="1" colspan="1">9·92 mo</td>
</tr>
<tr><td colspan="6" valign="bottom" align="left" rowspan="1"><hr></hr>
</td>
</tr>
<tr><td align="left" valign="top" rowspan="1" colspan="1"><bold>Oromotor weakness</bold>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">9/12 (75%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">7/8 (88%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">4/6 (67%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">13/53 (25%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">10/21 (48%)</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="TFN1"><p><bold>Abbreviations:</bold>
BPP = bilateral perisylvian
polymicrogyria; F = female; M = male; mo = months;
OFC = occipito-frontal circumference; PMG = polymicrogyria;
SD = standard deviations; smMIPs = single molecule molecular
inversion probes; WES = whole exome sequencing; yrs =
years.</p>
</fn>
<fn id="TFN2"><label>*</label>
<p>Of these 80 patients, clinical data were available on 53 patients. However,
all 80 patients were confirmed to have polymicrogyria by assessment of their
neuroimaging.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="T2" position="float" orientation="landscape"><label>Table 2</label>
<caption><p>Summary of the clinical features and neuroimaging features of patients harboring
<italic>PI3KR2</italic>
mutations (N=20)</p>
</caption>
<table frame="box" rules="all"><thead><tr><th valign="middle" align="center" rowspan="1" colspan="1">N</th>
<th valign="middle" align="center" rowspan="1" colspan="1">DB#</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Sex</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Age</th>
<th valign="middle" align="center" rowspan="1" colspan="1">OFC<break></break>
(cm) at<break></break>
birth</th>
<th valign="middle" align="center" rowspan="1" colspan="1">OFC<break></break>
(cm) at
last<break></break>
assessment</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Polymicrogy<break></break>
ria</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Additional<break></break>
brain<break></break>
abnormalities</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Reason
of<break></break>
first<break></break>
medical<break></break>
evaluation<break></break>
(age)</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Epilepsy<break></break>
(onset)</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Neurological<break></break>
examination</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Oromotor<break></break>
weakness</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Cognitive<break></break>
level</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Other<break></break>
clinical<break></break>
features</th>
</tr>
</thead>
<tbody><tr><td colspan="14" align="center" valign="middle" rowspan="1"><bold>Patients with the
constitutional c.1117G>A, p.Gly373Arg <italic>PIK3R2</italic>
mutation</bold>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR11-321</td>
<td align="center" valign="middle" rowspan="1" colspan="1">F</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2·5 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">44 (+7·5 SD)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">59 (+7·5) at 2.5 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">BPP grade 1–2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Moderate ventriculomegaly,
dysmyelination</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Macrocephaly (birth)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Epilepsy, no details available</td>
<td align="center" valign="middle" rowspan="1" colspan="1">No details available</td>
<td align="center" valign="middle" rowspan="1" colspan="1">No details available</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Significant LD, global developmental
delay</td>
<td align="center" valign="middle" rowspan="1" colspan="1">–</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR12-099</td>
<td align="center" valign="middle" rowspan="1" colspan="1">F</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">43 (+7)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">55.5 (+4) at 3·5 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">BPP grade 1–2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Moderate ventriculomegaly, thick CC, thin
WM</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Progressive macrocephaly (3 months)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">No seizures</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Quadriparesis</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Dysphagia, speech delays (non-verbal;
mimics sounds), excessive drooling</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Severe ID, poor head control, wheel-hair
bound,</td>
<td align="center" valign="middle" rowspan="1" colspan="1">GI malrotation, laryngomalacia</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">3</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR12-415</td>
<td align="center" valign="middle" rowspan="1" colspan="1">M</td>
<td align="center" valign="middle" rowspan="1" colspan="1">18 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">40 (+5)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">63·6 (+6) at 18 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">BPP grade 1–2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Moderate ventriculomegaly, thick CC</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Macrocephaly and hypotonia (infancy)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Rare focal seizures with unresponsiveness
(2 yrs)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Hypotonia</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Non-verbal</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Severe ID (IQ <35), walked with
assistance at 4 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Divergent strabismus</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">4</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR12-303</td>
<td align="center" valign="middle" rowspan="1" colspan="1">F</td>
<td align="center" valign="middle" rowspan="1" colspan="1">14 mo</td>
<td align="center" valign="middle" rowspan="1" colspan="1">39 (+3)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">47·7 (+1–2) at 14
mo</td>
<td align="center" valign="middle" rowspan="1" colspan="1">BPP grade 3–4</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Prominent PV in BG, mild
Ventriculomegaly, thin CC, mild CBTE, CSPV, hippocampal dysgenesis</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Eye deviation, PMG on MRI (shortly after
birth)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">None</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Hypotonia, hypokinesia</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Poor suck/swallow, poor swallow
coordination, status post G-tube, excessive drooling, markedly delayed
speech</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Severe ID</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Hyperopia, severe astigmatism, GERD</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">5</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR13-242</td>
<td align="center" valign="middle" rowspan="1" colspan="1">M</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">41·9 (+5·5)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">58 (+6) at 5 age</td>
<td align="center" valign="middle" rowspan="1" colspan="1">BPP grade 3–4</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Moderate ventriculomegaly, thin CC,
prominent PV spaces, CSPV</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Macrocephaly, ventriculomegaly detected
on prenatal US</td>
<td align="center" valign="middle" rowspan="1" colspan="1">None</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Normal</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Speech delay</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Mild-mod ID, walked at 12 mo, fine motor
delays</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Attention deficit, sensory processing
issues, LGA, transient hypoglycemia at birth</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">6</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR13-298</td>
<td align="center" valign="middle" rowspan="1" colspan="1">F</td>
<td align="center" valign="middle" rowspan="1" colspan="1">8 yrs 7 mo</td>
<td align="center" valign="middle" rowspan="1" colspan="1">No details available</td>
<td align="center" valign="middle" rowspan="1" colspan="1">59·5 (+6) at 8·5
yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">BPP grade 1–2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Hydrocephalus status post ventriculostomy
(10 months), CBTE (1–5 mm), stretched CC, thin WM</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Ventriculomgaly on prenatal US (in utero,
GA 34 weeks)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Infantile spasms evolved into myoclonic
seizures (1 yr), intractable</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Axial hypotonia, appendicular
hypertonia</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Dysphagia, dysarthria, profuse
drooling</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Severe ID, non-ambulatory, non-verbal, no
social/communication skills<xref rid="TFN3" ref-type="table-fn">*</xref>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Connective tissue laxity, GERD, short
stature at 8 yrs</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">7</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR08-305<sup>a</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">M</td>
<td align="center" valign="middle" rowspan="1" colspan="1">6 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">No details available</td>
<td align="center" valign="middle" rowspan="1" colspan="1">57 (+4–5) at 3 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">BPP grade 1–2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Mild ventriculomegaly, mild CBTE
(1–3 mm), mildly thick CC</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Eye deviation (1 week), macrocephaly (3
months)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Focal seizures with unresponsiveness (1
yr)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Hypotonia, oculomotor apraxia</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Delayed speech</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Mod ID. Walked at 16 mo, delayed fine
motor skills, 80 words at 6 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">GERD, dysmorphic facial
features<sup>b</sup>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">8</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR12-319</td>
<td align="center" valign="middle" rowspan="1" colspan="1">F</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">39 (+3)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">55 (+3·5) at 5 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">BPP grade 1–2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Severe ventriculomegaly, thin/stretched
CC</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Macrocephaly, multiple muscular VSDs
(birth)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Focal seizures with unresponsiveness (1
mo)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Hemiparesis</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Dysphagia with fatigue with food</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Moderate ID, walked at 2.5 yrs, speech
delay</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Multiple VSD, esotropia, hyperopia,
astigmatism, broad thumbs, sandal gap toes</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">9</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR13-088</td>
<td align="center" valign="middle" rowspan="1" colspan="1">F</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">No details available</td>
<td align="center" valign="middle" rowspan="1" colspan="1">52 (+4) at 16 mo</td>
<td align="center" valign="middle" rowspan="1" colspan="1">BPP grade 1–2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Moderate ventriculomgaly, CBTE
(1–5 mm), mildly thick CC</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Developmental delays (6 mo)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">None</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Hemiparesis,</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Expressive speech delay, increased
drooling</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Mild ID</td>
<td align="center" valign="middle" rowspan="1" colspan="1">None</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">10</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR13-157a1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">F</td>
<td align="center" valign="middle" rowspan="1" colspan="1">8.5 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">38 (+2)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">55·5 (+2) at 8·5
yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">BPP grade 1–2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Ventriculomegaly</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Seizures commencing at 15 months</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Focal seizures with unresponsiveness (15
mo)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Normal</td>
<td align="center" valign="middle" rowspan="1" colspan="1">None</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Developmental delay at 2 yrs, behind
peers, IQ not formally assessed.</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Cutis marmorata, Wt +2 SD</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">11</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR13-157a2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">M</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">40.5 (+4–5)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">47·5 (+4–5) at 4
mo</td>
<td align="center" valign="middle" rowspan="1" colspan="1">BPP grade 1–2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Mild ventriculomegaly</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Macrocephaly identified on prenatal
ultrasound; first seizure at 7 weeks</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Focal seizures with unresponsiveness (2
mo), intractable</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Cortical blindness, otherwise normal
neurological examination</td>
<td align="center" valign="middle" rowspan="1" colspan="1">None</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Mild developmental delay. At 21 mo: gross
motor 15 mo, speech 12 mo, fine motor 9 mo, social 9 mo</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Cutis marmorata, 1 cutaneous
hemangioma</td>
</tr>
<tr><td colspan="14" align="center" valign="middle" rowspan="1"><bold>Patient with the
constitutional c.1126A>G, p.Lys376Glu <italic>PIK3R2</italic>
mutation</bold>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">12</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR08-308</td>
<td align="center" valign="middle" rowspan="1" colspan="1">F</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">35 (+0–1 SD)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">52·3 (+1–2) at 5
yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">BPP grade 1–2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Mild ventriculom galy, mildly thick
CC</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Macrocephaly (3 months)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">None</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Hypotonia</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Expressive language delays, early
dysphagia</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Moderate ID, walked at 4 yrs. BSID at 10
mo: cognition 3 mo, fine motor 2 mo, social-emotional 4 mo, language
(receptive/e xpressive 3 mo, motor 3–4 mo</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Cutaneous capillary malformation</td>
</tr>
<tr><td colspan="14" align="center" valign="middle" rowspan="1"><bold>Patients with the
mosaic c.1117G>A, p.Gly373Arg <italic>PIK3R2</italic>
mutation</bold>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">13</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR09-216</td>
<td align="center" valign="middle" rowspan="1" colspan="1">M</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2·5 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">39 (+2·5 SD)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">57 (+4 SD) at 4 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">BPP grade 3</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Mild ventriculomegaly, CBTE (1–5
mm), thin CC</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Early developmental delays (8–10
mo)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">None</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Hypotonia</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Expressive speech delay, difficulties
chewing and swallowing</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Mild ID, walked with support 18 mo,
3–4 words at 18 mo, poor coordination</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Skin hyperextensibility</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">14</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LP99-083</td>
<td align="center" valign="middle" rowspan="1" colspan="1">F</td>
<td align="center" valign="middle" rowspan="1" colspan="1">16 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1<sup>st</sup>
available OFC 49·6
cm at 10m (+3·6 SD)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">56 cm (+3·8 SD) at 5 yrs
7 mo</td>
<td align="center" valign="middle" rowspan="1" colspan="1">BPP grade 3–4</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Thick CC, mild CBTE (3 mm)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Developmental delays, macrocephaly (10
mo)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Rare generalized tonic-clonic seizures
(12 yrs), off AED</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Spastic quadriparesis</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Profound oral dysphagia, minimal to no
oral motor control. Non-verbal</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Severe ID, at 14 yrs, walks short
distances on knees, uses 3–4 signs, points and uses iPad
pictures to indicate needs.</td>
<td align="center" valign="middle" rowspan="1" colspan="1">A few episodes of mild ketotic
hypoglycemia at 5–6 yrs, subsequently resolved</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">15</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR11-322</td>
<td align="center" valign="middle" rowspan="1" colspan="1">F</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2·5 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">ND</td>
<td align="center" valign="middle" rowspan="1" colspan="1">50 (+2 SD) at 22 mo</td>
<td align="center" valign="middle" rowspan="1" colspan="1">BPP grade 3</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Thick CC</td>
<td align="center" valign="middle" rowspan="1" colspan="1">No details available</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Epilepsy, no details available</td>
<td align="center" valign="middle" rowspan="1" colspan="1">No details available</td>
<td align="center" valign="middle" rowspan="1" colspan="1">No details available</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Significant ID. Crawls and babbles at 22
mo; not walking</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Icthyosis, consanguineous parents</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">16</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR13-409</td>
<td align="center" valign="middle" rowspan="1" colspan="1">F</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">ND (born in El Salvador)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">54 (+2·5) at 3·95
yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">BPP grade 3</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Moderate ventriculomegaly</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Global developmental delay, macrocephaly,
static encephalopathy, diffuse hypotonia (4 mo)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Complex febrile seizures (6 mo),
myoclonic jerks</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Hypotonia</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Dysphagia, G-tube dependent, poor
vocalizations</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Severe ID, non-ambulatory</td>
<td align="center" valign="middle" rowspan="1" colspan="1">G-tube dependent, temperature
dysregulation</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">17</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR13-302</td>
<td align="center" valign="middle" rowspan="1" colspan="1">F</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">40 (+5 SD)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">54 (+3) at 3 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">BPP grade 3</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Mildly thick CC, prominent PV spaces</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Macrocephaly (birth)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">None</td>
<td align="center" valign="middle" rowspan="1" colspan="1">No details available</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Increased drooling, no dysphagia</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Developmental regression at 18 mo (had 30
words, all lost), loss of social skills, non-verbal</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Severely autistic, small cutaneous
capillary malformation</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">18</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1734P</td>
<td align="center" valign="middle" rowspan="1" colspan="1">M</td>
<td align="center" valign="middle" rowspan="1" colspan="1">14 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">38 (+2 SD)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">59 (+2–3) at 14 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">BPP grade 3</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Ventriculomegaly (L>R)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Epilepsy (18 mo)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Rare focal seizures with unresponsiveness
(18 mo)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Normal</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Dysarthria</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Within average (FSIQ: 78, PIQ: 78, VIQ:
97)<xref rid="TFN6" ref-type="table-fn">1</xref>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">None</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">19</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1317N</td>
<td align="center" valign="middle" rowspan="1" colspan="1">F</td>
<td align="center" valign="middle" rowspan="1" colspan="1">22 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">40 (+3 SD)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">60 (+3 SD) at 22 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">BPP grade 3</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Ventriculomegaly</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Language delay (3.5 yrs)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Frequent focal seizures with
unresponsiveness (4.2 yrs)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Sialorrhea</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Dysarthria, increased drooling</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Mild disability (FSIQ: 41, VCI: 55, POI:
52, WMI: 53, PSI: 58)<xref rid="TFN7" ref-type="table-fn">2</xref>
; mild
impairment in adaptive skills</td>
<td align="center" valign="middle" rowspan="1" colspan="1">None</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">20</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR11-278</td>
<td align="center" valign="middle" rowspan="1" colspan="1">M</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4 yrs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">40·5 (+5 SD)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">60.2 cm (+7–8) at 4 yrs 4
mo</td>
<td align="center" valign="middle" rowspan="1" colspan="1">BPP grade 1–2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Moderate ventriculomegaly, thin CC,
prominent PV spaces, CSPV</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Megalencephaly and PMG (in utero)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Focal seizures with unresponsiveness (15
mo)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Hypotonia</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Dysphagia, dysarthria, increased
drooling</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Mild ID, normal gross and fine motor
skills</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LGA</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="TFN3"><label>*</label>
<p>Additional relevant clinical information:</p>
</fn>
<fn id="TFN4"><p><bold>LR08-305</bold>
<sup>a</sup>
: this child is part of a large sibship of
African-American ancestry that consists of 11 children, including five
affected ones (<xref rid="SD2" ref-type="supplementary-material">Supplementary Figure 2</xref>
, family 3). Dysmorphic features seen in
the affected child include heavy eyebrows, synophrys, deep set eyes, long
eyelashes, full lips, broad looking thumbs, clinodactyly, large great toes.
This child’s mother, also mutation-positive, is known to have
macrocephaly, hydrocephalus, epilepsy and schizoaffective disorder, with
limited additional medical data. Therefore, this mother was not considered
independently in this manuscript.</p>
</fn>
<fn id="TFN5"><p><bold>Abbreviations:</bold>
</p>
</fn>
<fn id="TFN6"><label>1</label>
<p>WISC-R;</p>
</fn>
<fn id="TFN7"><label>2</label>
<p>WAIS-IV.</p>
</fn>
<fn id="TFN8"><p>Abbreviations: AED = anti-epileptic drugs; CBTE = cerebellar
tonsillar ectopia; CC = corpus callosum; CSPV = cavum septum
pellucidum et vergae; DB = database number; F = female; FSIQ
= full scale intellectual quotient; GERD = gastro-esophageal
reflux; GI = gastrointestinal; ID = intellectual disability;
IQ = intelligence quotient; LD = learning disability; LGA
= large for gestational age; M = male; mo = months;
MC = myoclonic; OFC = occipito-frontal circumference; PIQ
= performance intellectual quotient; PMG = polymicrogyria;
POI = perceptual organization index; PSI = processing speed
index; PV = perivascular; SD = standard deviation; US
= ultrasound; VCI = verbal comprehension index; VIQ
= verbal intellectual quotient; VSD = ventricular septal
defect; WM = white matter; WMI = working memory index; Wt
= weight; yrs = years, BSID = Bayley scale of infant
development.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="T3" position="float" orientation="landscape"><label>Table 3</label>
<caption><p>Mutations, levels of mosaicisim and methods of detection of
<italic>PIK3R2</italic>
mutation-positive patients (N=20)
[<italic>PIK3R2</italic>
, NM_005027.2]</p>
</caption>
<table frame="box" rules="all"><thead><tr><th valign="middle" align="center" rowspan="1" colspan="1">N</th>
<th valign="middle" align="center" rowspan="1" colspan="1">DB#</th>
<th valign="middle" align="center" rowspan="1" colspan="1">cDNA change</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Amino acid change</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Germline or mosaic</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Tissue tested</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Alternate allele fractions (AAF)<xref rid="TFN10" ref-type="table-fn">a</xref>
</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Testing method</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Inheritance</th>
</tr>
</thead>
<tbody><tr><td colspan="9" align="center" valign="top" rowspan="1"><bold>Constitutional
<italic>PIK3R2</italic>
mutations</bold>
</td>
</tr>
<tr><td align="center" valign="top" rowspan="1" colspan="1">1</td>
<td align="center" valign="top" rowspan="1" colspan="1">LR11-321</td>
<td align="center" valign="top" rowspan="1" colspan="1">c.1117G>A</td>
<td align="center" valign="top" rowspan="1" colspan="1">p.Gly373Arg</td>
<td align="center" valign="top" rowspan="1" colspan="1">Germline</td>
<td align="center" valign="top" rowspan="1" colspan="1">Blood</td>
<td align="center" valign="top" rowspan="1" colspan="1">115/262 (43·9%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">smMIPs, Sanger</td>
<td align="center" valign="top" rowspan="1" colspan="1"><italic>De novo</italic>
</td>
</tr>
<tr><td align="center" valign="top" rowspan="1" colspan="1">2</td>
<td align="center" valign="top" rowspan="1" colspan="1">LR12-099</td>
<td align="center" valign="top" rowspan="1" colspan="1">c.1117G>A</td>
<td align="center" valign="top" rowspan="1" colspan="1">p.Gly373Arg</td>
<td align="center" valign="top" rowspan="1" colspan="1">Germline</td>
<td align="center" valign="top" rowspan="1" colspan="1">Blood</td>
<td align="center" valign="top" rowspan="1" colspan="1">171/388 (44·1%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">smMIPs, Sanger</td>
<td align="center" valign="top" rowspan="1" colspan="1"><italic>De novo</italic>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">3</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR12-415</td>
<td align="center" valign="middle" rowspan="1" colspan="1">c.1117G>A</td>
<td align="center" valign="middle" rowspan="1" colspan="1">p.Gly373Arg</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Germline</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Blood<break></break>
Saliva</td>
<td align="center" valign="middle" rowspan="1" colspan="1">146/321
(45·4%)<break></break>
132/316 (41·7%)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">smMIPs, Sanger</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><italic>De novo</italic>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">4</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR12-303</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LRc.1117G>A</td>
<td align="center" valign="middle" rowspan="1" colspan="1">p.Gly373Arg</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Possibly germline</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Saliva</td>
<td align="center" valign="middle" rowspan="1" colspan="1">125/251 (49·8%)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">smMIPs, Sanger</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><italic>De novo</italic>
</td>
</tr>
<tr><td align="center" valign="top" rowspan="1" colspan="1">5</td>
<td align="center" valign="top" rowspan="1" colspan="1">LR13-242</td>
<td align="center" valign="top" rowspan="1" colspan="1">c.1117G>A</td>
<td align="center" valign="top" rowspan="1" colspan="1">p.Gly373Arg</td>
<td align="center" valign="top" rowspan="1" colspan="1">Germline</td>
<td align="center" valign="top" rowspan="1" colspan="1">Blood</td>
<td align="center" valign="top" rowspan="1" colspan="1">Heterozygous<xref rid="TFN11" ref-type="table-fn">b</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">WES</td>
<td align="center" valign="top" rowspan="1" colspan="1"><italic>De novo</italic>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">6</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR13-298</td>
<td align="center" valign="middle" rowspan="1" colspan="1">c.1117G>A</td>
<td align="center" valign="middle" rowspan="1" colspan="1">p.Gly373Arg</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Germline</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Blood<break></break>
Saliva</td>
<td align="center" valign="middle" rowspan="1" colspan="1">N/A (50·0%)<break></break>
N/A
(50·0%)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Sanger</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><italic>De novo</italic>
</td>
</tr>
<tr><td align="center" valign="top" rowspan="1" colspan="1">7<break></break>
P</td>
<td align="center" valign="top" rowspan="1" colspan="1">LR08-305<break></break>
LR08-305m</td>
<td align="center" valign="top" rowspan="1" colspan="1">c.1117G>A<break></break>
c.1117G>A</td>
<td align="center" valign="top" rowspan="1" colspan="1">p.Gly373Arg<break></break>
p.Gly373Arg</td>
<td align="center" valign="top" rowspan="1" colspan="1">Germline<break></break>
Germline</td>
<td align="center" valign="top" rowspan="1" colspan="1">Blood<break></break>
Blood</td>
<td align="center" valign="top" rowspan="1" colspan="1">23/48 (47·9%)<break></break>
33/80
(41·3%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">smMIPs, Sanger<break></break>
smMIPs, Sanger</td>
<td align="center" valign="top" rowspan="1" colspan="1">Maternal<break></break>
N/A</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">8</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR12-319</td>
<td align="center" valign="middle" rowspan="1" colspan="1">c.1117G>A</td>
<td align="center" valign="middle" rowspan="1" colspan="1">p.Gly373Arg</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Possibly germline</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Saliva</td>
<td align="center" valign="middle" rowspan="1" colspan="1">102/219 (46·6%)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">smMIPs, Sanger</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><italic>De novo</italic>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">9</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR13-088</td>
<td align="center" valign="middle" rowspan="1" colspan="1">c.1117G>A</td>
<td align="center" valign="middle" rowspan="1" colspan="1">p.Gly373Arg</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Germline</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Saliva<break></break>
Blood</td>
<td align="center" valign="middle" rowspan="1" colspan="1">33/71 (46·4%)<break></break>
N/A
(50·0%)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">smMIPs<break></break>
Sanger</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><italic>De novo</italic>
</td>
</tr>
<tr><td align="center" valign="top" rowspan="1" colspan="1">10</td>
<td align="center" valign="top" rowspan="1" colspan="1">LR13-157a1<xref rid="TFN12" ref-type="table-fn">c</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">c.1117G>A</td>
<td align="center" valign="top" rowspan="1" colspan="1">p.Gly373Arg</td>
<td align="center" valign="top" rowspan="1" colspan="1">Germline</td>
<td align="center" valign="top" rowspan="1" colspan="1">Blood</td>
<td align="center" valign="top" rowspan="1" colspan="1">N/A (50·0%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">Sanger</td>
<td align="center" valign="top" rowspan="1" colspan="1">Presumed parental germline mosaicism</td>
</tr>
<tr><td align="center" valign="top" rowspan="1" colspan="1">11</td>
<td align="center" valign="top" rowspan="1" colspan="1">LR13-157a2<xref rid="TFN12" ref-type="table-fn">c</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">c.1117G>A</td>
<td align="center" valign="top" rowspan="1" colspan="1">p.Gly373Arg</td>
<td align="center" valign="top" rowspan="1" colspan="1">Germline</td>
<td align="center" valign="top" rowspan="1" colspan="1">Blood</td>
<td align="center" valign="top" rowspan="1" colspan="1">N/A (50·0%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">Sanger</td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="center" valign="top" rowspan="1" colspan="1">P</td>
<td align="center" valign="top" rowspan="1" colspan="1">LR13-137f</td>
<td align="center" valign="top" rowspan="1" colspan="1">c.1117G>A</td>
<td align="center" valign="top" rowspan="1" colspan="1">p.Gly373Arg</td>
<td align="center" valign="top" rowspan="1" colspan="1">–</td>
<td align="center" valign="top" rowspan="1" colspan="1">Blood</td>
<td align="center" valign="top" rowspan="1" colspan="1">0/494 (0·00%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">smMIPs</td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="center" valign="top" rowspan="1" colspan="1">P</td>
<td align="center" valign="top" rowspan="1" colspan="1">LR13-157m</td>
<td align="center" valign="top" rowspan="1" colspan="1">c.1117G>A</td>
<td align="center" valign="top" rowspan="1" colspan="1">p.Gly373Arg</td>
<td align="center" valign="top" rowspan="1" colspan="1">–</td>
<td align="center" valign="top" rowspan="1" colspan="1">Blood</td>
<td align="center" valign="top" rowspan="1" colspan="1">0/263 (0·00%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">smMIPs</td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="center" valign="top" rowspan="1" colspan="1">12</td>
<td align="center" valign="top" rowspan="1" colspan="1">LR08-308</td>
<td align="center" valign="top" rowspan="1" colspan="1">c.1126A>G</td>
<td align="center" valign="top" rowspan="1" colspan="1">p.Lys376Glu<xref rid="TFN13" ref-type="table-fn">d</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">Germline</td>
<td align="center" valign="top" rowspan="1" colspan="1">Blood</td>
<td align="center" valign="top" rowspan="1" colspan="1">111/197 (56·3%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">smMIPs, Sanger</td>
<td align="center" valign="top" rowspan="1" colspan="1"><italic>De novo</italic>
</td>
</tr>
<tr><td colspan="9" align="center" valign="top" rowspan="1"><bold>Mosaic
<italic>PIK3R2</italic>
mutations</bold>
</td>
</tr>
<tr><td align="center" valign="top" rowspan="1" colspan="1">13</td>
<td align="center" valign="top" rowspan="1" colspan="1">LR09-216</td>
<td align="center" valign="top" rowspan="1" colspan="1">c.1117G>A</td>
<td align="center" valign="top" rowspan="1" colspan="1">p.Gly373Arg</td>
<td align="center" valign="top" rowspan="1" colspan="1">Mosaic</td>
<td align="center" valign="top" rowspan="1" colspan="1">Blood</td>
<td align="center" valign="top" rowspan="1" colspan="1">10/377 (2·6%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">smMIPs, Sanger</td>
<td align="center" valign="top" rowspan="1" colspan="1"><italic>De novo</italic>
</td>
</tr>
<tr><td align="center" valign="top" rowspan="1" colspan="1">14</td>
<td align="center" valign="top" rowspan="1" colspan="1">LP99-083</td>
<td align="center" valign="top" rowspan="1" colspan="1">c.1117G>A</td>
<td align="center" valign="top" rowspan="1" colspan="1">p.Gly373Arg</td>
<td align="center" valign="top" rowspan="1" colspan="1">Mosaic</td>
<td align="center" valign="top" rowspan="1" colspan="1">Blood</td>
<td align="center" valign="top" rowspan="1" colspan="1">41/778 (5·20%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">Agilent SureSelect</td>
<td align="center" valign="top" rowspan="1" colspan="1">N/A</td>
</tr>
<tr><td align="center" valign="top" rowspan="1" colspan="1">15</td>
<td align="center" valign="top" rowspan="1" colspan="1">LR11-322</td>
<td align="center" valign="top" rowspan="1" colspan="1">c.1117G>A</td>
<td align="center" valign="top" rowspan="1" colspan="1">p.Gly373Arg</td>
<td align="center" valign="top" rowspan="1" colspan="1">Mosaic</td>
<td align="center" valign="top" rowspan="1" colspan="1">Blood</td>
<td align="center" valign="top" rowspan="1" colspan="1">36/493 (7·3%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">smMIPs</td>
<td align="center" valign="top" rowspan="1" colspan="1"><italic>De novo</italic>
</td>
</tr>
<tr><td align="center" valign="top" rowspan="1" colspan="1">16</td>
<td align="center" valign="top" rowspan="1" colspan="1">LR13-409</td>
<td align="center" valign="top" rowspan="1" colspan="1">c.1117G>A</td>
<td align="center" valign="top" rowspan="1" colspan="1">p.Gly373Arg</td>
<td align="center" valign="top" rowspan="1" colspan="1">Mosaic</td>
<td align="center" valign="top" rowspan="1" colspan="1">Blood</td>
<td align="center" valign="top" rowspan="1" colspan="1">37/216 (17·1%)</td>
<td align="center" valign="top" rowspan="1" colspan="1">smMIPs</td>
<td align="center" valign="top" rowspan="1" colspan="1">N/A</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">17</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR13-302</td>
<td align="center" valign="middle" rowspan="1" colspan="1">c.1117G>A</td>
<td align="center" valign="middle" rowspan="1" colspan="1">p.Gly373Arg</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Mosaic</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Saliva<break></break>
Blood</td>
<td align="center" valign="middle" rowspan="1" colspan="1">17/53
(32·0%)<break></break>
Undetectable</td>
<td align="center" valign="middle" rowspan="1" colspan="1">smMIPs<break></break>
Sanger</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><italic>De novo</italic>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">18</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1734P</td>
<td align="center" valign="middle" rowspan="1" colspan="1">c.1117G>A</td>
<td align="center" valign="middle" rowspan="1" colspan="1">p.Gly373Arg</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Mosaic</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Blood<break></break>
Blood<break></break>
Saliva</td>
<td align="center" valign="middle" rowspan="1" colspan="1">10/86
(11·6%)<break></break>
565/5453
(10·4%)<break></break>
2030/6889 (29·4%)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">WES<break></break>
Amplicon
sequencing<break></break>
Amplicon sequencing</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><italic>De novo</italic>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">19</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1317N</td>
<td align="center" valign="middle" rowspan="1" colspan="1">c.1117G>A</td>
<td align="center" valign="middle" rowspan="1" colspan="1">p.Gly373Arg</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Mosaic</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Blood<break></break>
Blood<break></break>
Saliva</td>
<td align="center" valign="middle" rowspan="1" colspan="1">20/132 (15%)<break></break>
861/6449
(13·3%)<break></break>
275/634 (43·4%)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">WES<break></break>
Amplicon
sequencing<break></break>
Amplicon sequencing</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><italic>De novo</italic>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">20</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LR11-278</td>
<td align="center" valign="middle" rowspan="1" colspan="1">c.1117G>A</td>
<td align="center" valign="middle" rowspan="1" colspan="1">p.Gly373Arg</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Mosaic</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Saliva<break></break>
Skin<break></break>
Blood<break></break>
Lipoma</td>
<td align="center" valign="middle" rowspan="1" colspan="1">39/106
(36·7%)<break></break>
144/561
(25·6%)<break></break>
117/1052
(11·1%)<break></break>
1/7 (14·2%)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">smMIPs, Sanger</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><italic>De novo</italic>
</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="TFN9"><p>The genomic coordinates for these mutations are: chr19:g.18273784G>A
(p.Gly373Arg), and chr19:g.18273793A>G (p.Lys376Glu)</p>
</fn>
<fn id="TFN10"><label>a</label>
<p>Alternate allele fractions (AAF) are based on the number of alternate or
non-reference/total alleles (%).</p>
</fn>
<fn id="TFN11"><label>b</label>
<p>This patient underwent trio-based clinical whole exome sequencing.
99·5% of <italic>PIK3R2</italic>
was covered at a minimum of
10X. Overall mean depth of coverage was 759X, with a quality threshold of
99·8%.</p>
</fn>
<fn id="TFN12"><label>c</label>
<p>Poor DNA quality. Therefore, next generation sequencing was not performed. No
other tissue sources were available to analyze on this family.</p>
</fn>
<fn id="TFN13"><label>d</label>
<p>This mutation is not present in any of the public databases (dbSNP138, 1000
genomes, EVS, ExAC Server). It affects an evolutionarily conserved amino
acid residue and is predicted to be damaging using multiple in-silico
prediction programs (SIFT, Polyphen-2, MutationTaster).</p>
</fn>
<fn id="TFN14"><p><bold>Abbreviations:</bold>
AAF = alternate allele fraction; f
= father; m = mother; N/A = not available; NGS
= next generation sequencing; P = parents; smMIPs =
single molecule molecular inversion probes.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Asie/explor/AustralieFrV1/Data/Pmc/Curation
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 002C32 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Curation/biblio.hfd -nk 002C32 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Wicri/Asie |area= AustralieFrV1 |flux= Pmc |étape= Curation |type= RBID |clé= PMC:4672724 |texte= Characterization of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next generation sequencing study }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Curation/RBID.i -Sk "pubmed:26520804" \ | HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Curation/biblio.hfd \ | NlmPubMed2Wicri -a AustralieFrV1
![]() | This area was generated with Dilib version V0.6.33. | ![]() |