Characterization of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next generation sequencing study
Identifieur interne : 002D82 ( Pmc/Corpus ); précédent : 002D81; suivant : 002D83Characterization of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next generation sequencing study
Auteurs : Ghayda Mirzaa ; Valerio Conti ; Andrew E. Timms ; Christopher D. Smyser ; Sarah Ahmed ; Melissa Carter ; Sarah Barnett ; Robert B. Hufnagel ; Amy Goldstein ; Yoko Narumi-Kishimoto ; Carissa Olds ; Sarah Collins ; Kathreen Johnston ; Jean-François Deleuze ; Patrick Nitschké ; Kathryn Friend ; Catharine Harris ; Allison Goetsch ; Beth Martin ; Evan August Boyle ; Elena Parrini ; Davide Mei ; Lorenzo Tattini ; Anne Slavotinek ; Ed Blair ; Christopher Barnett ; Jay Shendure ; Jamel Chelly ; William B. Dobyns ; Renzo GuerriniSource :
- 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 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><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Conti, Valerio" sort="Conti, Valerio" uniqKey="Conti V" first="Valerio" last="Conti">Valerio Conti</name>
<affiliation><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>
</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><nlm:aff id="A4">Center for Developmental Biology and Regenerative, Medicine, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
</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><nlm:aff id="A5">Departments of Neurology and Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ahmed, Sarah" sort="Ahmed, Sarah" uniqKey="Ahmed S" first="Sarah" last="Ahmed">Sarah Ahmed</name>
<affiliation><nlm:aff id="A2">Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Carter, Melissa" sort="Carter, Melissa" uniqKey="Carter M" first="Melissa" last="Carter">Melissa Carter</name>
<affiliation><nlm:aff id="A6">Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Barnett, Sarah" sort="Barnett, Sarah" uniqKey="Barnett S" first="Sarah" last="Barnett">Sarah Barnett</name>
<affiliation><nlm:aff id="A7">Division of Medical Genetics, University of Missouri, Missouri, USA</nlm:aff>
</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><nlm:aff id="A8">Division of Human Genetics, Cincinnati Children’s Hospital, Cincinnati, Ohio, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Goldstein, Amy" sort="Goldstein, Amy" uniqKey="Goldstein A" first="Amy" last="Goldstein">Amy Goldstein</name>
<affiliation><nlm:aff id="A9">Division of Child Neurology, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA</nlm:aff>
</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><nlm:aff id="A10">Department of Pediatrics, Shimada Ryoiku Center Hachiouji, Tokyo, Japan</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Olds, Carissa" sort="Olds, Carissa" uniqKey="Olds C" first="Carissa" last="Olds">Carissa Olds</name>
<affiliation><nlm:aff id="A2">Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Collins, Sarah" sort="Collins, Sarah" uniqKey="Collins S" first="Sarah" last="Collins">Sarah Collins</name>
<affiliation><nlm:aff id="A2">Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Johnston, Kathreen" sort="Johnston, Kathreen" uniqKey="Johnston K" first="Kathreen" last="Johnston">Kathreen Johnston</name>
<affiliation><nlm:aff id="A11">Genetics Department, The Permanente Medical Group, San Francisco, California, USA</nlm:aff>
</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><nlm:aff id="A12">Centre National de Génotypage, Evry, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nitschke, Patrick" sort="Nitschke, Patrick" uniqKey="Nitschke P" first="Patrick" last="Nitschké">Patrick Nitschké</name>
<affiliation><nlm:aff id="A13">Plateforme de Bioinformatique Paris-Descartes, Institut Imagine, Paris, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Friend, Kathryn" sort="Friend, Kathryn" uniqKey="Friend K" first="Kathryn" last="Friend">Kathryn Friend</name>
<affiliation><nlm:aff id="A14">Genetics and Molecular Pathology, Women’s and Children’s Hospital, North Adelaide, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Harris, Catharine" sort="Harris, Catharine" uniqKey="Harris C" first="Catharine" last="Harris">Catharine Harris</name>
<affiliation><nlm:aff id="A7">Division of Medical Genetics, University of Missouri, Missouri, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Goetsch, Allison" sort="Goetsch, Allison" uniqKey="Goetsch A" first="Allison" last="Goetsch">Allison Goetsch</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Martin, Beth" sort="Martin, Beth" uniqKey="Martin B" first="Beth" last="Martin">Beth Martin</name>
<affiliation><nlm:aff id="A16">Department of Genome Sciences, University of Washington, Seattle, Washington, USA</nlm:aff>
</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><nlm:aff id="A17">Department of Genetics, Stanford University School of Medicine, Stanford, California, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Parrini, Elena" sort="Parrini, Elena" uniqKey="Parrini E" first="Elena" last="Parrini">Elena Parrini</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Mei, Davide" sort="Mei, Davide" uniqKey="Mei D" first="Davide" last="Mei">Davide Mei</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Tattini, Lorenzo" sort="Tattini, Lorenzo" uniqKey="Tattini L" first="Lorenzo" last="Tattini">Lorenzo Tattini</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Slavotinek, Anne" sort="Slavotinek, Anne" uniqKey="Slavotinek A" first="Anne" last="Slavotinek">Anne Slavotinek</name>
<affiliation><nlm:aff id="A18">Department of Pediatrics, Division of Genetics, University of California, San Francisco, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Blair, Ed" sort="Blair, Ed" uniqKey="Blair E" first="Ed" last="Blair">Ed Blair</name>
<affiliation><nlm:aff id="A19">Department of Clinical Genetics, Churchill Hospital, Oxford University Hospitals, Headington, United Kingdom</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Barnett, Christopher" sort="Barnett, Christopher" uniqKey="Barnett C" first="Christopher" last="Barnett">Christopher Barnett</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Shendure, Jay" sort="Shendure, Jay" uniqKey="Shendure J" first="Jay" last="Shendure">Jay Shendure</name>
<affiliation><nlm:aff id="A16">Department of Genome Sciences, University of Washington, Seattle, Washington, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chelly, Jamel" sort="Chelly, Jamel" uniqKey="Chelly J" first="Jamel" last="Chelly">Jamel Chelly</name>
<affiliation><nlm:aff id="A21">Pôle de biologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A22">IGBMC, Translational Medicine and Neurogenetics Department. Illkirch, France</nlm:aff>
</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><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Guerrini, Renzo" sort="Guerrini, Renzo" uniqKey="Guerrini R" first="Renzo" last="Guerrini">Renzo Guerrini</name>
<affiliation><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>
</affiliation>
<affiliation><nlm:aff id="A23">IRCCS Stella Maris Foundation, Pisa, Italy</nlm:aff>
</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>
</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><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Conti, Valerio" sort="Conti, Valerio" uniqKey="Conti V" first="Valerio" last="Conti">Valerio Conti</name>
<affiliation><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>
</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><nlm:aff id="A4">Center for Developmental Biology and Regenerative, Medicine, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
</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><nlm:aff id="A5">Departments of Neurology and Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ahmed, Sarah" sort="Ahmed, Sarah" uniqKey="Ahmed S" first="Sarah" last="Ahmed">Sarah Ahmed</name>
<affiliation><nlm:aff id="A2">Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Carter, Melissa" sort="Carter, Melissa" uniqKey="Carter M" first="Melissa" last="Carter">Melissa Carter</name>
<affiliation><nlm:aff id="A6">Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Barnett, Sarah" sort="Barnett, Sarah" uniqKey="Barnett S" first="Sarah" last="Barnett">Sarah Barnett</name>
<affiliation><nlm:aff id="A7">Division of Medical Genetics, University of Missouri, Missouri, USA</nlm:aff>
</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><nlm:aff id="A8">Division of Human Genetics, Cincinnati Children’s Hospital, Cincinnati, Ohio, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Goldstein, Amy" sort="Goldstein, Amy" uniqKey="Goldstein A" first="Amy" last="Goldstein">Amy Goldstein</name>
<affiliation><nlm:aff id="A9">Division of Child Neurology, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA</nlm:aff>
</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><nlm:aff id="A10">Department of Pediatrics, Shimada Ryoiku Center Hachiouji, Tokyo, Japan</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Olds, Carissa" sort="Olds, Carissa" uniqKey="Olds C" first="Carissa" last="Olds">Carissa Olds</name>
<affiliation><nlm:aff id="A2">Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Collins, Sarah" sort="Collins, Sarah" uniqKey="Collins S" first="Sarah" last="Collins">Sarah Collins</name>
<affiliation><nlm:aff id="A2">Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Johnston, Kathreen" sort="Johnston, Kathreen" uniqKey="Johnston K" first="Kathreen" last="Johnston">Kathreen Johnston</name>
<affiliation><nlm:aff id="A11">Genetics Department, The Permanente Medical Group, San Francisco, California, USA</nlm:aff>
</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><nlm:aff id="A12">Centre National de Génotypage, Evry, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nitschke, Patrick" sort="Nitschke, Patrick" uniqKey="Nitschke P" first="Patrick" last="Nitschké">Patrick Nitschké</name>
<affiliation><nlm:aff id="A13">Plateforme de Bioinformatique Paris-Descartes, Institut Imagine, Paris, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Friend, Kathryn" sort="Friend, Kathryn" uniqKey="Friend K" first="Kathryn" last="Friend">Kathryn Friend</name>
<affiliation><nlm:aff id="A14">Genetics and Molecular Pathology, Women’s and Children’s Hospital, North Adelaide, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Harris, Catharine" sort="Harris, Catharine" uniqKey="Harris C" first="Catharine" last="Harris">Catharine Harris</name>
<affiliation><nlm:aff id="A7">Division of Medical Genetics, University of Missouri, Missouri, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Goetsch, Allison" sort="Goetsch, Allison" uniqKey="Goetsch A" first="Allison" last="Goetsch">Allison Goetsch</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Martin, Beth" sort="Martin, Beth" uniqKey="Martin B" first="Beth" last="Martin">Beth Martin</name>
<affiliation><nlm:aff id="A16">Department of Genome Sciences, University of Washington, Seattle, Washington, USA</nlm:aff>
</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><nlm:aff id="A17">Department of Genetics, Stanford University School of Medicine, Stanford, California, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Parrini, Elena" sort="Parrini, Elena" uniqKey="Parrini E" first="Elena" last="Parrini">Elena Parrini</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Mei, Davide" sort="Mei, Davide" uniqKey="Mei D" first="Davide" last="Mei">Davide Mei</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Tattini, Lorenzo" sort="Tattini, Lorenzo" uniqKey="Tattini L" first="Lorenzo" last="Tattini">Lorenzo Tattini</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Slavotinek, Anne" sort="Slavotinek, Anne" uniqKey="Slavotinek A" first="Anne" last="Slavotinek">Anne Slavotinek</name>
<affiliation><nlm:aff id="A18">Department of Pediatrics, Division of Genetics, University of California, San Francisco, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Blair, Ed" sort="Blair, Ed" uniqKey="Blair E" first="Ed" last="Blair">Ed Blair</name>
<affiliation><nlm:aff id="A19">Department of Clinical Genetics, Churchill Hospital, Oxford University Hospitals, Headington, United Kingdom</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Barnett, Christopher" sort="Barnett, Christopher" uniqKey="Barnett C" first="Christopher" last="Barnett">Christopher Barnett</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Shendure, Jay" sort="Shendure, Jay" uniqKey="Shendure J" first="Jay" last="Shendure">Jay Shendure</name>
<affiliation><nlm:aff id="A16">Department of Genome Sciences, University of Washington, Seattle, Washington, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chelly, Jamel" sort="Chelly, Jamel" uniqKey="Chelly J" first="Jamel" last="Chelly">Jamel Chelly</name>
<affiliation><nlm:aff id="A21">Pôle de biologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A22">IGBMC, Translational Medicine and Neurogenetics Department. Illkirch, France</nlm:aff>
</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><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Guerrini, Renzo" sort="Guerrini, Renzo" uniqKey="Guerrini R" first="Renzo" last="Guerrini">Renzo Guerrini</name>
<affiliation><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>
</affiliation>
<affiliation><nlm:aff id="A23">IRCCS Stella Maris Foundation, Pisa, Italy</nlm:aff>
</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>
<body><sec sec-type="intro" id="S5"><title>Introduction</title>
<p id="P7">Polymicrogyria is a cortical malformation characterized by excessive gyration
and disordered lamination, and is among the most common malformations of cortical
development (MCD).<sup><xref rid="R1" ref-type="bibr">1</xref>
</sup>
Bilateral
perisylvian polymicrogyria (BPP) is the most common sub-type of
polymicrogyria,<sup><xref rid="R2" ref-type="bibr">2</xref>
</sup>
and was
first reported as a distinct anatomoclinical syndrome in 1993.<sup><xref rid="R3" ref-type="bibr">3</xref>
</sup>
Many heterogeneous non-genetic and genetic
etiologies have been proposed for polymicrogyria, in general, and BPP in
particular.<sup><xref rid="R4" ref-type="bibr">4</xref>
</sup>
Extrinsic
non-genetic etiologies include vascular or hypoxemic insults (e.g. twin-twin
transfusion syndrome), and congenital cytomegalovirus infection.<sup><xref rid="R1" ref-type="bibr">1</xref>
</sup>
Genetic causes are collectively rare for BPP
and typically occur in clinically recognizable syndromic forms, the most common of
which are 1p36.3 and 22q11.2 deletion syndromes. To date, only one gene –
<italic>RTTN</italic>
– has been associated with isolated BPP in two
unrelated families.<sup><xref rid="R5" ref-type="bibr">5</xref>
</sup>
</p>
<p id="P8">The aim of our study was to identify additional genetic causes of BPP. Using
whole exome sequencing and targeted sequencing methods, we identified mosaic and
constitutional mutations in the <italic>PIK3R2</italic>
gene in a subset of children
with BPP with normal to large head size.</p>
</sec>
<sec sec-type="methods" id="S6"><title>Methods</title>
<sec id="S7"><title>Patient Cohort</title>
<p id="P9">This study was conducted at the Seattle Children’s Research
Institute (SCRI) and the University of Florence Meyer’s
Children’s Hospital. Patients at both centers were enrolled in the
developmental brain disorders research program. Patients included in this study
were children less than 18 years of age with polymicrogyria identified by brain
imaging, with or without brain overgrowth (or megalencephaly). Patients with
inadequate imaging and/or clinical data were excluded from this study. Informed
written consent was obtained from all of the patients’ legal guardians
to share clinical, neuroimaging and electroencephalographic (EEG) data, as well
as provide key research samples including blood, saliva, and skin, when
available. Clinical and neuroimaging studies were reviewed by the investigators.
This study was approved by the Seattle Children’s Institutional Review
Board (IRB) and the Pediatric Review Board of the Tuscany Region.</p>
</sec>
<sec id="S8"><title>Magnetic resonance imaging</title>
<p id="P10">A comprehensive MRI investigation was performed in every patient, using
different imaging systems including either 1·5-, 3- or 7-Tesla scans.
Minimal sequences requirement consisted of noncontrast-enhanced spin echo,
inversion recovery, and gradient echo sequences performed in the axial,
sagittal, and coronal planes. All patients were examined with 5-mm or lower
slice thickness. The ultra high-field 7-Tesla MRI included 3D-T1 weighted
fast-spoiled gradient echo (FSPGR), 3D susceptibility-weighted angiography
(SWAN), 2D T2*-weighted targeted dual-echo gradient-recalled echo (GRE),
2D T2-weighted DSE and 2D grey-white matter tissue border enhancement (TBE)
FSE-IR.</p>
</sec>
<sec id="S9"><title>Molecular methods</title>
<p id="P11">Genomic DNA was extracted from patients’ tissues using standard
protocols using the Qiagen Puregene Blood Core Kit with RNase for blood, and the
Oragene Saliva Kit following the manufacturers’ recommendations. First,
DNA samples from eight child-parent trios with BPP were subjected to whole exome
sequencing (WES). Patients selected for WES were those for whom an underlying
genetic cause has not been identified by prior standard testing that includes a
chromosomal microarray, and who have no clinical or imaging findings suggestive
of a non-genetic etiology. Of these eight patients, two had megalencephaly
(defined as occipito-frontal circumference, OFC, > 2 standard deviations, SD,
above the mean for age and gender), two had borderline small head size (OFC 2 or
more SD below the mean for age and gender), and the remaining four were
normocephalic. The parents of all eight children were clinically unaffected.
Mean occipito-frontal circumference measurements and standard deviations for age
and sex were calculated using the standard Nellhaus Head Circumference Charts
for children from birth to 18 years.<sup><xref rid="R6" ref-type="bibr">6</xref>
</sup>
</p>
<p id="P12">To further assess the frequency of the <italic>PIK3R2</italic>
mutation,
p.Gly373Arg, that was seen in two of our patients who underwent whole exome
sequencing (and was therefore considered, recurrent), we developed an allelic
discrimination (AD) assay to screen a cohort of 80 children with polymicrogyria
broadly (without using head size as a selection criteria). The presence of two
primer/probe pairs marked with two different fluorescent dyes in the same AD
assay allowed us to assess the allelic status at the mutation site. In parallel,
we screened 38 patients using single molecule molecular inversion probes
(smMIPs) for mutations in <italic>PIK3R2</italic>
.<sup><xref rid="R7" ref-type="bibr">7</xref>
</sup>
These 38 patients had BPP in association
with either a normal head size (N = 6) or large head size (N =
32). An additional patient with features of the
megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH)
underwent clinical trio-based WES independently.</p>
<sec id="S10"><title>WES analysis</title>
<p id="P13">Library preparation, exome enrichment and WES were performed at the
French National Centre for Genotyping (CNG, Evry, France). Libraries were
prepared from 3 μg genomic DNA extracted from whole blood using an
optimized SureSelect Human Exome kit (Agilent). Captured, purified and
clonally amplified libraries targeting the exome were then sequenced on a
HiSeq 2000 (Illumina). Sequence reads were aligned to the human genome (hg19
assembly) using BWA software. Downstream processing was carried out with the
Genome analysis toolkit (GATK), SAMtools and Picard Tools. Single-nucleotide
variants and indels were subsequently called by the SAMtools suite (mpileup,
bcftools, vcfutil). All calls with a read coverage ≤5× and a
Phred-scaled SNP quality of ≤20 were filtered out. Substitution and
variation calls were made with the SAMtools pipeline (mpileup). Variants
were annotated with an in-house Paris Descartes bioinformatics platform
pipeline based on the Ensembl database (release 67). Exome sequencing
quality data were homogeneous with an average mean depth higher than 100X.
Coverage depth greater than 15X and 5X were obtained for ~97% and
~99% of the target. We analysed variants affecting coding regions
and essential splice sites and excluded all variants with frequencies higher
than 1% in multiple genome databases including dbSNP, 1000 Genomes,
the NHLBI Exome Variant Server (EVS), the Exome Aggregation Consortium
(ExAC), and a local Paris Descartes Bioinformatics platform database.</p>
</sec>
<sec id="S11"><title>Multiplex targeted sequencing using smMIPs.<sup><xref rid="R7" ref-type="bibr">7</xref>
</sup>
</title>
<p id="P14">We designed a pool of 35 smMIP oligonucleotides targeting the coding
sequences of <italic>PIK3R2</italic>
. smMIPs were tiled across a total of
3340 base pair (bp) of genomic sequence, including all 2202 coding
nucleotides of the targeted genes. 100 ng capture reactions were performed
in parallel. Massively parallel sequencing was performed using the Illumina
HiSeq. Variants were filtered against the public databases (dbSNP, 1000
Genomes, EVS, ExAC) mentioned above. smMIP sequencing data was processed
with MIPgen and PEAR 0.8.1,<sup><xref rid="R8" ref-type="bibr">8</xref>
</sup>
both with default options, with the exception of
introducing a penalty of 80 for soft clipping during the BWA mem mapping, to
produce high quality smc-reads (single molecule consensus reads). smc-reads
were analyzed with GATK v3.1–1 as recommended using the
IndelRealigner and HaplotypeCaller tools on the targeted regions. smc-reads
were processed with Freebayes using the -F 0 option to capture low frequency
variants. All variants with at least two reads were retained for downstream
analysis. Variants were merged across all samples and allele balances
calculated.</p>
</sec>
<sec id="S12"><title>Amplicon sequencing</title>
<p id="P15">To screen for the recurrent <italic>PIK3R2</italic>
mutation,
p.Gly373Arg, we performed locus-specific amplification of genomic DNA
followed by GS Junior sequencing. We designed fusion primers containing
genome-specific sequences along with distinct MIDs (multiplex identifier
sequences) used to differentiate samples being run together on the same
plate and sequencing adapters to generate amplicons ranging in size from 290
to 310 bp using primer3plus software. Primer sequences are available upon
request (Dr. Renzo Guerrini). Small DNA fragments were removed using
Agencourt AMPure XP (Beckman Coulter, Beverly, MA) according to the
manufacturer’s protocol. All amplicons were quantified using the
Quant-iT PicoGreen dsDNA reagent (Invitrogen Corporation, Life Technologies,
Carlsbad, CA), pooled at equimolar ratios, amplified by emulsion PCR using
the GS Junior Titanium emPCR kit (Lib-A kit, Roche Applied Science,
Mannheim, Germany) and pyrosequenced in the sense and antisense strands on a
GS Junior sequencer (Roche) following the manufacturer’s
instructions. We performed data analysis using the GS Amplicon Variant
Analyzer version 3.0 (AVAv3.0) software (Roche).</p>
</sec>
<sec id="S13"><title>Sanger sequencing</title>
<p id="P16">We performed confirmation of constitutional mutations by direct
Sanger sequencing. PCR amplification was performed with 50 ng of genomic DNA
using Taq DNA polymerase (Applied Biosystems). Primers used to amplify the
coding and flanking noncoding regions of <italic>PIK3R2</italic>
were
designed using Primer 3. Double-stranded DNA sequence analysis was performed
using the Big Dye Terminator chemistry (Applied Biosystems), and reactions
were run on the ABI 3730_l Genetic Analyzer (Applied Biosystems). Sequence
chromatograms were analyzed using Mutation Surveyor software version 3.30.
Sequences were compared with normal control samples and the reference
sequences for <italic>PIK3R2</italic>
.</p>
</sec>
<sec id="S14"><title>Statistical analysis</title>
<p id="P17">P-values were calculated by using Fisher’s exact test.
95% confidence intervals were calculated by using the method
introduced by Newcombe.<sup><xref rid="R9" ref-type="bibr">9</xref>
</sup>
</p>
</sec>
</sec>
</sec>
<sec id="S15"><title>Role of the funding source</title>
<p id="P18">This study was funded by the US National Institutes of Health under NINDS
grants K08NS092898 (to G.M. M.), NS058721 (to W.B.D.), and by EU Seventh Framework
Programme (FP7) under the project DESIRE grant agreement N602531 (to R.G. and J.C.),
E-RareJTC2011 (grant to R.G. and J.C.) and FRM (Equipe FRM; J.C. –
DEQ20130326477). All authors had full access to all data in the study and had final
responsibility for the decision to submit for publication. The content is solely the
responsibility of the authors and does not necessarily represent the official views
of the funding sources. The funding sources had no role in study design, data
collection, data analysis, data interpretation, manuscript writing or decision to
submit the manuscript for publication. The MIPgen Design Software is open-source and
freely available for academic use but copyright/patent protected (by J.S. and
E.A.B.) and requires a license for commercial use”.</p>
</sec>
<sec sec-type="results" id="S16"><title>Results</title>
<p id="P19">Sporadic unexplained cases of BPP are by far among the most frequent
conditions of the heterogeneous group of MCD. In order to further delineate the
contribution of genetic causes corresponding to <italic>de novo</italic>
mutation
events, we selected eight child-parent trios. All families tested by WES had a
single affected patient (sporadic case) with BPP. <xref rid="F1" ref-type="fig">Figure 1</xref>
highlights our overall experimental workflow for detecting and
prioritizing sequence variants and the validation methods of our molecular findings.
This workflow is an adaptation of the one we have previously used to search for
MCD-related genes.<sup><xref rid="R10" ref-type="bibr">10</xref>
,<xref rid="R11" ref-type="bibr">11</xref>
</sup>
In line with previous studies we identified
approximately 7000 variants in each exomed individual and an average of 245
variations per subject after filtering.<sup><xref rid="R10" ref-type="bibr">10</xref>
,<xref rid="R12" ref-type="bibr">12</xref>
,<xref rid="R13" ref-type="bibr">13</xref>
</sup>
<xref rid="SD1" ref-type="supplementary-material">Supplementary Tables 1 and
2</xref>
provide data on WES quality metrics, as well as <italic>de novo
variants</italic>
identified in this cohort, respectively.</p>
<p id="P20">Filtering of exome data and search for variations in the same gene in
unrelated subjects revealed the same recurrent mutation (c.1117G>A, p.Gly373Arg),
in <italic>PIK3R2</italic>
in two patients (Patients 18 and 19). This mutation was
not present in any of the public databases. However, close look at the reads
generated by the high throughput sequencing using the Integrated Genome Viewer (IGV)
interface revealed that this variant is present in 10 reads out of 86 (12%)
for patient 18 and 20 reads out of 132 (15%) for patient 19. This deviation
from 50% of reads bearing the variant or alternate allele expected for
heterozygous constitutional mutations was suggestive of somatic mosaicism of this
mutation in <italic>PIK3R2</italic>
. As with standard WES, variation in read depth
between DNA samples is due to quantity and quality of the initial DNA, efficiency of
DNA binding to target, amplification of the final library and clusters, and
sequencing efficiency. To further confirm and quantify the suspected somatic
mosaicism, we performed deep targeted sequencing of the coding sequences of
<italic>PIK3R2</italic>
using DNA extracted from blood and saliva of these two
patients by Amplicon sequencing, which showed variable mutation levels in both
patients among tissues tested, confirming somatic mosaicism.</p>
<p id="P21">Given the identification of a recurrent mosaic mutation (p.Gly373Arg) in
<italic>PIK3R2</italic>
in BPP, which is also the same mutation identified
previously in MPPH<sup><xref rid="R14" ref-type="bibr">14</xref>
</sup>
, we sought to
search for mutations in this gene in a cohort of 118 patients with polymicrogyria.
Thirty-eight had BPP with normal or large head size (including 32 with MPPH) and
were tested by smMIPs and Sanger Sequencing. This testing strategy identified
mutations in 17 patients, 16 of whom were found to have the same
<italic>PIK3R2</italic>
mutation identified by WES (p.Gly373Arg). Another
patient with MPPH (patient 5) was independently studied by clinical WES and found to
have the same <italic>PIK3R2</italic>
mutation as well. One patient was identified
to have a <italic>de novo</italic>
missense mutation within the same functional
domain of the <italic>PIK3R2</italic>
gene, p.Lys376Glu. Eighty additional patients
with polymicrogyria broadly were tested only for the recurrent
<italic>PIK3R2</italic>
mutation (c.1117G>A, p.Gly373Arg) by amplicon
sequencing and were found to be negative. The clinical characteristics of all
patients included in this study are summarized in <xref rid="T1" ref-type="table">Table 1</xref>
.</p>
<p id="P22">As the same <italic>PIK3R2</italic>
mutation was detected in a subset of
patients with polymicrogyria among a cohort of 126, we calculated the probability
for the recurrent <italic>PIK3R2</italic>
mutation occurring by chance in our
cohort. Comparing the allele frequency of the <italic>PIK3R2</italic>
nonsynonymous
variant in our cohort (19/(126 • 2)); with the one reported in the largest
public database (ExAC; 0/33,113) showed an overwhelming significant enrichment of
<italic>PIK3R2</italic>
variant in our cohort using Fisher’s exact test
(p-value < 2.2 × 10<sup>−16</sup>
) (<xref rid="SD1" ref-type="supplementary-material">Supplementary Tables 3–6</xref>
).</p>
<p id="P23">Across the cohort, mutations were constitutional in 12 and mosaic in eight
patients. Among the mosaic patients, we observed substantial variation in alternate
(mutant) allele levels within individual samples, ranging from 2·6 (10/377)
to 36·7% (39/106) of reads, equivalent to
5·2–73·4% 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. To exclude artifactual low frequency variant detection due to
sample cross-contamination or index cross talk, we confirmed mutations using
independent captures or Sanger sequencing. Patient 12 had a different de novo
missense mutation of <italic>PIK3R2</italic>
(c.1126A>G, p.Lys376Glu), that was
not present in any of the public databases and is predicted to be pathogenic using
in silico analysis. This <italic>de novo</italic>
mutation also affects a highly
evolutionarily conserved amino acid residue within the SH domain of PIK3R2, and is
therefore predicted to be pathogenic.<sup><xref rid="R15" ref-type="bibr">15</xref>
</sup>
The clinical-neuroimaging and molecular findings of our
<italic>PIK3R2</italic>
mutation-positive patients are summarized in <xref rid="T2" ref-type="table">Tables 2</xref>
and <xref rid="T3" ref-type="table">3</xref>
, respectively. Representative brain MRI images for patients with
constitutional and mosaic mutations are shown in <xref rid="F2" ref-type="fig">Figures 2</xref>
and <xref rid="F3" ref-type="fig">3</xref>
, respectively. All
patients had BPP, with or without megalencephaly. Below, we summarize the most
distinctive phenotypic characteristics of these patients which include
polymicrogyria, megalencephaly, ventriculomegaly, epilepsy, and oromotor
weakness.</p>
<p id="P24">Polymicrogyria only affected the perisylvian cortex or extended beyond it
with perisylvian predominance. The severity spectrum ranged from BPP restricted to
the posterior perisylvian regions <italic>(grade 4)</italic>
to BPP involving the
entire perisylvian regions <italic>(grade 3)</italic>
, to BPP extending variable
distances anteriorly, posteriorly, and inferiorly from the perisylvian regions but
sparing the occipital and frontal lobes <italic>(grade 2)</italic>
, to extensive BPP
that includes one or both poles with the Sylvian fissures extended posteriorly and
often oriented superiorly (<italic>grade 1</italic>
).<sup><xref rid="R16" ref-type="bibr">16</xref>
</sup>
The extent of involvement was bilateral, but
often mildly asymmetric in most individuals.</p>
<p id="P25">Thirteen of 20 (65%) of individuals in our cohort had megalencephaly
defined as OFC > 2 standard deviations (SD) above the mean for age and gender,
fulfilling the diagnostic criteria for MPPH.<sup><xref rid="R17" ref-type="bibr">17</xref>
</sup>
MEG was predominantly congenital in onset in these
individuals; with later OFCs reported as large as 7·5 SD above the mean.
7/20 (35%) individuals were normocephalic.</p>
<p id="P26">Ventriculomegaly, ranging from mild to severe, was seen in 17/20
(85%) individuals, including one with hydrocephalus requiring neurosurgical
intervention (by placement of a ventriculostomy drain) The corpus callosum appeared
thin or stretched in some of these individuals.</p>
<p id="P27">Other neuroimaging abnormalities seen in our cohort include a variably thick
corpus callosum (7/20; 35%), cerebellar tonsillar ectopia (5/20;
25%), mild white matter dysmyelination with prominent perivascular spaces
(7/20; 35%), and cavum septum pellucidum et vergae (5/20; 25%).</p>
<p id="P28">Epilepsy occurred in 14/20 (70%) individuals. Seizure onset ranged
from 1 month to 12 years of age (with a mean age of onset of 2 years and 3 months
across the entire cohort, except for patients 1 and 15 for whom age of seizure onset
was unknown). Seizures were predominantly focal, although no clearly recurrent
seizure pattern emerged. Although epilepsy was a prominent clinical feature, it was
the reason for first referral in a minority of patients. In that subset, it
manifested with severe, intractable seizures, including one patient who had
infantile spasms that evolved into myoclonic seizures. Overall, severe epilepsies
were most often seen in patients with constitutional mutations, who also had an
overall earlier age at seizure onset (mean 11 months vs. 3·89 years for
patients with constitutional vs. mosaic mutations, respectively).</p>
<p id="P29">Symptoms of oromotor dysfunction such as expressive language or speech
delay, difficulties handling oral secretions (such as profuse drooling) and
dysphagia were present in the majority of our patients (9/12; 75%; of
patients with constitutional mutations and 7/8; 87·5%; of patients
with mosaic mutations).</p>
<p id="P30">Other notable manifestations included cutaneous capillary malformations
(seen in four patients), and multiple ventricular septal defects (seen in one
patient). Two patients had hypoglycemia. In one (patient 5), it was transient at
birth. The other (patient 14) had atypical ketotic hypoglycemia at six years of age.
All of the patients in our series had intellectual disability that varied from mild
to severe. One patient with MPPH (patient 17) exhibited early severe autistic
features.</p>
<p id="P31">Constitutional <italic>PIK3R2</italic>
mutations were <italic>de
novo</italic>
, with the exception of two families. The first family (of patient
7) consists of a large sibship of 11 children from multiple fathers, of whom five
have megalencephaly, BPP and variable hydrocephalus. One of these five children also
had postaxial polydactyly, a known feature of MPPH. The mother has macrocephaly,
hydrocephalus, intellectual disability, epilepsy and schizoaffective disorder, but
no brain imaging was available. Both child and mother harbored the
<italic>PIK3R2</italic>
mutation in peripheral blood-derived DNA at mutant
allele levels of 47% (23/48) and 41% (33/80) of reads, respectively,
suggestive of maternal inheritance. Samples were not available from the other
affected children. The second family (of patients 10 and 11) consists of two
affected siblings (boy and girl) with congenital megalencephaly, BPP, mild
ventriculomegaly, epilepsy and intellectual disability. Both siblings also had cutis
marmorata. Parental testing of blood-derived DNA was negative by deep targeted
sequencing, suggestive of parental germline mosaicism. The pedigrees of these
families are shown in the <xref rid="SD2" ref-type="supplementary-material">Supplementary Figure</xref>
.</p>
</sec>
<sec sec-type="discussion" id="S17"><title>Discussion</title>
<p id="P32">In this study, we report <italic>PIK3R2</italic>
mutations in 20 children
including 13 with MPPH syndrome and seven with BPP without megalencephaly.
<italic>PIK3R2</italic>
mutations identified in our cohort include <italic>de
novo</italic>
constitutional mutations, mutations inherited from an affected
parent or from parental germline mosaicism, as well as mosaic mutations. Our results
show that mutations of this gene are associated with a spectrum of malformations of
cortical development ranging from isolated BPP with a normal head size to BPP with
megalencephaly, including the MPPH syndrome (Research in context).</p>
<p id="P33">Bilateral perisylvian polymicrogyria (BPP) is the most common subtype of
polymicrogyria and has been proposed to be an etiologically heterogeneous
anatomoclinical syndrome, featuring a combination of oromotor dysfunction, cognitive
impairment and epilepsy.<sup><xref rid="R1" ref-type="bibr">1</xref>
, <xref rid="R18" ref-type="bibr">18</xref>
,<xref rid="R19" ref-type="bibr">19</xref>
</sup>
Among the genetic causes, BPP has most often been reported
in individuals with copy number variants, especially 1p36.3 and 22q11.2 deletion
syndromes.<sup><xref rid="R20" ref-type="bibr">20</xref>
,<xref rid="R21" ref-type="bibr">21</xref>
</sup>
However, genetic heterogeneity has been
proposed based on reports of large families with possible autosomal dominant or
X-linked inheritance with incomplete penetrance.<sup><xref rid="R19" ref-type="bibr">19</xref>
, <xref rid="R22" ref-type="bibr">22</xref>
</sup>
Polymicrogyria
of variable severity and distribution has been reported in many brain malformation
syndromes caused by mutations in a growing number of genes including <italic>NDE1,
WDR62, OCLN, RAB3GAP1, RAB3GAP2, RAB18, DYNC1H1, KIF5C, EOMES</italic>
,
<italic>RTTN</italic>
, <italic>FH</italic>
and <italic>KIAA1279</italic>
, as
well as many of the tubulin genes (<italic>TUBA1A, TUBA8, TUBB2B, TUBB3,
TUBB</italic>
).<sup><xref rid="R1" ref-type="bibr">1</xref>
</sup>
However, only
for the <italic>TUBA1A</italic>
, <italic>TUBB2B</italic>
and <italic>OCLN</italic>
genes has polymicrogyria been neuropathologically demonstrated.<sup><xref rid="R23" ref-type="bibr">23</xref>
–<xref rid="R25" ref-type="bibr">25</xref>
</sup>
For malformation syndromes related to the remaining genes, the
defining characteristics of polymicrogyria, which are typically microscopic
(multiple small microgyri, formed by thinned cortex, fused together) have been
inferred based on the macroscopic appearance of the gyral pattern, as visible by MRI
(gyri of irregular size and shape, cortical infolding and thickening related to
fused microgyri). However, the underlying architerctural substrate and developmental
mechanisms might vary in the different polymicrogyria syndromes, in spite of similar
imaging features.</p>
<p id="P34">Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR
pathway are known to cause a wide spectrum of developmental brain and body
disorders. Specifically, mutations of <italic>PIK3CA, PIK3R2, PTEN, AKT3</italic>
and <italic>CCND2</italic>
have been associated with focal, segmental (multifocal)
and generalized megalencephaly (MEG) with variable other features (<xref rid="SD1" ref-type="supplementary-material">Supplementary Table 7</xref>
).<sup><xref rid="R14" ref-type="bibr">14</xref>
,<xref rid="R26" ref-type="bibr">26</xref>
–<xref rid="R28" ref-type="bibr">28</xref>
</sup>
<italic>PIK3R2</italic>
mutations specifically cause the
megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH),<sup><xref rid="R14" ref-type="bibr">14</xref>
,<xref rid="R17" ref-type="bibr">17</xref>
</sup>
a relatively rare developmental brain disorder
characterized by megalencephaly, polymicrogyria, ventriculomegaly often leading to
hydrocephalus, and postaxial polydactyly. <sup><xref rid="R17" ref-type="bibr">17</xref>
, <xref rid="R29" ref-type="bibr">29</xref>
–<xref rid="R32" ref-type="bibr">32</xref>
</sup>
To date, mutations of
<italic>PIK3R2</italic>
have been reported in 15 individuals with this
syndrome.<sup><xref rid="R14" ref-type="bibr">14</xref>
,<xref rid="R33" ref-type="bibr">33</xref>
,<xref rid="R34" ref-type="bibr">34</xref>
</sup>
Mutations in two additional core pathway genes –<italic>AKT3</italic>
and
<italic>CCND2</italic>
– have recently been associated with MPPH as
well.<sup><xref rid="R14" ref-type="bibr">14</xref>
,<xref rid="R28" ref-type="bibr">28</xref>
</sup>
While mutations in PI3K-AKT-MTOR pathway
genes such as <italic>PIK3CA</italic>
have been predominately post-zygotic or
mosaic, mutations of <italic>PIK3R2, AKT3</italic>
and <italic>CCND2</italic>
have
been predominantly <italic>de novo</italic>
constitutional, with only one
<italic>PIK3R2</italic>
mosaic mutation reported to date.<sup><xref rid="R35" ref-type="bibr">35</xref>
</sup>
</p>
<p id="P35">Our data show that mutations of <italic>PIK3R2</italic>
are an important
cause of BPP, which otherwise remains etiologically heterogeneous. Overall,
constitutional and mosaic <italic>PIK3R2</italic>
mutations accounted for
15% (19/126) of our cohort of patients with polymicrogyria, with mosaic
mutations accounting for (8/126) 6·3% of the cohort. This rate is
higher than that observed in most MCD.<sup><xref rid="R1" ref-type="bibr">1</xref>
,
<xref rid="R35" ref-type="bibr">35</xref>
</sup>
Epilepsy was a prominent
clinical feature. Although no association with particular epilepsy syndromes was
apparent, an earlier age at seizure onset and more severe epilepsy outcomes were
also observed in patients with constitutional mutations.</p>
<p id="P36"><italic>PIK3R2</italic>
encodes the p85β regulatory subunit of the
PI3K-AKT-MTOR pathway. The mutational spectrum is very narrow as all but one of
reported patients harbored the same missense mutation, p.Gly373Arg. This gain of
function mutation lies within the sequence homology (SH) domain of the gene and is
seen infrequently in somatic tissues in cancer.<sup><xref rid="R36" ref-type="bibr">36</xref>
</sup>
Our data therefore expand on the phenotypic spectrum of
<italic>PIK3R2</italic>
mutations, reporting the first <italic>PIK3R2</italic>
mutations in BPP alone without other features of MPPH syndrome. We also report a
second mutation of <italic>PIK3R2</italic>
(p.Lys376Glu) in a girl who has BPP.</p>
<p id="P37">Mutations of other upstream (<italic>PTEN, PIK3CA</italic>
), central
(<italic>AKT3, TSC1, TSC2</italic>
) and downstream (<italic>CCND2</italic>
)
genes within the PI3K-AKT-MTOR pathway are also associated with a wide range of
developmental brain disorders. The phenotypic spectrum of brain involvement ranges
from bilateral diffuse megalencephaly with normal gyral pattern to megalencephaly
with polymicrogyria to hemimegalencephaly to focal cortical dysplasia (FCD) type 2
(<xref rid="SD1" ref-type="supplementary-material">Supplementary Table
7</xref>
).<sup><xref rid="R14" ref-type="bibr">14</xref>
, <xref rid="R26" ref-type="bibr">26</xref>
–<xref rid="R28" ref-type="bibr">28</xref>
,
<xref rid="R37" ref-type="bibr">37</xref>
–<xref rid="R38" ref-type="bibr">38</xref>
</sup>
</p>
<p id="P38">Our findings show that mosaic mutations of <italic>PIK3R2</italic>
cause a
regional brain malformation, similar to our experience with
<italic>PIK3CA</italic>
.<sup><xref rid="R14" ref-type="bibr">14</xref>
</sup>
While the level of mosaicism partly explains the variable severity, the basis of the
perisylvian predominance is not known. Bearing in mind the limited sensitivity of
MRI investigations, we hypothesize that the perisylvian region is more vulnerable to
perturbations caused by <italic>PIK3R2</italic>
mutations, even when occurring in a
limited number of randomly distributed cells. The primary fissure first appears as a
depression from the 5<sup>th</sup>
intrauterine month and completes opercularization
after birth.<sup><xref rid="R39" ref-type="bibr">39</xref>
</sup>
The closure of the
frontal and temporal opercula over the insula is among the most complex
morphological changes occurring in the postembryonic cerebral hemispheres.<sup><xref rid="R40" ref-type="bibr">40</xref>
</sup>
Deviations in cortical growth due
to increased cell proliferation or impaired microvascular development, both likely
to occur with <italic>PIK3R2</italic>
mutations, might interfere with the dynamics
and cytoarchitectural determinants that generate the pattern of cortical folding in
the perisylvian region.<sup><xref rid="R39" ref-type="bibr">39</xref>
,<xref rid="R41" ref-type="bibr">41</xref>
</sup>
However, it remains difficult to
determine to what extent a regional brain malformation such as perisylvian
polymicrogyria results from enhanced local vulnerability due to altered dynamics of
cortical development or just reflects the regional expression of the mutant
gene.</p>
<p id="P39">While our exome analysis pipeline allowed the detection of mosaic mutations
in two of our BPP patients, it is possible that other mosaic mutations in this
cohort were missed due to either poor coverage or very low level of mosaicism. We
speculate this is unlikely as the average depth of coverage across our exomes is
141X and full coverage of <italic>PIK3R2</italic>
coding exons was checked for our
eight trios. Further, as we used a site-specific method (amplicon sequencing) to
efficiently screen our cohort of 80 patients with polymicrogyria, we may have missed
other mutations within the <italic>PIK3R2</italic>
gene in this group. One
additional potential limitation with respect to findings described in this report is
that the study is based mainly on analysis of DNA extracted from peripheral tissues
(blood, saliva), and brain tissues were not accessible to detect or confirm mosaic
mutations. We expect that future NGS studies of additional patients will further
delineate the frequency of <italic>PIK3R2</italic>
mutations in polymicrogyria in
general, and BPP in particular. Finally, our study similar to others expands the
number of families with possible germline mosaicism. The role of germline mosaicism
(i.e. mosaic mutations in the germline cells of a parent) is increasingly being
recognized as the cause of genetic disorders. <sup><xref rid="R42" ref-type="bibr">42</xref>
–<xref rid="R43" ref-type="bibr">43</xref>
</sup>
We
anticipate that the frequency of germline mosaicism in the <italic>PIK3R2</italic>
related spectrum in particular will be further delineated with future NGS studies as
well.</p>
<p id="P40">In summary, our report shows that both constitutional and mosaic mutations
of <italic>PIK3R2</italic>
cause a spectrum of developmental brain disorders,
similar to several other PI3K-AKT-MTOR pathway genes. In addition, we report the
second pathogenic mutation of this gene, the second family with probable parental
germline mosaicism, and the first evidence of parent-child transmission of MPPH.
These data have important implications for familial testing and recurrence risk
counseling.</p>
</sec>
<sec sec-type="supplementary-material" id="S18"><title>Supplementary Material</title>
<supplementary-material content-type="local-data" id="SD1"><label>1</label>
<media xlink:href="NIHMS737729-supplement-1.pdf" orientation="portrait" xlink:type="simple" id="d37e1129" position="anchor"></media>
</supplementary-material>
<supplementary-material content-type="local-data" id="SD2"><label>2</label>
<media xlink:href="NIHMS737729-supplement-2.pptx" orientation="portrait" xlink:type="simple" id="d37e1133" position="anchor"></media>
</supplementary-material>
</sec>
</body>
<back><ack id="S19"><p><bold>Funding.</bold>
This study was funded by the US National Institutes of Health
under NINDS grants K08NS092898 (to G.M.M.), NS058721 (to W.B.D.), and by EU 7th
Framework Programme (FP7) under the project DESIRE grant N602531 (to R.G. and J.C.),
E-RareJTC2011 (to R.G. and J.C.) and FRM (Equipe FRM; J.C. DEQ20130326477).</p>
<p>We thank the patients, their families and referring physicians for their contribution
to our ongoing work on these disorders.</p>
</ack>
<fn-group><fn id="FN2" fn-type="conflict"><p><bold>Conflicts of Interest</bold>
</p>
<p>The authors report no conflict of interest.</p>
</fn>
<fn id="FN3"><p><bold>Web links:</bold>
</p>
<p>Exome Aggregation Consortium (ExAC), Cambridge, MA (URL: <ext-link ext-link-type="uri" xlink:href="http://exac.broadinstitute.org">http://exac.broadinstitute.org</ext-link>
) [accessed August,
2015].</p>
<p>Freebayes, <ext-link ext-link-type="uri" xlink:href="https://github.com/ekg/freebayes">https://github.com/ekg/freebayes</ext-link>
</p>
<p>IGV, <ext-link ext-link-type="uri" xlink:href="http://www.broadinstitute.org/igv/">http://www.broadinstitute.org/igv/</ext-link>
</p>
<p>National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project,</p>
<p><ext-link ext-link-type="uri" xlink:href="http://evs.gs.washington.edu/EVS/">http://evs.gs.washington.edu/EVS/</ext-link>
</p>
<p>PEAR, <ext-link ext-link-type="uri" xlink:href="http://www.exelixis-lab.org/web/software/pear">http://www.exelixis-lab.org/web/software/pear</ext-link>
</p>
<p>Primer3, <ext-link ext-link-type="uri" xlink:href="http://www.bioinformatics.nl/cgi-bin/primer3plus/primer3plus.cgi/">http://www.bioinformatics.nl/cgi-bin/primer3plus/primer3plus.cgi/</ext-link>
</p>
<p>Picard, <ext-link ext-link-type="uri" xlink:href="http://picard.sourceforge.net/">http://picard.sourceforge.net/</ext-link>
</p>
</fn>
<fn id="FN4" fn-type="con"><p><bold>Contributors</bold>
</p>
<p>G.M.M., R.G., and W.B.D designed the study. G.M.M., S.C., V.C. B.M. and D.M.
performed the genetic experiments. G.M., V.C., A.R.T., E.A.B., D.M., J-F.D.,
P.N., J.S. and J.C. analyzed the molecular data. G.M.M., C.D.S., S.A., M.C.,
S.B., R.B.H., A.G., Y.N-K., C.A., K.J., K.F., K.H., C.H., A.G., E.P., A.S.,
E.B., C.B., W.B.D., and R.G. recruited and evaluated the study subjects. C.A.
provided administrative support and recruited study subjects, G.M.M., R.G., and
W.B.D. supervised the study. G.M.M. and R.G. wrote the manuscript.</p>
</fn>
<fn id="FN5"><p content-type="publisher-disclaimer">This is a PDF file of an unedited manuscript
that has been accepted for publication. As a service to our customers we are
providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is
published in its final citable form. Please note that during the production
process errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.</p>
</fn>
</fn-group>
<ref-list><ref id="R1"><label>1</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Guerrini</surname>
<given-names>R</given-names>
</name>
<name><surname>Dobyns</surname>
<given-names>WB</given-names>
</name>
</person-group>
<article-title>Malformations of cortical development: clinical features and
genetic causes</article-title>
<source>Lancet Neurol</source>
<year>2014</year>
<volume>13</volume>
<fpage>710</fpage>
<lpage>26</lpage>
<pub-id pub-id-type="pmid">24932993</pub-id>
</element-citation>
</ref>
<ref id="R2"><label>2</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Leventer</surname>
<given-names>RJ</given-names>
</name>
<name><surname>Jansen</surname>
<given-names>A</given-names>
</name>
<name><surname>Pilz</surname>
<given-names>DT</given-names>
</name>
<name><surname>Stoodley</surname>
<given-names>N</given-names>
</name>
<name><surname>Marini</surname>
<given-names>C</given-names>
</name>
<name><surname>Dubeau</surname>
<given-names>F</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Clinical and imaging heterogeneity of polymicrogyria: a study of
328 patients</article-title>
<source>Brain</source>
<year>2010</year>
<volume>133</volume>
<fpage>1415</fpage>
<lpage>27</lpage>
<pub-id pub-id-type="pmid">20403963</pub-id>
</element-citation>
</ref>
<ref id="R3"><label>3</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kuzniecky</surname>
<given-names>RI</given-names>
</name>
<name><surname>Andermann</surname>
<given-names>F</given-names>
</name>
<name><surname>Guerrini</surname>
<given-names>R</given-names>
</name>
</person-group>
<article-title>The congenital bilateral perisylvian syndrome: study of 31
patients. The congenital bilateral perisylvian syndrome multicenter
collaborative study</article-title>
<source>Lancet</source>
<year>1993</year>
<volume>341</volume>
<fpage>608</fpage>
<lpage>12</lpage>
<pub-id pub-id-type="pmid">8094839</pub-id>
</element-citation>
</ref>
<ref id="R4"><label>4</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Stutterd</surname>
<given-names>CA</given-names>
</name>
<name><surname>Leventer</surname>
<given-names>RJ</given-names>
</name>
</person-group>
<article-title>Polymicrogyria: a common and heterogeneous malformation of
cortical development</article-title>
<source>Am J Med Genet C Semin Med Genet</source>
<year>2014</year>
<month>6</month>
<volume>166C</volume>
<fpage>227</fpage>
<lpage>39</lpage>
<pub-id pub-id-type="pmid">24888723</pub-id>
</element-citation>
</ref>
<ref id="R5"><label>5</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kheradmand Kia</surname>
<given-names>S</given-names>
</name>
<name><surname>Verbeek</surname>
<given-names>E</given-names>
</name>
<name><surname>Engelen</surname>
<given-names>E</given-names>
</name>
<name><surname>Schot</surname>
<given-names>R</given-names>
</name>
<name><surname>Poot</surname>
<given-names>RA</given-names>
</name>
<name><surname>de Coo</surname>
<given-names>IFM</given-names>
</name>
<etal></etal>
</person-group>
<article-title>RTTN mutations link primary cilia function to organization of the
human cerebral cortex</article-title>
<source>Am J Hum Genet</source>
<year>2012</year>
<volume>91</volume>
<fpage>533</fpage>
<lpage>40</lpage>
<pub-id pub-id-type="pmid">22939636</pub-id>
</element-citation>
</ref>
<ref id="R6"><label>6</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nellhaus</surname>
<given-names>G</given-names>
</name>
</person-group>
<article-title>Head circumference from birth to eighteen years. Practical
composite international and interracial graphs</article-title>
<source>Pediatrics</source>
<year>1968</year>
<volume>41</volume>
<issue>1</issue>
<fpage>106</fpage>
<lpage>14</lpage>
<pub-id pub-id-type="pmid">5635472</pub-id>
</element-citation>
</ref>
<ref id="R7"><label>7</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hiatt</surname>
<given-names>JB</given-names>
</name>
<name><surname>Pritchard</surname>
<given-names>CC</given-names>
</name>
<name><surname>Salipante</surname>
<given-names>SJ</given-names>
</name>
<name><surname>O’Roak</surname>
<given-names>BJ</given-names>
</name>
<name><surname>Shendure</surname>
<given-names>J</given-names>
</name>
</person-group>
<article-title>Single molecule molecular inversion probes for targeted,
high-accuracy detection of low-frequency variation</article-title>
<source>Genome Res</source>
<year>2013</year>
<volume>23</volume>
<issue>5</issue>
<fpage>843</fpage>
<lpage>54</lpage>
<pub-id pub-id-type="pmid">23382536</pub-id>
</element-citation>
</ref>
<ref id="R8"><label>8</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Boyle</surname>
<given-names>EA</given-names>
</name>
<name><surname>O’Roak</surname>
<given-names>BJ</given-names>
</name>
<name><surname>Martin</surname>
<given-names>BK</given-names>
</name>
<name><surname>Kumar</surname>
<given-names>A</given-names>
</name>
<name><surname>Shendure</surname>
<given-names>J</given-names>
</name>
</person-group>
<article-title>MIPgen: optimized modeling and design of molecular inversion
probes for targeted resequencing</article-title>
<source>Bioinforma Oxf Engl</source>
<year>2014</year>
<volume>30</volume>
<fpage>2670</fpage>
<lpage>2</lpage>
</element-citation>
</ref>
<ref id="R9"><label>9</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Newcombe</surname>
</name>
<name><surname>Robert</surname>
<given-names>G</given-names>
</name>
</person-group>
<article-title>Two- sided confidence intervals for the single proportion:
comparison of seven methods</article-title>
<source>Statistics in medicine</source>
<volume>17</volume>
<issue>8</issue>
<year>1998</year>
<fpage>857</fpage>
<lpage>872</lpage>
<pub-id pub-id-type="pmid">9595616</pub-id>
</element-citation>
</ref>
<ref id="R10"><label>10</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Poirier</surname>
<given-names>K</given-names>
</name>
<name><surname>Lebrun</surname>
<given-names>N</given-names>
</name>
<name><surname>Broix</surname>
<given-names>L</given-names>
</name>
<name><surname>Tian</surname>
<given-names>G</given-names>
</name>
<name><surname>Saillour</surname>
<given-names>Y</given-names>
</name>
<name><surname>Boscheron</surname>
<given-names>C</given-names>
</name>
<name><surname>Parrini</surname>
<given-names>E</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations
of cortical development and microcephaly</article-title>
<source>Nat Genet</source>
<year>2013</year>
<volume>45</volume>
<fpage>639</fpage>
<lpage>47</lpage>
<pub-id pub-id-type="pmid">23603762</pub-id>
</element-citation>
</ref>
<ref id="R11"><label>11</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Poirier</surname>
<given-names>K</given-names>
</name>
<name><surname>Martinovic</surname>
<given-names>J</given-names>
</name>
<name><surname>Laquerrière</surname>
<given-names>A</given-names>
</name>
<name><surname>Cavallin</surname>
<given-names>M</given-names>
</name>
<name><surname>Fallet-Bianco</surname>
<given-names>C</given-names>
</name>
<name><surname>Desguerre</surname>
<given-names>I</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Rare ACTG1 variants in fetal microlissencephaly</article-title>
<source>Eur J Med Genet</source>
<year>2015</year>
<volume>58</volume>
<fpage>416</fpage>
<lpage>8</lpage>
<pub-id pub-id-type="pmid">26188271</pub-id>
</element-citation>
</ref>
<ref id="R12"><label>12</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Vissers</surname>
<given-names>LE</given-names>
</name>
<name><surname>de Ligt</surname>
<given-names>J</given-names>
</name>
<name><surname>Gilissen</surname>
<given-names>C</given-names>
</name>
<name><surname>Janssen</surname>
<given-names>I</given-names>
</name>
<name><surname>Steehouwer</surname>
<given-names>M</given-names>
</name>
<name><surname>de Vries</surname>
<given-names>P</given-names>
</name>
<etal></etal>
</person-group>
<article-title>A de novo paradigm for mental retardation</article-title>
<source>Nat Genet</source>
<year>2010</year>
<volume>42</volume>
<fpage>1109</fpage>
<lpage>12</lpage>
<pub-id pub-id-type="pmid">21076407</pub-id>
</element-citation>
</ref>
<ref id="R13"><label>13</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Li</surname>
<given-names>Y</given-names>
</name>
<name><surname>Vinckenbosch</surname>
<given-names>N</given-names>
</name>
<name><surname>Tian</surname>
<given-names>G</given-names>
</name>
<name><surname>Huerta-Sanchez</surname>
<given-names>E</given-names>
</name>
<name><surname>Jiang</surname>
<given-names>T</given-names>
</name>
<name><surname>Jiang</surname>
<given-names>H</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Resequencing of 200 human exomes identifies an excess of
low-frequency non-synonymous coding variants</article-title>
<source>Nat Genet</source>
<year>2010</year>
<volume>42</volume>
<fpage>969</fpage>
<lpage>72</lpage>
<pub-id pub-id-type="pmid">20890277</pub-id>
</element-citation>
</ref>
<ref id="R14"><label>14</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rivière</surname>
<given-names>J-B</given-names>
</name>
<name><surname>Mirzaa</surname>
<given-names>GM</given-names>
</name>
<name><surname>O’Roak</surname>
<given-names>BJ</given-names>
</name>
<name><surname>Beddaoui</surname>
<given-names>M</given-names>
</name>
<name><surname>Alcantara</surname>
<given-names>D</given-names>
</name>
<name><surname>Conway</surname>
<given-names>RL</given-names>
</name>
<etal></etal>
</person-group>
<article-title>De novo germline and postzygotic mutations in AKT3, PIK3R2 and
PIK3CA cause a spectrum of related megalencephaly syndromes</article-title>
<source>Nat Genet</source>
<year>2012</year>
<volume>44</volume>
<fpage>934</fpage>
<lpage>40</lpage>
<pub-id pub-id-type="pmid">22729224</pub-id>
</element-citation>
</ref>
<ref id="R15"><label>15</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Richards</surname>
<given-names>S</given-names>
</name>
<name><surname>Aziz</surname>
<given-names>N</given-names>
</name>
<name><surname>Bale</surname>
<given-names>S</given-names>
</name>
<name><surname>Bick</surname>
<given-names>D</given-names>
</name>
<name><surname>Das</surname>
<given-names>S</given-names>
</name>
<name><surname>Gastier-Foster</surname>
<given-names>J</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Standards and guidelines for the interpretation of sequence
variants: a joint consensus recommendation of the American College of
Medical Genetics and Genomics and the Association for Molecular
Pathology</article-title>
<source>Genet Med</source>
<year>2015</year>
<volume>17</volume>
<fpage>405</fpage>
<lpage>24</lpage>
<pub-id pub-id-type="pmid">25741868</pub-id>
</element-citation>
</ref>
<ref id="R16"><label>16</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Leventer</surname>
<given-names>RJ</given-names>
</name>
<name><surname>Jansen</surname>
<given-names>A</given-names>
</name>
<name><surname>Pilz</surname>
<given-names>DT</given-names>
</name>
<name><surname>Stoodley</surname>
<given-names>N</given-names>
</name>
<name><surname>Marini</surname>
<given-names>C</given-names>
</name>
<name><surname>Dubeau</surname>
<given-names>F</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Clinical and imaging heterogeneity of polymicrogyria: a study of
328 patients</article-title>
<source>Brain</source>
<year>2010</year>
<volume>133</volume>
<fpage>1415</fpage>
<lpage>27</lpage>
<pub-id pub-id-type="pmid">20403963</pub-id>
</element-citation>
</ref>
<ref id="R17"><label>17</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mirzaa</surname>
<given-names>G</given-names>
</name>
<name><surname>Dodge</surname>
<given-names>NN</given-names>
</name>
<name><surname>Glass</surname>
<given-names>I</given-names>
</name>
<name><surname>Day</surname>
<given-names>C</given-names>
</name>
<name><surname>Gripp</surname>
<given-names>K</given-names>
</name>
<name><surname>Nicholson</surname>
<given-names>L</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Megalencephaly and perisylvian polymicrogyria with postaxial
polydactyly and hydrocephalus: a rare brain malformation syndrome associated
with mental retardation and seizures</article-title>
<source>Neuropediatrics</source>
<year>2004</year>
<volume>35</volume>
<fpage>353</fpage>
<lpage>9</lpage>
<pub-id pub-id-type="pmid">15627943</pub-id>
</element-citation>
</ref>
<ref id="R18"><label>18</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Barkovich</surname>
<given-names>AJ</given-names>
</name>
<name><surname>Hevner</surname>
<given-names>R</given-names>
</name>
<name><surname>Guerrini</surname>
<given-names>R</given-names>
</name>
</person-group>
<article-title>Syndromes of bilateral symmetrical polymicrogyria</article-title>
<source>AJNR</source>
<year>1999</year>
<volume>20</volume>
<fpage>1814</fpage>
<lpage>21</lpage>
<pub-id pub-id-type="pmid">10588102</pub-id>
</element-citation>
</ref>
<ref id="R19"><label>19</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Guerreiro</surname>
<given-names>MM</given-names>
</name>
<name><surname>Andermann</surname>
<given-names>E</given-names>
</name>
<name><surname>Guerrini</surname>
<given-names>R</given-names>
</name>
<name><surname>Dobyns</surname>
<given-names>WB</given-names>
</name>
<name><surname>Kuzniecky</surname>
<given-names>R</given-names>
</name>
<name><surname>Silver</surname>
<given-names>K</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Familial perisylvian polymicrogyria: a new familial syndrome of
cortical maldevelopment</article-title>
<source>Ann Neurol</source>
<year>2000</year>
<volume>48</volume>
<fpage>39</fpage>
<lpage>48</lpage>
<pub-id pub-id-type="pmid">10894214</pub-id>
</element-citation>
</ref>
<ref id="R20"><label>20</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dobyns</surname>
<given-names>WB</given-names>
</name>
<name><surname>Mirzaa</surname>
<given-names>G</given-names>
</name>
<name><surname>Christian</surname>
<given-names>SL</given-names>
</name>
<name><surname>Petras</surname>
<given-names>K</given-names>
</name>
<name><surname>Roseberry</surname>
<given-names>J</given-names>
</name>
<name><surname>Clark</surname>
<given-names>GD</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Consistent chromosome abnormalities identify novel polymicrogyria
loci in 1p36.3, 2p16.1-p23.1, 4q21.21-q22.1, 6q26-q27, and
21q2</article-title>
<source>Am J Med Genet A</source>
<year>2008</year>
<volume>146A</volume>
<fpage>1637</fpage>
<lpage>54</lpage>
<pub-id pub-id-type="pmid">18536050</pub-id>
</element-citation>
</ref>
<ref id="R21"><label>21</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Robin</surname>
<given-names>NH</given-names>
</name>
<name><surname>Taylor</surname>
<given-names>CJ</given-names>
</name>
<name><surname>McDonald-McGinn</surname>
<given-names>DM</given-names>
</name>
<name><surname>Zackai</surname>
<given-names>EH</given-names>
</name>
<name><surname>Bingham</surname>
<given-names>P</given-names>
</name>
<name><surname>Collins</surname>
<given-names>KJ</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Polymicrogyria and deletion 22q11.2 syndrome: Window to the
etiology of a common cortical malformation</article-title>
<source>Am J Med Genet A</source>
<year>2006</year>
<volume>140</volume>
<fpage>2416</fpage>
<lpage>25</lpage>
<pub-id pub-id-type="pmid">17036343</pub-id>
</element-citation>
</ref>
<ref id="R22"><label>22</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Borgatti</surname>
<given-names>R</given-names>
</name>
<name><surname>Triulzi</surname>
<given-names>F</given-names>
</name>
<name><surname>Zucca</surname>
<given-names>C</given-names>
</name>
<name><surname>Piccinelli</surname>
<given-names>P</given-names>
</name>
<name><surname>Balottin</surname>
<given-names>U</given-names>
</name>
<name><surname>Carrozzo</surname>
<given-names>R</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Bilateral perisylvian polymicrogyria in three
generations</article-title>
<source>Neurology</source>
<year>1999</year>
<volume>52</volume>
<fpage>1910</fpage>
<lpage>3</lpage>
<pub-id pub-id-type="pmid">10371547</pub-id>
</element-citation>
</ref>
<ref id="R23"><label>23</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jaglin</surname>
<given-names>XH</given-names>
</name>
<name><surname>Poirier</surname>
<given-names>K</given-names>
</name>
<name><surname>Saillour</surname>
<given-names>Y</given-names>
</name>
<name><surname>Buhler</surname>
<given-names>E</given-names>
</name>
<name><surname>Tian</surname>
<given-names>G</given-names>
</name>
<name><surname>Bahi-Buisson</surname>
<given-names>N</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Mutations in the beta-tubulin gene TUBB2B result in asymmetrical
polymicrogyria</article-title>
<source>Nat Genet</source>
<year>2009</year>
<volume>41</volume>
<fpage>746</fpage>
<lpage>52</lpage>
<pub-id pub-id-type="pmid">19465910</pub-id>
</element-citation>
</ref>
<ref id="R24"><label>24</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fallet-Bianco</surname>
<given-names>C</given-names>
</name>
<name><surname>Laquerrière</surname>
<given-names>A</given-names>
</name>
<name><surname>Poirier</surname>
<given-names>K</given-names>
</name>
<name><surname>Razavi</surname>
<given-names>F</given-names>
</name>
<name><surname>Guimiot</surname>
<given-names>F</given-names>
</name>
<name><surname>Dias</surname>
<given-names>P</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Mutations in tubulin genes are frequent causes of various foetal
malformations of cortical development including
microlissencephaly</article-title>
<source>Acta Neuropathol Commun</source>
<year>2014</year>
<volume>25</volume>
<issue>2</issue>
<fpage>69</fpage>
<pub-id pub-id-type="pmid">25059107</pub-id>
</element-citation>
</ref>
<ref id="R25"><label>25</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>O’Driscoll</surname>
<given-names>MC</given-names>
</name>
<name><surname>Daly</surname>
<given-names>SB</given-names>
</name>
<name><surname>Urquhart</surname>
<given-names>JE</given-names>
</name>
<name><surname>Black</surname>
<given-names>GC</given-names>
</name>
<name><surname>Pilz</surname>
<given-names>DT</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Recessive mutations in the gene encoding the tight junction
protein occludin cause band-like calcification with simplified gyration and
polymicrogyria</article-title>
<source>Am J Hum Genet</source>
<year>2010</year>
<volume>87</volume>
<fpage>354</fpage>
<lpage>64</lpage>
<pub-id pub-id-type="pmid">20727516</pub-id>
</element-citation>
</ref>
<ref id="R26"><label>26</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Poduri</surname>
<given-names>A</given-names>
</name>
<name><surname>Evrony</surname>
<given-names>GD</given-names>
</name>
<name><surname>Cai</surname>
<given-names>X</given-names>
</name>
<name><surname>Elhosary</surname>
<given-names>PC</given-names>
</name>
<name><surname>Beroukhim</surname>
<given-names>R</given-names>
</name>
<name><surname>Lehtinen</surname>
<given-names>MK</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Somatic activation of AKT3 causes hemispheric developmental brain
malformations</article-title>
<source>Neuron</source>
<year>2012</year>
<volume>74</volume>
<fpage>41</fpage>
<lpage>8</lpage>
<pub-id pub-id-type="pmid">22500628</pub-id>
</element-citation>
</ref>
<ref id="R27"><label>27</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lee</surname>
<given-names>JH</given-names>
</name>
<name><surname>Huynh</surname>
<given-names>M</given-names>
</name>
<name><surname>Silhavy</surname>
<given-names>JL</given-names>
</name>
<name><surname>Kim</surname>
<given-names>S</given-names>
</name>
<name><surname>Dixon-Salazar</surname>
<given-names>T</given-names>
</name>
<name><surname>Heiberg</surname>
<given-names>A</given-names>
</name>
<etal></etal>
</person-group>
<article-title>De novo somatic mutations in components of the PI3K-AKT3-mTOR
pathway cause hemimegalencephaly</article-title>
<source>Nat Genet</source>
<year>2012</year>
<volume>44</volume>
<fpage>941</fpage>
<lpage>5</lpage>
<pub-id pub-id-type="pmid">22729223</pub-id>
</element-citation>
</ref>
<ref id="R28"><label>28</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mirzaa</surname>
<given-names>GM</given-names>
</name>
<name><surname>Parry</surname>
<given-names>DA</given-names>
</name>
<name><surname>Fry</surname>
<given-names>AE</given-names>
</name>
<name><surname>Giamanco</surname>
<given-names>KA</given-names>
</name>
<name><surname>Schwartzentruber</surname>
<given-names>J</given-names>
</name>
<name><surname>Vanstone</surname>
<given-names>M</given-names>
</name>
<etal></etal>
</person-group>
<article-title>De novo CCND2 mutations leading to stabilization of cyclin D2
cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus
syndrome</article-title>
<source>Nat Genet</source>
<year>2014</year>
<volume>46</volume>
<fpage>510</fpage>
<lpage>5</lpage>
<pub-id pub-id-type="pmid">24705253</pub-id>
</element-citation>
</ref>
<ref id="R29"><label>29</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Colombani</surname>
<given-names>M</given-names>
</name>
<name><surname>Chouchane</surname>
<given-names>M</given-names>
</name>
<name><surname>Pitelet</surname>
<given-names>G</given-names>
</name>
<name><surname>Morales</surname>
<given-names>L</given-names>
</name>
<name><surname>Callier</surname>
<given-names>P</given-names>
</name>
<name><surname>Pinard</surname>
<given-names>JP</given-names>
</name>
<etal></etal>
</person-group>
<article-title>A new case of megalencephaly and perisylvian polymicrogyria with
post-axial polydactyly and hydrocephalus: MPPH syndrome</article-title>
<source>Eur J Med Genet</source>
<year>2006</year>
<volume>49</volume>
<fpage>466</fpage>
<lpage>71</lpage>
<pub-id pub-id-type="pmid">16807158</pub-id>
</element-citation>
</ref>
<ref id="R30"><label>30</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Garavelli</surname>
<given-names>L</given-names>
</name>
<name><surname>Guareschi</surname>
<given-names>E</given-names>
</name>
<name><surname>Errico</surname>
<given-names>S</given-names>
</name>
<name><surname>Simoni</surname>
<given-names>A</given-names>
</name>
<name><surname>Bergonzini</surname>
<given-names>P</given-names>
</name>
<name><surname>Zollino</surname>
<given-names>M</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Megalencephaly and Perisylvian Polymicrogyria with Postaxial
Polydactyly and Hydrocephalus (MPPH): Report of a New Case</article-title>
<source>Neuropediatrics</source>
<year>2007</year>
<volume>38</volume>
<fpage>200</fpage>
<lpage>3</lpage>
<pub-id pub-id-type="pmid">18058629</pub-id>
</element-citation>
</ref>
<ref id="R31"><label>31</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Osterling</surname>
<given-names>WL</given-names>
</name>
<name><surname>Boyer</surname>
<given-names>RS</given-names>
</name>
<name><surname>Hedlund</surname>
<given-names>GL</given-names>
</name>
<name><surname>Bale</surname>
<given-names>JF</given-names>
<suffix>Jr</suffix>
</name>
</person-group>
<article-title>MPPH syndrome: two new cases</article-title>
<source>Pediatr Neurol</source>
<year>2011</year>
<volume>44</volume>
<fpage>370</fpage>
<lpage>3</lpage>
<pub-id pub-id-type="pmid">21481746</pub-id>
</element-citation>
</ref>
<ref id="R32"><label>32</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pisano</surname>
<given-names>T</given-names>
</name>
<name><surname>Meloni</surname>
<given-names>M</given-names>
</name>
<name><surname>Cianchetti</surname>
<given-names>C</given-names>
</name>
<name><surname>Falchi</surname>
<given-names>M</given-names>
</name>
<name><surname>Nucaro</surname>
<given-names>A</given-names>
</name>
<name><surname>Pruna</surname>
<given-names>D</given-names>
</name>
</person-group>
<article-title>Megalencephaly, polymicrogyria, and hydrocephalus (MPPH)
syndrome: a new case with syndactyly</article-title>
<source>J Child Neurol</source>
<year>2008</year>
<volume>23</volume>
<fpage>916</fpage>
<lpage>8</lpage>
<pub-id pub-id-type="pmid">18474936</pub-id>
</element-citation>
</ref>
<ref id="R33"><label>33</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nakamura</surname>
<given-names>K</given-names>
</name>
<name><surname>Kato</surname>
<given-names>M</given-names>
</name>
<name><surname>Tohyama</surname>
<given-names>J</given-names>
</name>
<name><surname>Shiohama</surname>
<given-names>T</given-names>
</name>
<name><surname>Hayasaka</surname>
<given-names>K</given-names>
</name>
<name><surname>Nishiyama</surname>
<given-names>K</given-names>
</name>
<etal></etal>
</person-group>
<article-title>AKT3 and PIK3R2 mutations in two patients with
megalencephaly-related syndromes: MCAP and MPPH</article-title>
<source>Clin Genet</source>
<year>2014</year>
<volume>85</volume>
<fpage>396</fpage>
<lpage>8</lpage>
<pub-id pub-id-type="pmid">23745724</pub-id>
</element-citation>
</ref>
<ref id="R34"><label>34</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tapper</surname>
<given-names>WJ</given-names>
</name>
<name><surname>Foulds</surname>
<given-names>N</given-names>
</name>
<name><surname>Cross</surname>
<given-names>NCP</given-names>
</name>
<name><surname>Aranaz</surname>
<given-names>P</given-names>
</name>
<name><surname>Score</surname>
<given-names>J</given-names>
</name>
<name><surname>Hidalgo-Curtis</surname>
<given-names>C</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Megalencephaly syndromes: exome pipeline strategies for detecting
low-level mosaic mutations</article-title>
<source>PloS One</source>
<year>2014</year>
<volume>9</volume>
<fpage>e86940</fpage>
<pub-id pub-id-type="pmid">24497998</pub-id>
</element-citation>
</ref>
<ref id="R35"><label>35</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jamuar</surname>
<given-names>SS</given-names>
</name>
<name><surname>Lam</surname>
<given-names>A-TN</given-names>
</name>
<name><surname>Kircher</surname>
<given-names>M</given-names>
</name>
<name><surname>D’Gama</surname>
<given-names>AM</given-names>
</name>
<name><surname>Wang</surname>
<given-names>J</given-names>
</name>
<name><surname>Barry</surname>
<given-names>BJ</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Somatic mutations in cerebral cortical
malformations</article-title>
<source>N Engl J Med</source>
<year>2014</year>
<volume>371</volume>
<fpage>733</fpage>
<lpage>43</lpage>
<pub-id pub-id-type="pmid">25140959</pub-id>
</element-citation>
</ref>
<ref id="R36"><label>36</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cheung</surname>
<given-names>LWT</given-names>
</name>
<name><surname>Hennessy</surname>
<given-names>BT</given-names>
</name>
<name><surname>Li</surname>
<given-names>J</given-names>
</name>
<name><surname>Yu</surname>
<given-names>S</given-names>
</name>
<name><surname>Myers</surname>
<given-names>AP</given-names>
</name>
<name><surname>Djordjevic</surname>
<given-names>B</given-names>
</name>
<etal></etal>
</person-group>
<article-title>High frequency of PIK3R1 and PIK3R2 mutations in endometrial
cancer elucidates a novel mechanism for regulation of PTEN protein
stability</article-title>
<source>Cancer Discov</source>
<year>2011</year>
<volume>1</volume>
<fpage>170</fpage>
<lpage>85</lpage>
<pub-id pub-id-type="pmid">21984976</pub-id>
</element-citation>
</ref>
<ref id="R37"><label>37</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>D’Gama</surname>
<given-names>AM</given-names>
</name>
<name><surname>Geng</surname>
<given-names>Y</given-names>
</name>
<name><surname>Couto</surname>
<given-names>JA</given-names>
</name>
<name><surname>Martin</surname>
<given-names>B</given-names>
</name>
<name><surname>Boyle</surname>
<given-names>EA</given-names>
</name>
<name><surname>LaCoursiere</surname>
<given-names>CM</given-names>
</name>
<etal></etal>
</person-group>
<article-title>mTOR pathway mutations cause hemimegalencephaly and focal
cortical dysplasia</article-title>
<source>Ann Neurol</source>
<year>2015</year>
<volume>77</volume>
<fpage>720</fpage>
<lpage>5</lpage>
<pub-id pub-id-type="pmid">25599672</pub-id>
</element-citation>
</ref>
<ref id="R38"><label>38</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mirzaa</surname>
<given-names>GM</given-names>
</name>
<name><surname>Poduri</surname>
<given-names>A</given-names>
</name>
</person-group>
<article-title>Megalencephaly and hemimegalencephaly: breakthroughs in molecular
etiology</article-title>
<source>Am J Med Genet C Semin Med Genet</source>
<year>2014</year>
<volume>166C</volume>
<issue>2</issue>
<fpage>156</fpage>
<lpage>72</lpage>
<pub-id pub-id-type="pmid">24888963</pub-id>
</element-citation>
</ref>
<ref id="R39"><label>39</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ronan</surname>
<given-names>L</given-names>
</name>
<name><surname>Fletcher</surname>
<given-names>PC</given-names>
</name>
</person-group>
<article-title>From genes to folds: a review of cortical gyrification
theory</article-title>
<source>Brain Struct Funct</source>
<year>2014</year>
<month>12</month>
<day>16</day>
<comment>Epud ahead of print</comment>
</element-citation>
</ref>
<ref id="R40"><label>40</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>O’Rahilly</surname>
<given-names>R</given-names>
</name>
<name><surname>Müller</surname>
<given-names>F</given-names>
</name>
</person-group>
<article-title>Significant features in the early prenatal development of the
human brain</article-title>
<source>Ann Anat</source>
<year>2008</year>
<volume>190</volume>
<fpage>105</fpage>
<lpage>18</lpage>
<pub-id pub-id-type="pmid">18356030</pub-id>
</element-citation>
</ref>
<ref id="R41"><label>41</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Budday</surname>
<given-names>S</given-names>
</name>
<name><surname>Raybaud</surname>
<given-names>C</given-names>
</name>
<name><surname>Kuhl</surname>
<given-names>E</given-names>
</name>
</person-group>
<article-title>A mechanical model predicts morphological abnormalities in the
developing human brain</article-title>
<source>Sci Rep</source>
<year>2014</year>
<volume>4</volume>
<fpage>5644</fpage>
<pub-id pub-id-type="pmid">25008163</pub-id>
</element-citation>
</ref>
<ref id="R42"><label>42</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Campbell</surname>
<given-names>IM</given-names>
</name>
<name><surname>Stewart</surname>
<given-names>JR</given-names>
</name>
<name><surname>James</surname>
<given-names>RA</given-names>
</name>
<name><surname>Lupski</surname>
<given-names>JR</given-names>
</name>
<name><surname>Stankiewicz</surname>
<given-names>P</given-names>
</name>
<name><surname>Olofsson</surname>
<given-names>P</given-names>
</name>
<name><surname>Shaw</surname>
<given-names>CA</given-names>
</name>
</person-group>
<article-title>Parent of origin, mosaicism, and recurrence risk: probabilistic
modeling explains the broken symmetry of transmission
genetics</article-title>
<source>Am J Hum Genet</source>
<year>2014</year>
<volume>95</volume>
<issue>4</issue>
<fpage>345</fpage>
<lpage>59</lpage>
<pub-id pub-id-type="pmid">25242496</pub-id>
</element-citation>
</ref>
<ref id="R43"><label>43</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Campbell</surname>
<given-names>IM</given-names>
</name>
<name><surname>Yuan</surname>
<given-names>B</given-names>
</name>
<name><surname>Robberecht</surname>
<given-names>C</given-names>
</name>
<name><surname>Pfundt</surname>
<given-names>R</given-names>
</name>
<name><surname>Szafranski</surname>
<given-names>P</given-names>
</name>
<name><surname>McEntagart</surname>
<given-names>ME</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Parental somatic mosaicism is underrecognized and influences
recurrence risk of genomic disorders</article-title>
<source>Am J Hum Genet</source>
<year>2014</year>
<volume>95</volume>
<issue>2</issue>
<fpage>173</fpage>
<lpage>82</lpage>
<pub-id pub-id-type="pmid">25087610</pub-id>
</element-citation>
</ref>
</ref-list>
</back>
<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/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 002D82 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 002D82 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Wicri/Asie |area= AustralieFrV1 |flux= Pmc |étape= Corpus |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/Corpus/RBID.i -Sk "pubmed:26520804" \ | HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd \ | NlmPubMed2Wicri -a AustralieFrV1
![]() | This area was generated with Dilib version V0.6.33. | ![]() |