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         headline:De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes
         description:William Dobyns and colleagues report de novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA in the sporadic overgrowth syndromes megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) and megalencephaly-capillary malformation (MCAP). Megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes are sporadic overgrowth disorders associated with markedly enlarged brain size and other recognizable features1,2,3,4,5. We performed exome sequencing in 3 families with MCAP or MPPH, and our initial observations were confirmed in exomes from 7 individuals with MCAP and 174 control individuals, as well as in 40 additional subjects with megalencephaly, using a combination of Sanger sequencing, restriction enzyme assays and targeted deep sequencing. We identified de novo germline or postzygotic mutations in three core components of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway. These include 2 mutations in AKT3, 1 recurrent mutation in PIK3R2 in 11 unrelated families with MPPH and 15 mostly postzygotic mutations in PIK3CA in 23 individuals with MCAP and 1 with MPPH. Our data highlight the central role of PI3K-AKT signaling in vascular, limb and brain development and emphasize the power of massively parallel sequencing in a challenging context of phenotypic and genetic heterogeneity combined with postzygotic mosaicism.
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      headline:De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes
      description:William Dobyns and colleagues report de novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA in the sporadic overgrowth syndromes megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) and megalencephaly-capillary malformation (MCAP). Megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes are sporadic overgrowth disorders associated with markedly enlarged brain size and other recognizable features1,2,3,4,5. We performed exome sequencing in 3 families with MCAP or MPPH, and our initial observations were confirmed in exomes from 7 individuals with MCAP and 174 control individuals, as well as in 40 additional subjects with megalencephaly, using a combination of Sanger sequencing, restriction enzyme assays and targeted deep sequencing. We identified de novo germline or postzygotic mutations in three core components of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway. These include 2 mutations in AKT3, 1 recurrent mutation in PIK3R2 in 11 unrelated families with MPPH and 15 mostly postzygotic mutations in PIK3CA in 23 individuals with MCAP and 1 with MPPH. Our data highlight the central role of PI3K-AKT signaling in vascular, limb and brain development and emphasize the power of massively parallel sequencing in a challenging context of phenotypic and genetic heterogeneity combined with postzygotic mosaicism.
      datePublished:2012-06-24T00:00:00Z
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         Cell signalling
         Disease genetics
         Growth disorders
         Mutation
         Biomedicine
         general
         Human Genetics
         Cancer Research
         Agriculture
         Gene Function
         Animal Genetics and Genomics
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      name:Nature Genetics
      issn:
         1546-1718
         1061-4036
      volumeNumber:44
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            name:Erasmus Medical Center
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      name:Wendy S Meschino
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            name:Providence Child Neurology, Providence Sacred Heart Medical Center and Children's Hospital
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            name:Hospital for Sick Children
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      name:Birgit Zirn
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            address:
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            type:Organization
      name:Jay Shendure
      affiliation:
            name:University of Washington
            address:
               name:Department of Genome Sciences, University of Washington, Seattle, USA
               type:PostalAddress
            type:Organization
      name:John M Graham
      affiliation:
            name: Cedars-Sinai Medical Center, Medical Genetics Institute, Los Angeles, California, USA.
            address:
               name: Cedars-Sinai Medical Center, Medical Genetics Institute, Los Angeles, California, USA.,
               type:PostalAddress
            type:Organization
      name:Kym M Boycott
      affiliation:
            name:Children's Hospital of Eastern Ontario Research Institute, University of Ottawa
            address:
               name:Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada
               type:PostalAddress
            type:Organization
            name:Children's Hospital of Eastern Ontario
            address:
               name:Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada
               type:PostalAddress
            type:Organization
      name:William B Dobyns
      affiliation:
            name:Center for Integrative Brain Research, Seattle Children's Hospital
            address:
               name:Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, USA
               type:PostalAddress
            type:Organization
            name:University of Washington
            address:
               name:Department of Pediatrics, University of Washington, Seattle, USA
               type:PostalAddress
            type:Organization
            name:University of Washington
            address:
               name:Department of Neurology, University of Washington, Seattle, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, USA
      name:Department of Human Genetics, University of Chicago, Chicago, USA
      name:Department of Genome Sciences, University of Washington, Seattle, USA
      name:Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada
      name:Genome Damage & Stability Centre, University of Sussex, Falmer, UK
      name:Department of Pediatrics and Human Development, Michigan State University, East Lansing, USA
      name:Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, USA
      name:Genome Quebec Innovation Centre, McGill University, Montreal, Canada
      name:Division of Medical Genetics, A.I. duPont Hospital for Children, Wilmington, USA
      name:Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada
      name:Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada
      name:Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, USA
      name:Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, USA
      name:Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, USA
      name: Cedars-Sinai Medical Center, Medical Genetics Institute, Los Angeles, California, USA.,
      name:Department of Human Genetics, University Hospital Essen, Essen, Germany
      name:Department of Paediatrics, Queen's University, Kingston, Canada
      name:Department of Medical Genetics, University of British Columbia, Vancouver, Canada
      name:Department of Medical Genetics, University of Calgary, Calgary, Canada
      name:Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Canada
      name:Department of Dermatology, Medical College of Wisconsin, Milwaukee, USA
      name:Department of Pediatrics, Medical College of Wisconsin, Milwaukee, USA
      name:Department of Medical Genetics, University of Calgary, Calgary, Canada
      name:Department of Medical Genetics, University of Calgary, Calgary, Canada
      name:Department of Medical Genetics, MassGeneral Hospital for Children, Boston, USA
      name:Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
      name:Department of Genetics, North York General Hospital, Toronto, Canada
      name:Providence Child Neurology, Providence Sacred Heart Medical Center and Children's Hospital, Spokane, USA
      name:Clinical Genetics Department, St George's Hospital, University of London, London, UK
      name:Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel
      name:Institute of Human Genetics, University Medical Center Hamburg–Eppendorf, Hamburg, Germany
      name:Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Canada
      name:Department of Neuropediatrics, University of Goettingen, Goettingen, Germany
      name:Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada
      name:Department of Human Genetics, McGill University, Montreal, Canada
      name:Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada
      name:Genome Damage & Stability Centre, University of Sussex, Falmer, UK
      name:Department of Genome Sciences, University of Washington, Seattle, USA
      name: Cedars-Sinai Medical Center, Medical Genetics Institute, Los Angeles, California, USA.,
      name:Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada
      name:Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada
      name:Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, USA
      name:Department of Pediatrics, University of Washington, Seattle, USA
      name:Department of Neurology, University of Washington, Seattle, USA
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