title: PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution.
abstract: Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations ofPIK3CAhave been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identifiedPIK3CAmutations in 60 individuals. Several other individuals (n= 12) were identified separately to have mutations inPIK3CAby clinical targeted-panel testing (n= 6), whole-exome sequencing (n= 5), or Sanger sequencing (n= 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29PIK3CAmutations were novel. We also identified constitutionalPIK3CAmutations in 10 patients. Our molecular data, combined with review of the literature, show thatPIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations.
authors.affiliation: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.|Center for Integrative Brain Research and.
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authors.affiliation: Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington, USA.
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authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Evan August
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authors.affiliation: Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.
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authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
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authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
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authors.forename: Carissa
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authors.affiliation: Whole Exome Sequencing Program, GeneDx, Gaithersburg, Maryland, USA.
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authors.affiliation: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.|Center for Integrative Brain Research and.
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authors.affiliation: Department of Pediatrics, and Pediatric Neurology and Developmental Medicine, University Children's Hospital, Tübingen, Germany.
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authors.affiliation: Mount Sinai Hospital, The Prenatal Diagnosis and Medical Genetics Division, Department of Obstetrics and Gynecology, and.|Department of Pediatrics, Division of Clinical and Metabolic Genetics, University of Toronto, Toronto, Ontario, Canada.
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authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Saint Louis University, St. Louis, Missouri, USA.
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authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Saint Louis University, St. Louis, Missouri, USA.
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authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Saint Louis University, St. Louis, Missouri, USA.
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authors.affiliation: Department of Pediatrics, University of Vermont College of Medicine, Burlington, Vermont, USA.
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authors.affiliation: Division of Genetics, Department of Pediatrics, and.|Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
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authors.affiliation: Genetics Service, Department of Pediatric Medicine, KK Women's and Children's Hospital, Singapore.
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authors.affiliation: Greenwood Genetic Center, Greenwood, South Carolina, USA.
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authors.affiliation: Department of Neurology, University of Washington, Seattle, Washington, USA.|Providence Child Neurology, Providence Sacred Heart Medical Center and Children's Hospital, Spokane, Washington, USA.
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authors.affiliation: Clinical Genetics Unit, IRCCS Santa Maria Nuova Hospital, Reggio Emilia, Italy.
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authors.affiliation: University of California, San Francisco, San Francisco/Genetic Medicine Central California, San Francisco, California, USA.
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authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
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authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.|Howard Hughes Medical Institute, Seattle, Washington, USA.
authors.forename: Jay
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authors.affiliation: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.|Center for Integrative Brain Research and.|Department of Neurology, University of Washington, Seattle, Washington, USA.
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mesh_terms: D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D054220:Malformations of Cortical Development / Q000235:genetics*; D009030:Mosaicism; D009154:Mutation; D010641:Phenotype; D014018:Tissue Distribution; D054079:Vascular Malformations / Q000235:genetics*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human