title: Identification and Characterization of a Novel Constitutional PIK3CA Mutation in a Child Lacking the Typical Segmental Overgrowth of "PIK3CA-Related Overgrowth Spectrum".
abstract: Activating somatic PIK3CA mutations underlie a growing heterogeneous spectrum of segmental overgrowth disorders. We report the identification and evaluation of a novel de novo constitutional PIK3CA mutation (NM_006218.2:c.335T>A, p.Ile112Asn) in a child with congenital megalencephaly and macrosomia. Functional characterization of patient cells using a variety of endpoints demonstrates increased phosphatidylinositol-3-kinase (PI3K) activity. The mutation lies in a linker region adjacent to the p85 (PIK3R2) binding domain of the p110α (PIK3CA) catalytic subunit of PI3K. We show that altered stoichiometry within the p85-p110 complex likely underlies the hyperactive PI3K-AKT-mTOR signaling in this instance. Our findings expand upon the recently proposed "PIK3CA-related overgrowth spectrum" associated with PIKC3A mutations and PI3K hyperactivation, adding constitutional PIK3CA mutations as an underlying cause of megalencephaly and macrosomia in newborns.
authors.affiliation: Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU Dresden, Germany.|Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Di Donato
authors.affiliation: Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU Dresden, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rump
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.|Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.
authors.forename: Ghayda M
authors.initials: GM
authors.lastname: Mirzaa
authors.affiliation: Genome Damage & Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Alcantara
authors.affiliation: Genome Damage & Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
authors.forename: Antony
authors.initials: A
authors.lastname: Oliver
authors.affiliation: Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU Dresden, Germany.
authors.forename: Evelin
authors.initials: E
authors.lastname: Schrock
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.|Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.affiliation: Genome Damage & Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: O'Driscoll
mesh_terms: D002648:Child; D058534:Class I Phosphatidylinositol 3-Kinases; D006801:Humans; D008297:Male; D058627:Megalencephaly / Q000235:genetics; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human
keywords: PIK3CA; macrocephaly; overgrowth; p110α