2. Academic Validation
  3. Identification and Characterization of a Novel Constitutional PIK3CA Mutation in a Child Lacking the Typical Segmental Overgrowth of "PIK3CA-Related Overgrowth Spectrum"

Identification and Characterization of a Novel Constitutional PIK3CA Mutation in a Child Lacking the Typical Segmental Overgrowth of "PIK3CA-Related Overgrowth Spectrum"

  • Hum Mutat. 2016 Mar;37(3):242-5. doi: 10.1002/humu.22933.
Nataliya Di Donato 1 2,  Andreas Rump 1,  Ghayda M Mirzaa 2 3,  Diana Alcantara 4,  Antony Oliver 4,  Evelin Schrock 1,  William B Dobyns 2 3,  Mark O'Driscoll 4
Affiliations

Affiliations

  • 1 Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU Dresden, Germany.
  • 2 Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.
  • 3 Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.
  • 4 Genome Damage & Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
PMID: 26593112 DOI: 10.1002/humu.22933
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.

Keywords

PIK3CA; macrocephaly; overgrowth; p110α.

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