2. Academic Validation
  3. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes

De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes

  • Nat Genet. 2012 Jun 24;44(8):934-40. doi: 10.1038/ng.2331.
Jean-Baptiste Rivière 1,  Ghayda M Mirzaa,  Brian J O'Roak,  Margaret Beddaoui,  Diana Alcantara,  Robert L Conway,  Judith St-Onge,  Jeremy A Schwartzentruber,  Karen W Gripp,  Sarah M Nikkel,  Thea Worthylake,  Christopher T Sullivan,  Thomas R Ward,  Hailly E Butler,  Nancy A Kramer,  Beate Albrecht,  Christine M Armour,  Linlea Armstrong,  Oana Caluseriu,  Cheryl Cytrynbaum,  Beth A Drolet,  A Micheil Innes,  Julie L Lauzon,  Angela E Lin,  Grazia M S Mancini,  Wendy S Meschino,  James D Reggin,  Anand K Saggar,  Tally Lerman-Sagie,  Gökhan Uyanik,  Rosanna Weksberg,  Birgit Zirn,  Chandree L Beaulieu,  Finding of Rare Disease Genes (FORGE) Canada Consortium,  Jacek Majewski,  Dennis E Bulman,  Mark O'Driscoll,  Jay Shendure,  John M Graham Jr,  Kym M Boycott,  William B Dobyns
Affiliations

Affiliation

  • 1 Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, Washington, USA.
PMID: 22729224 DOI: 10.1038/ng.2331
Abstract

Megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes are sporadic overgrowth disorders associated with markedly enlarged brain size and other recognizable features. 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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