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

Jean Baptiste Rivière, 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 CytrynbaumBeth 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, Gã Khan Uyanik, Rosanna Weksberg, Birgit Zirn, Chandree L. Beaulieu, Jacek Majewski, Dennis E. Bulman, Mark O'Driscoll, Jay Shendure, John M. Graham, Kym M. Boycott, William B. Dobyns

Research output: Contribution to journalArticlepeer-review

553 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)934-940
Number of pages7
JournalNature genetics
Issue number8
StatePublished - Aug 2012
Externally publishedYes

ASJC Scopus subject areas

  • Genetics


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