Faculty Collaboration Database

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

Date

06/26/2012

Pubmed ID

22729224

Pubmed Central ID

PMC3408813

DOI

10.1038/ng.2331

Scopus ID

2-s2.0-84864400015 (requires institutional sign-in at Scopus site)   563 Citations

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.

Author List

Rivière JB, Mirzaa GM, O'Roak BJ, Beddaoui M, Alcantara D, Conway RL, St-Onge J, Schwartzentruber JA, Gripp KW, Nikkel SM, Worthylake T, Sullivan CT, Ward TR, Butler HE, Kramer NA, Albrecht B, Armour CM, Armstrong L, Caluseriu O, Cytrynbaum C, Drolet BA, Innes AM, Lauzon JL, Lin AE, Mancini GM, Meschino WS, Reggin JD, Saggar AK, Lerman-Sagie T, Uyanik G, Weksberg R, Zirn B, Beaulieu CL, Finding of Rare Disease Genes (FORGE) Canada Consortium, Majewski J, Bulman DE, O'Driscoll M, Shendure J, Graham JM Jr, Boycott KM, Dobyns WB

MESH terms used to index this publication - Major topics in bold

Class I Phosphatidylinositol 3-Kinases
Exome
Germ-Line Mutation
Humans
Hydrocephalus
Malformations of Cortical Development
Megalencephaly
Mutation
Mutation, Missense
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
Syndrome