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

journal contribution
posted on 2023-06-08, 12:05 authored by Jean-Baptiste Rivière, Ghayda M Mirzaa, Brian J O'Roak, Margaret Beddaoui, Diana AlcantaraDiana 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 Canada Consortium (FORGE):, Jacek Majewski, Dennis E Bulman, Mark O'DriscollMark O'Driscoll, Jay Shendure, John M Graham Jr, Kym M Boycott, William B Dobyns
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.

History

Publication status

  • Published

Journal

Nature Genetics

ISSN

1546-1718

Publisher

Nature Publishing Group

Issue

8

Volume

44

Page range

934-940

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2012-08-14

First Compliant Deposit (FCD) Date

2012-07-07

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