2012-08-01
De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes
Publication
Publication
Nature Genetics , Volume 44 - Issue 8 p. 934- 940
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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| doi.org/10.1038/ng.2331, hdl.handle.net/1765/57145 | |
| Nature Genetics | |
| Organisation | Department of Clinical Genetics |
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Riviere, J.-B., Mirzaa, G., O'Roak, B., Beddaoui, M., Alcantara, D., Conway, R., … Dobyns, W. (2012). De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nature Genetics, 44(8), 934–940. doi:10.1038/ng.2331 |
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