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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 《Nature genetics》2012,44(8):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. 相似文献
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