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

• Published in: Nature genetics Vol. 44; no. 8; pp. 934 - 940
• Main Authors: RIVIERE, Jean-Baptiste, MIRZAA, Ghayda M, WORTHYLAKE, Thea, SULLIVAN, Christopher T, WARD, Thomas R, BUTLER, Hailly E, KRAMER, Nancy A, ALBRECHT, Beate, ARMOUR, Christine M, ARMSTRONG, Linlea, CALUSERIU, Oana, CYTRYNBAUM, Cheryl, O'ROAK, Brian J, DROLET, Beth A, INNES, Amicheil, LAUZON, Juliel, LIN, Angela E, MANCINI, Grazia M. S, MESCHINO, Wendy S, REGGIN, James D, SAGGAR, Anand K, LERMAN-SAGIE, Tally, UYANIK, Gokhan, BEDDAOUI, Margaret, WEKSBERG, Rosanna, ZIRN, Birgit, BEAULIEU, Chandree L, MAJEWSKI, Jacek, BULMAN, Dennis E, O'DRISCOLL, Mark, SHENDURE, Jay, GRAHAM, John M, BOYCOTT, Kym M, DOBYNS, William B, ALCANTARA, Diana, CONWAY, Robert L, ST-ONGE, Judith, SCHWARTZENTRUBER, Jeremy A, GRIPP, Karen W, NIKKEL, Sarah M
• Format: Journal Article
• Language: English
• Published: New York, NY Nature Publishing Group 01.08.2012
• Subjects: Abnormalities; Biological and medical sciences; Brain; Class I Phosphatidylinositol 3-Kinases; Complex syndromes; Enzymes; Exome; Experiments; Fundamental and applied biological sciences. Psychology; Gene mutations; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Germ-Line Mutation; Health aspects; Humans; Hydrocephalus - enzymology; Hydrocephalus - genetics; Hydrocephalus - pathology; Kinases; Malformations of Cortical Development - enzymology; Malformations of Cortical Development - genetics; Malformations of Cortical Development - pathology; Malformations of the nervous system; Medical genetics; Medical research; Medical sciences; Megalencephaly - enzymology; Megalencephaly - genetics; Megalencephaly - pathology; Mutation; Mutation, Missense; Neurology; Phosphatidylinositol 3-Kinases - genetics; Physiological aspects; Protein kinases; Proto-Oncogene Proteins c-akt - genetics; Siblings; Syndrome; Womens health; United Kingdom; Nervous system diseases; Enzyme; Transferases; Congenital disease; De novo; Syndrome; Cerebral disorder; 1-Phosphatidylinositol 3-kinase; Spectrum; Megalencephaly; Malformation; Germ line; Central nervous system disease; Mutation
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.2331

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.