De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes
In: Nature genetics, Jg. 44 (2012-03-30), Heft 8
Online
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Zugriff:
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(1-5). 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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De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes
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Autor/in / Beteiligte Person: | Dobyns, William B. ; Weksberg, Rosanna ; Ward, Thomas R. ; Meschino, Wendy S. ; Alcantara, Diana ; Bulman, Dennis E. ; Graham, John M. ; Lin, Angela E. ; Sullivan, Christopher T. ; Armstrong, Linlea ; Grazia M.S. Mancini ; Beddaoui, Margaret ; O'Roak, Brian J. ; Majewski, Jacek ; Schwartzentruber, Jeremy ; Nikkel, Sarah M. ; Cytrynbaum, Cheryl ; Jean Baptiste Rivière ; Gripp, Karen W. ; Drolet, Beth A. ; Shendure, Jay ; Albrecht, Beate ; Zirn, Birgit ; Beaulieu, Chandree L. ; Conway, Robert L. ; Armour, Christine M. ; Mirzaa, Ghayda M. ; Caluseriu, Oana ; Gã Khan Uyanik ; Butler, Hailly ; Boycott, Kym M. ; Saggar, Anand ; St-Onge, Judith ; Kramer, Nancy ; Lerman-Sagie, Tally ; Reggin, James D. ; Worthylake, Thea ; Lauzon, Julie ; A. Micheil Innes ; O'Driscoll, Mark ; Genetics, Clinical |
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Zeitschrift: | Nature genetics, Jg. 44 (2012-03-30), Heft 8 |
Veröffentlichung: | 2012 |
Medientyp: | unknown |
ISSN: | 1546-1718 (print) ; 1061-4036 (print) |
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