• Jean-Baptiste Rivière, Bregje W M van Bon, Alexander Hoischen, Stanislav S Kholmanskikh, Brian J O'Roak, Christian Gilissen, Sabine Gijsen, Christopher T Sullivan, Susan L Christian, Omar A Abdul-Rahman, Joan F Atkin, Nicolas Chassaing, Valerie Drouin-Garraud, Andrew E Fry, Jean-Pierre Fryns, Karen W Gripp, Marlies Kempers, Tjitske Kleefstra, Grazia M S Mancini, Małgorzata J M Nowaczyk, Conny M A van Ravenswaaij-Arts, Tony Roscioli, Michael Marble, Jill A Rosenfeld, Victoria M Siu, Bert B A de Vries, Jay Shendure, Alain Verloes, Joris A Veltman, Han G Brunner, M Elizabeth Ross, Daniela T Pilz, and William B Dobyns.
• Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, Washington, USA.
• Nat. Genet. 2012 Apr 1;44(4):440-4, S1-2.

AbstractBrain malformations are individually rare but collectively common causes of developmental disabilities. Many forms of malformation occur sporadically and are associated with reduced reproductive fitness, pointing to a causative role for de novo mutations. Here, we report a study of Baraitser-Winter syndrome, a well-defined disorder characterized by distinct craniofacial features, ocular colobomata and neuronal migration defect. Using whole-exome sequencing of three proband-parent trios, we identified de novo missense changes in the cytoplasmic actin-encoding genes ACTB and ACTG1 in one and two probands, respectively. Sequencing of both genes in 15 additional affected individuals identified disease-causing mutations in all probands, including two recurrent de novo alterations (ACTB, encoding p.Arg196His, and ACTG1, encoding p.Ser155Phe). Our results confirm that trio-based exome sequencing is a powerful approach to discover genes causing sporadic developmental disorders, emphasize the overlapping roles of cytoplasmic actin proteins in development and suggest that Baraitser-Winter syndrome is the predominant phenotype associated with mutation of these two genes.

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