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De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome.

ABSTRACT: Brain 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.

SUBMITTER: Riviere JB 

PROVIDER: S-EPMC3677859 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome.

Rivière Jean-Baptiste JB   van Bon Bregje W M BW   Hoischen Alexander A   Kholmanskikh Stanislav S SS   O'Roak Brian J BJ   Gilissen Christian C   Gijsen Sabine S   Sullivan Christopher T CT   Christian Susan L SL   Abdul-Rahman Omar A OA   Atkin Joan F JF   Chassaing Nicolas N   Drouin-Garraud Valerie V   Fry Andrew E AE   Fryns Jean-Pierre JP   Gripp Karen W KW   Kempers Marlies M   Kleefstra Tjitske T   Mancini Grazia M S GM   Nowaczyk Małgorzata J M MJ   van Ravenswaaij-Arts Conny M A CM   Roscioli Tony T   Marble Michael M   Rosenfeld Jill A JA   Siu Victoria M VM   de Vries Bert B A BB   Shendure Jay J   Verloes Alain A   Veltman Joris A JA   Brunner Han G HG   Ross M Elizabeth ME   Pilz Daniela T DT   Dobyns William B WB  

Nature genetics 20120226 4

Brain 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 ident  ...[more]

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