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De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome [Letter]

Rivière, Jean-Baptiste, van Bon, Bregje W. M., Hoischen, Alexander, Kholmanskikh, Stanislav S., O'Roak, Brian J., Gilissen, Christian, Gijsen, Sabine, Sullivan, Christopher T., Christian, Susan L., Abdul-Rahman, Omar A., Atkin, Joan F., Chassaing, Nicolas, Drouin-Garraud, Valerie, Fry, Andrew Evan, Fryns, Jean-Pierre, Gripp, Karen W., Kempers, Marlies, Kleefstra, Tjitske, Mancini, Grazia M. S., Nowaczyk, Malgorzata J. M., van Ravenswaaij-Arts, Conny M. A., Roscioli, Tony, Marble, Michael, Rosenfeld, Jill A., Siu, Victoria M., de Vries, Bert B. A., Shendure, Jay, Verloes, Alain, Veltman, Joris A., Brunner, Han G., Ross, M. Elizabeth, Pilz, Daniela T. and Dobyns, William B. 2012. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome [Letter]. Nature Genetics 44 (4) , pp. 440-444. 10.1038/ng.1091

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Abstract

Brain malformations are individually rare but collectively common causes of developmental disabilities1, 2, 3. Many forms of malformation occur sporadically and are associated with reduced reproductive fitness, pointing to a causative role for de novo mutations4, 5. Here, we report a study of Baraitser-Winter syndrome, a well-defined disorder characterized by distinct craniofacial features, ocular colobomata and neuronal migration defect6, 7. 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Postgraduate Medical and Dental Education
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RM Therapeutics. Pharmacology
Publisher: Nature Publishing Group
ISSN: 1061-4036
Last Modified: 12 Jan 2018 19:27
URI: http://orca.cf.ac.uk/id/eprint/37529

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