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

Authors

Jean Baptiste Rivière, Seattle Children's Hospital
Bregje W.M. Van Bon, Radboud University Medical Center
Alexander Hoischen, Radboud University Medical Center
Stanislav S. Kholmanskikh, Weill Cornell Medicine
Brian J. O'Roak, University of Washington
Christian Gilissen, Radboud University Medical Center
Sabine Gijsen, Radboud University Medical Center
Christopher T. Sullivan, Seattle Children's Hospital
Susan L. Christian, Seattle Children's Hospital
Omar A. Abdul-Rahman, University of Mississippi Medical Center
Joan F. Atkin, The Ohio State University
Nicolas Chassaing, CHU de Toulouse
Valerie Drouin-Garraud, CHU Rouen Normandie
Andrew E. Fry, University Hospital of Wales
Jean Pierre Fryns, KU Leuven– University Hospital Leuven
Karen W. Gripp, Alfred I. duPont Hospital for Children
Marlies Kempers, Radboud University Medical Center
Tjitske Kleefstra, Radboud University Medical Center
Grazia M.S. Mancini, Erasmus MC
Małgorzata J.M. Nowaczyk, McMaster University
Conny M.A. Van Ravenswaaij-Arts, Universitair Medisch Centrum Groningen
Tony Roscioli, Radboud University Medical Center
Michael Marble, LSUHSC School of Medicine
Jill A. Rosenfeld, PerkinElmer, Inc.
Victoria M. Siu, Western UniversityFollow
Bert B.A. De Vries, Radboud University Medical Center

Document Type

Article

Publication Date

4-1-2012

Journal

Nature Genetics

Volume

44

Issue

4

First Page

440

Last Page

444

URL with Digital Object Identifier

10.1038/ng.1091

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 acting-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. © 2012 Nature America, Inc. All rights reserved.