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

Brain malformations are individually rare but collectively common causes of developmental disabilities(1–3). Many forms occur sporadically and have reduced reproductive fitness, pointing towards a causative role for de novo mutations(4,5). Here we report our studies of Baraitser-Winter syndrome, a well-defined syndrome characterized by distinct craniofacial features, ocular colobomata and a neuronal migration defect(6,7). By using whole-exome sequencing in three proband-parent trios, we identified de novo missense changes in the cytoplasmic actin genes ACTB and ACTG1 in one and two probands, respectively. Sequencing of both genes in fifteen additional patients revealed disease-causing mutations in all probands, including two recurrent de novo mutations (ACTB p.Arg196His and ACTG1 p.Ser155Phe). Our results confirm that trio-based exome sequencing is a powerful approach to discover the genes causing sporadic developmental disorders, emphasize the overlapping roles of cytoplasmic actins in development, and suggest that Baraitser-Winter syndrome is the predominant phenotype associated with mutations of these two genes.