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

Nature Genetics volume 44, pages 440–444 (2012)Cite this article

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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.

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Figure 1: Craniofacial appearance and magnetic resonance imaging (MRI) of an individual with Baraitser-Winter syndrome.
Figure 2: Protein blot analysis of β- and γ-actin isoforms in lymphoblastoid cells derived from an unaffected control (09.1359) and two individuals with deletion or duplication of ACTB or ACTG1 carrying the recurrent mutations in ACTB encoding p.Arg196His (LR04-173) and in ACTG1 encoding p.Ser155Phe (LP98-096).
Figure 3: Cytoskeletal organization, morphology and F-actin stability in lymphoblastoid cells derived from an unaffected control (09.1359) and two individuals with Baraitser-Winter syndrome (LR04-173 and LP98-096).

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  • 04 March 2012

    In the version of this article initially published online, the proband from trio 1 was incorrectly identified as LP98-083 in the second paragraph of the main text. The correct identification number for this subject is LP92-083. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank the families for their contribution to this study. We thank all members of the Northwest Genomics Center and Genomic Disorders Group Nijmegen, as well as personnel from the Microarray Facility and Sequencing Facility Nijmegen, for excellent technical assistance. This work was supported by grants from the US National Institutes of Health (NS058721 to W.B.D. and NS048120 to M.E.R.), the Netherlands Organization for Health Research and Development (ZonMW; 917-66-363 and 911-08-025 to J.A.V.), the European Union (EU)-funded TECHGENE project (Health-F5-2009-223143 to J.A.V.) and the AnEUploidy project (LSHG-CT-2006-37627 to A.H., B.W.M.v.B., H.G.B. and J.A.V.). J.-B.R. is supported by a Banting Postdoctoral Fellowship from the Canadian Institutes of Health Research. T.R. is supported by an Australian National Health and Medical Research Council (NHMRC) postdoctoral fellowship. We thank the Simons Foundation Autism Research Initiative (SFARI) that provided control exome data (191889), the National Institute of Environmental Health Services (NIEHS) Environmental Genome Project for providing support for this project (HHSN273200800010C) and the NHLBI GO Exome Sequencing Project and its ongoing studies that produced and provided exome variant calls for comparison, including the Lung GO Sequencing Project (HL-102923), the Women's Health Initiative (WHI) Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010).

Author information

Author notes

  1. Jean-Baptiste Rivière and Bregje W M van Bon: These authors contributed equally to this work.

  2. Daniela T Pilz and William B Dobyns: These authors jointly directed this work.

Authors and Affiliations

  1. Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, Washington, USA

    Jean-Baptiste Rivière, Christopher T Sullivan, Susan L Christian & William B Dobyns

  2. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Bregje W M van Bon, Alexander Hoischen, Christian Gilissen, Sabine Gijsen, Marlies Kempers, Tjitske Kleefstra, Tony Roscioli, Bert B A de Vries, Joris A Veltman & Han G Brunner

  3. Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York, USA

    Stanislav S Kholmanskikh & M Elizabeth Ross

  4. Department of Genome Sciences, University of Washington, Seattle, Washington, USA

    Brian J O'Roak & Jay Shendure

  5. Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi, USA

    Omar A Abdul-Rahman

  6. Department of Pediatrics, College of Medicine, Ohio State University, Columbus, Ohio, USA

    Joan F Atkin

  7. Department of Medical Genetics, Toulouse University Hospital and Toulouse III Paul-Sabatier University, Toulouse, France

    Nicolas Chassaing

  8. Department of Genetics, University Hospital, Rouen, France

    Valerie Drouin-Garraud

  9. Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK

    Andrew E Fry & Daniela T Pilz

  10. Departement Menselijke Erfelijkheid, Center for Human Genetics, University Hospital Leuven, Leuven, Belgium

    Jean-Pierre Fryns

  11. Division of Medical Genetics, Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA

    Karen W Gripp

  12. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands

    Grazia M S Mancini

  13. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada

    Małgorzata J M Nowaczyk

  14. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Conny M A van Ravenswaaij-Arts

  15. Department of Pediatrics, Louisiana State University Health Sciences Center and Children's Hospital of New Orleans, New Orleans, Louisiana, USA

    Michael Marble

  16. Signature Genomic Laboratories, PerkinElmer, Spokane, Washington, USA

    Jill A Rosenfeld

  17. Department of Pediatrics, University of Western Ontario, London, Ontario, Canada

    Victoria M Siu

  18. Département de Génétique, Hôpital Robert Debré, Paris, France

    Alain Verloes

  19. Department of Pediatrics, University of Washington, Seattle, Washington, USA

    William B Dobyns

  20. Department of Neurology, University of Washington, Seattle, Washington, USA

    William B Dobyns

Authors
  1. Jean-Baptiste Rivière
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Contributions

D.T.P., W.B.D., A.V. and H.G.B. designed the study. J.-B.R., B.W.M.v.B. and A.H. designed and performed the genetics experiments. S.S.K. performed the experiments in lymphoblastoid cell lines. J.-B.R., A.H., B.J.O. and C.G. performed the bioinformatics experiments. B.J.O. analyzed the control exome data sets. S.G. contributed to the genetics experiments. C.T.S. and S.L.C. prepared DNA samples and lymphoblastoid cell lines. O.A.A.-R., J.F.A., N.C., V.D.-G., A.E.F., J.-P.F., K.W.G., M.K., T.K., G.M.S.M., M.J.M.N., C.M.A.v.R.-A., T.R., B.B.A.d.V., M.M., V.M.S., A.V., H.G.B., D.T.P. and W.B.D. recruited and evaluated the study subjects. J.A.R. analyzed the Signature Genomic Laboratories data set. J.S. supervised B.J.O., J.A.V. supervised A.H., C.G. and S.G., H.G.B. supervised B.W.M.v.B., M.E.R. supervised and evaluated data with S.S.K. and wrote sections related to lymphoblastoid cell lines, and W.B.D. supervised J.-B.R. J.-B.R. and W.B.D. wrote the manuscript.

Corresponding authors

Correspondence to Daniela T Pilz or William B Dobyns.

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The authors declare no competing financial interests.

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Rivière, JB., van Bon, B., Hoischen, A. et al. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nat Genet 44, 440–444 (2012). https://doi.org/10.1038/ng.1091

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