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De novo mutations of SETBP1 cause Schinzel-Giedion syndrome

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Abstract

Schinzel-Giedion syndrome is characterized by severe mental retardation, distinctive facial features and multiple congenital malformations; most affected individuals die before the age of ten. We sequenced the exomes of four affected individuals (cases) and found heterozygous de novo variants in SETBP1 in all four. We also identified SETBP1 mutations in eight additional cases using Sanger sequencing. All mutations clustered to a highly conserved 11-bp exonic region, suggesting a dominant-negative or gain-of-function effect.

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Figure 1: Identification of SETBP1 mutations in individuals with Schinzel-Giedion syndrome.

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Acknowledgements

We thank the subjects and their parents for participation in this study. We thank S. Keijzers-Vloet, J. de Ligt, N. Leijsten and personnel from the Sequencing Facility Nijmegen for technical assistance and I. Saleem for referring patient 3 to us. This study was financially supported by the Netherlands Organization for Health Research and Development (ZonMW grants 917-66-36 and 911-08-025 to J.A.V. and 917-86-319 to B.B.A.d.V.), the EU-funded TECHGENE project (Health-F5-2009-223143 to P.A. and J.A.V.) and the AnEUploidy project (LSHG-CT-2006-37627 to A.Hoischen, B.W.M.v.B., H.G.B., B.B.A.d.V. and J.A.V.).

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Author notes

  1. Alexander Hoischen, Bregje W M van Bon and Christian Gilissen: These authors contributed equally to this work.

Authors and Affiliations

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

    Alexander Hoischen, Bregje W M van Bon, Christian Gilissen, Peer Arts, Bart van Lier, Marloes Steehouwer, Petra de Vries, Rick de Reuver, Nienke Wieskamp, Han G Brunner, Bert B A de Vries & Joris A Veltman

  2. Centre for Medical Genetics, Antwerp University Hospital, Antwerp, Belgium

    Geert Mortier

  3. Centre for Human Genetics, Leuven University Hospital, Leuven, Belgium

    Koen Devriendt

  4. Serviço de Genética de Coimbra, Hospital Pediátrico de Coimbra, Coimbra, Portugal

    Marta Z Amorim

  5. Centre for Human Genetics, Cliniques Universitaires St. Luc, Université Catholique de Louvain, Brussels, Belgium

    Nicole Revencu

  6. Canterbury Health Laboratories, Christchurch Hospital, Christchurch, New Zealand

    Alexa Kidd

  7. Centro de Genética Médica Doutor Jacinto Magalhães, Instituto Nacional de Saúde Doutor Ricardo, Porto, Portugal

    Mafalda Barbosa

  8. Department of Medical Genetics, Sydney Children's Hospital, Sydney, Australia

    Anne Turner

  9. Department of Clinical Genetics, The Children's Hospital at Westmead, Sydney, Australia

    Janine Smith

  10. Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham, UK

    Christina Oley

  11. Institute of Human Genetics, Newcastle upon Tyne Hospitals National Health Service Foundation Trust, Newcastle upon Tyne, UK

    Alex Henderson

  12. Northern Regional Genetics Service, Auckland, New Zealand

    Ian M Hayes

  13. South Australian Clinical Genetics Service, South Australian Pathology, Women's and Children's Hospital, North Adelaide, South Australia, Australia

    Elizabeth M Thompson

Authors
  1. Alexander Hoischen
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  2. Bregje W M van Bon
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  3. Christian Gilissen
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  4. Peer Arts
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  5. Bart van Lier
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  6. Marloes Steehouwer
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  7. Petra de Vries
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  8. Rick de Reuver
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  9. Nienke Wieskamp
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  10. Geert Mortier
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  11. Koen Devriendt
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  12. Marta Z Amorim
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  13. Nicole Revencu
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  14. Alexa Kidd
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  15. Mafalda Barbosa
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  16. Anne Turner
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  17. Janine Smith
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  18. Christina Oley
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  19. Alex Henderson
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  20. Ian M Hayes
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  21. Elizabeth M Thompson
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  22. Han G Brunner
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  23. Bert B A de Vries
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  24. Joris A Veltman
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Contributions

A. Hoischen, B.W.M.v.B., C.G., H.G.B., B.B.A.d.V. and J.A.V. conceived the project and planned the experiments. B.W.M.v.B., H.G.B. and B.B.A.d.V. performed review of phenotypes and sample collection. G.M., K.D., M.Z.A., N.R., A.K., M.B., A.T., J.S., C.O., A. Henderson, I.M.H. and E.M.T. clinically characterized the Schinzel-Giedion syndrome cases and collected blood samples. A. Hoischen, P.A. and B.v.L. performed next-generation sequencing experiments. M.S. and P.d.V. performed validation experiments. C.G., R.d.R. and N.W. analyzed and interpreted the data. A. Hoischen, B.W.M.v.B., C.G. and J.A.V. prepared the draft manuscript. All authors contributed to the final manuscript.

Corresponding author

Correspondence to Joris A Veltman.

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The authors declare no competing financial interests.

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Supplementary Text and Figures

Supplementary Tables 1–3, Supplementary Figures 1–3 and Supplementary Note (PDF 917 kb)

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Hoischen, A., van Bon, B., Gilissen, C. et al. De novo mutations of SETBP1 cause Schinzel-Giedion syndrome. Nat Genet 42, 483–485 (2010). https://doi.org/10.1038/ng.581

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  • DOI: https://doi.org/10.1038/ng.581

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