Bohring-Opitz syndrome is characterized by severe intellectual disability, distinctive facial features and multiple congenital malformations. We sequenced the exomes of three individuals with Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1, which is required for maintenance of both activation and silencing of Hox genes. In total, 7 out of 13 subjects with a Bohring-Opitz phenotype had de novo ASXL1 mutations, suggesting that the syndrome is genetically heterogeneous.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.




  1. 1.

    & Am. J. Dis. Child. 129, 1348–1349 (1975).

  2. 2.

    , & et al. Eur. J. Hum. Genet. 19, 513–519 (2011).

  3. 3.

    , , , & Am. J. Med. Genet. A. 140, 1257–1263 (2006).

  4. 4.

    et al. Nat. Genet. 42, 790–793 (2010).

  5. 5.

    et al. Am. J. Hum. Genet. 87, 418–423 (2010).

  6. 6.

    et al. Nat. Genet. 42, 483–485 (2010).

  7. 7.

    et al. Am. J. Hum. Genet. 81, 835–841 (2007).

  8. 8.

    et al. Eur. J. Med. Genet. 50, 243–255 (2007).

  9. 9.

    et al. Dev. Biol. 337, 9–15 (2010).

  10. 10.

    , & GeneReviews (eds Pagon, R.A., Bird, T.D., Dolan, C.R. & Stephens, K.) (University of Washington, Seattle, Washington, USA, 1993–2010 ).

  11. 11.

    et al. Br. J. Haematol. 151, 365–375 (2010).

  12. 12.

    et al. Leukemia 24, 1062–1065 (2010).

  13. 13.

    et al. Oncogene 19, 3902–3913 (2000).

  14. 14.

    et al. Am. J. Hum. Genet. 87, 129–138 (2010).

Download references


We thank the subjects and their parents for participation in this study. We thank P. Arts, M. Steehouwer and personnel from the Microarray Facility and Sequencing Facility Nijmegen for technical assistance. We thank N. Wieskamp, J. de Ligt and M. Rosario for bioinformatics support in data analysis. The authors are grateful to M. Sipponen and J. Ignatius for collaborative efforts relating to patient 4 and to C. Fisher for information on the Asxl1 knockout mouse. 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., 916-86-016 to L.E.L.M.V. and 917-86-319 to B.B.B.A.d.V.), the 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., B.B.B.A.d.V. and J.A.V.). The Family Federation of Finland is funded by Finland's Slot Machine Association (RAY). B. R.-S. was supported by a postdoctoral fellowship of the Fondo Investigación Sanitaria, Spain (FIS CD06/00019).

Author information

Author notes

    • Alexander Hoischen
    • , Bregje W M van Bon
    •  & Benjamín Rodríguez-Santiago

    These authors contributed equally to this work.


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

    • Alexander Hoischen
    • , Bregje W M van Bon
    • , Benjamín Rodríguez-Santiago
    • , Christian Gilissen
    • , Lisenka E L M Vissers
    • , Petra de Vries
    • , Irene Janssen
    • , Bart van Lier
    • , Joris A Veltman
    • , Han G Brunner
    •  & Bert B B A de Vries
  2. Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.

    • Benjamín Rodríguez-Santiago
  3. Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras, CIBERER, Barcelona, Spain.

    • Benjamín Rodríguez-Santiago
  4. Department of Clinical Genetics, St Michael's Hospital, Bristol, UK.

    • Rob Hastings
    • , Sarah F Smithson
    •  & Ruth Newbury-Ecob
  5. Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, Denmark.

    • Susanne Kjaergaard
  6. Institute of Human Genetics, Newcastle University, Newcastle Upon Tyne, UK.

    • Judith Goodship
  7. Department of Medical Genetics, Yorkhill Hospitals, Yorkhill, Glasgow, UK.

    • Ruth McGowan
  8. Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland.

    • Deborah Bartholdi
    •  & Anita Rauch
  9. Department of Medical Genetics, The Family Federation of Finland, Helsinki, Finland.

    • Maarit Peippo
  10. Department of Pediatric Genetics, Emma Kinderziekenhuis Academisch Medisch Centrum (AMC), Amsterdam, The Netherlands.

    • Jan M Cobben
  11. Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.

    • Dagmar Wieczorek
  12. Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany.

    • Gabriele Gillessen-Kaesbach


  1. Search for Alexander Hoischen in:

  2. Search for Bregje W M van Bon in:

  3. Search for Benjamín Rodríguez-Santiago in:

  4. Search for Christian Gilissen in:

  5. Search for Lisenka E L M Vissers in:

  6. Search for Petra de Vries in:

  7. Search for Irene Janssen in:

  8. Search for Bart van Lier in:

  9. Search for Rob Hastings in:

  10. Search for Sarah F Smithson in:

  11. Search for Ruth Newbury-Ecob in:

  12. Search for Susanne Kjaergaard in:

  13. Search for Judith Goodship in:

  14. Search for Ruth McGowan in:

  15. Search for Deborah Bartholdi in:

  16. Search for Anita Rauch in:

  17. Search for Maarit Peippo in:

  18. Search for Jan M Cobben in:

  19. Search for Dagmar Wieczorek in:

  20. Search for Gabriele Gillessen-Kaesbach in:

  21. Search for Joris A Veltman in:

  22. Search for Han G Brunner in:

  23. Search for Bert B B A de Vries in:


A.H., B.W.M.v.B., B.R.-S., H.G.B., 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.B.A.d.V. performed review of phenotypes and sample collection. H.G.B., R.H., S.F.S., R.N.-E., S.K., J.G., R.M., D.B., A.R., M.P., J.M.C., D.W. and G.G.-K. clinically characterized the Bohring-Opitz syndrome cases and collected blood samples. A.H., L.E.L.M.V., P.d.V., I.J. and B.v.L. performed next-generation sequencing experiments. P.d.V. and B.v.L. performed validation experiments. C.G., B.R.-S. and A.H. analyzed and interpreted the data. All authors contributed to the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Han G Brunner.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Tables 1–3, Supplementary Figures 1 and 2 and Supplementary Note.

About this article

Publication history





Further reading