De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome



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.

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Figure 1: Clinical presentation of subjects with Bohring-Opitz syndrome and ASXL1 mutations.

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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).

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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.

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Correspondence to Han G Brunner.

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The authors declare no competing financial interests.

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Supplementary Tables 1–3, Supplementary Figures 1 and 2 and Supplementary Note. (PDF 1080 kb)

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Hoischen, A., van Bon, B., Rodríguez-Santiago, B. et al. De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome. Nat Genet 43, 729–731 (2011).

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