Abstract
Nicolaides-Baraitser syndrome (NBS) is characterized by sparse hair, distinctive facial morphology, distal-limb anomalies and intellectual disability. We sequenced the exomes of ten individuals with NBS and identified heterozygous variants in SMARCA2 in eight of them. Extended molecular screening identified nonsynonymous SMARCA2 mutations in 36 of 44 individuals with NBS; these mutations were confirmed to be de novo when parental samples were available. SMARCA2 encodes the core catalytic unit of the SWI/SNF ATP-dependent chromatin remodeling complex that is involved in the regulation of gene transcription. The mutations cluster within sequences that encode ultra-conserved motifs in the catalytic ATPase region of the protein. These alterations likely do not impair SWI/SNF complex assembly but may be associated with disrupted ATPase activity. The identification of SMARCA2 mutations in humans provides insight into the function of the Snf2 helicase family.
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Acknowledgements
We thank the Genome of the Netherlands Project (GoNL) for providing their variant data. GoNL is one of the rainbow projects of the Dutch hub of the Biobanking and Biomolecular Research Infrastructure (BBMRI-NL). We thank S. Olabarriaga and M. Santcroos for their support in using the Dutch Grid for data analysis. We thank T.J.L. de Ravel and P. Brady for critical reading of the manuscript and G. Peeters for technical support. We are grateful to the subjects and their families for participating in this study. This work was made possible by grants from the Agency for Innovation by Science and Technology (IWT; SBO-60848), the Catholic University of Leuven (PFV/10/016 SymBioSys and GOA/12/015 to J.R.V., Y.M. and K.D.), the Queen Elisabeth Medical Foundation (GSKE 1113 to D. Hu and E.S.) and the type 3 large-infrastructure support InfraMouse by the Flanders Hercules Foundation (to D. Hu). B.A.N. is supported by a KOLUMB fellowship from the Foundation for Polish Science. S.B.S. was supported by the Fundação Para a Ciência e Tecnologia (SFRH/BD/46778/2008).
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J.R.V., K.D., R.H. and S.B.S. designed the experiments. J.K.J.V.H., A.S., Y.M., A.H.C.v.K. and B.D.C.v.S. performed bioinformatic analyses. S.B.S. and R.H. collected the study subjects. B.A.N. performed the sequencing. E.S. and D. Hu performed immunostaining. B.A.N., N.A. and P.v.D. performed functional studies. O.A.A.-R., M.-J.H.v.d.B., A.B., M.C., V.C.-D., M.A.D., I.F., A.F., J.-P.F., L.G., S.G., G.G.-K., B.D.H., D. Ho, J.K., M.K.-W., A.K., K.D.M., M.A.L., S. Maas, S. McKee, A.M., S.A.d.M., F.M.-P., E.O., J.P., E.R., N.S., I.S.-D., C.V., A.V., E.W., D.W., L.W., O.Z., K.D. and R.H. contributed clinical cases and clinical data for the study. B.A.N., J.K.J.V.H., S.B.S., K.D., R.H. and J.R.V. wrote the manuscript.
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Van Houdt, J., Nowakowska, B., Sousa, S. et al. Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome. Nat Genet 44, 445–449 (2012). https://doi.org/10.1038/ng.1105
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DOI: https://doi.org/10.1038/ng.1105
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