We found that the clinical phenotype associated with BRD4 haploinsufficiency overlapped with that of Cornelia de Lange syndrome (CdLS), which is most often caused by mutation of NIPBL. More typical CdLS was observed with a de novo BRD4 missense variant, which retained the ability to coimmunoprecipitate with NIPBL, but bound poorly to acetylated histones. BRD4 and NIPBL displayed correlated binding at super-enhancers and appeared to co-regulate developmental gene expression.
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We thank the CdLS Foundation of the UK and Ireland and particularly the families of the affected children for their time and support for the research. G.O., M.A., H.B., W.A.B., M.M.P. and D.R.F. were funded by the MRC University Unit award to the University of Edinburgh for the MRC Human Genetics Unit. The work of A.v.K. was supported by Carnegie Trust Research Incentive Grant 70382. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant WT098051). The views expressed in this publication are those of the authors and not necessarily those of the Wellcome Trust or the Department of Health. The research team acknowledges the support of the National Institute for Health Research through the Comprehensive Clinical Research Network.
The authors declare no competing financial interests.
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Olley, G., Ansari, M., Bengani, H. et al. BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange–like syndrome. Nat Genet 50, 329–332 (2018). https://doi.org/10.1038/s41588-018-0042-y
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