BRD4 and Cornelia de Lange Syndrome

BRD4 haploinsufficiency has been implicated in a Cornelia de Lange-like phenotype. A novel 19p13.12p13.11 deletion encompassing BRD4 was identified in a patient with congenital malformations and intellectual disability, overlapping prior deletion cases, supporting haploinsufficiency as a disease mechanism (PMID:30302754). This deletion, together with reported point mutations, links BRD4 to CdLS through its role in the NIPBL pathway.

Functional studies demonstrate a direct interaction between NIPBL and the ET domain of BRD4 in yeast two-hybrid and mammalian cells, with RNA-seq and ChIP-seq showing overlapping target genes and co-dependency for promoter occupancy. In vivo Drosophila mutants of Nipped-B and fs(1)h recapitulate genetic interaction, underpinning a transcriptional regulation defect consistent with the CdLS-like presentation (PMID:31320616). Key take-home: BRD4 haploinsufficiency shows limited genetic evidence but moderate functional support, warranting BRD4 evaluation in undiagnosed Cornelia de Lange-like disorders.

References

• Annals of human genetics • 2019 • Confirmation of BRD4 haploinsufficiency role in Cornelia de Lange-like phenotype and delineation of a 19p13.12p13.11 gene contiguous syndrome PMID:30302754
• Cell death & disease • 2019 • The Cornelia de Lange Syndrome-associated factor NIPBL interacts with BRD4 ET domain for transcription control of a common set of genes PMID:31320616

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