Researchers of the University of Edinburgh have identified mutations in BRD4 as the disease-causing genetic defect in patients with a Cornelia-de-Lange-like condition and have thus provided new insights into the pathomechanism underlying this syndrome. Cornelia-de-Lange syndrome (CdLS) is a clinically highly variable multisystem disorder associated with a range of malformations and disturbances in developmental processes. Mutations causing CdLS have so far been identified in a number of genes, some of which encoding key components of the cohesin complex. The most frequent cause of classic CdLS, however, are dominant mutations in NIPBL.

In their study published in Nature Genetics, the scientists have now identified heterozygous de novo mutations in BRD4 in their patients with a CdLS-like phenotype. BRD4 belongs to the family of BET (bromodomain and extra-terminal) proteins, which act as chromatin readers by binding to acetylated histones and regulate gene expression. High levels of BRD4 are found at super enhancers, i.e. important elements that drive transcription of genes involved in cell-type specification. In their functional analyses, the scientists showed that the heterozygous BRD4 mutations identified in their patients result in a loss of protein function and that BRD4 and NIPBL interact and seem to co-regulate gene expression during development.