Phenotype and genotype in 52 patients with Rubinstein–Taybi syndrome caused by <i>EP300</i> mutations

<jats:sec><jats:label /><jats:p>Rubinstein–Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, <jats:italic>CREBBP</jats:italic> in 60% and <jats:italic>EP300</jats:italic> in 8–10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co‐activators interacting with >400 proteins. Up to now 26 individuals with an <jats:italic>EP300</jats:italic> mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying <jats:italic>EP300</jats:italic> mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with <jats:italic>CREBBP</jats:italic> mutations. We demonstrate that <jats:italic>EP300</jats:italic> mutations cause a phenotype that typically resembles the classical RSTS phenotype due to <jats:italic>CREBBP</jats:italic> mutations to a great extent, although most facial signs are less marked with the exception of a low‐hanging columella. The limb anomalies are more similar to those in <jats:italic>CREBBP</jats:italic> mutated individuals except for angulation of thumbs and halluces which is very uncommon in <jats:italic>EP300</jats:italic> mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype–phenotype correlation is detected. Pre‐eclampsia occurs in 12/52 mothers of <jats:italic>EP300</jats:italic> mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an <jats:italic>EP300</jats:italic> mutated fetus the strongest known predictor for pre‐eclampsia. © 2016 Wiley Periodicals, Inc.</jats:p></jats:sec>