Clinical and molecular characterization of Rubinstein-Taybi syndrome patients carrying distinct novel mutations of the EP300 gene

Rubinstein-Taybi syndrome (RSTS) is a rare congenital neurodevelopmental disorder characterized by postnatal growth deficiency, skeletal abnormalities, dysmorphic features and cognitive deficit. Mutations in two genes, CREBBP and EP300, encoding two homologous transcriptional co-activators, have been identified in ~55% and ~3-5% of affected individuals, respectively. To date, only eight EP300-mutated-RSTS patients have been described and twelve additional mutations reported in the LOVD database. In this study, EP300 analysis were performed on 33 CREBBP-negative-RSTS patients leading to the identification of six unreported germline EP300 alterations comprising one deletion and five point mutations. All six patients showed a convincing, albeit mild, RSTS phenotype with minor skeletal anomalies, slight cognitive impairment and few major malformations. Beyond the expansion of the RSTS-EP300-mutated cohort, our study indicates that EP300-related-RSTS cases occur more frequently than previously thought (~8% vs 3-5%); furthermore novel EP300 mutations characterization in RSTS patients will enhance clinical practice and genotype-phenotype correlations.