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Background  Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant neurodevelopmental disorder characterized by broad thumbs and halluces. RSTS is caused by mutations in  CREBBP  and in  EP300  genes in 50–60% and 8%, respectively. Up to now, 76 RSTS- EP300  patients have been described. We present the clinical and molecular characterization of a cohort of RSTS patients carrying  EP300  mutations.    Methods  Patients were selected from a cohort of 72 individuals suspected of RSTS after being negative in  CREBBP  study. MLPA and panel-based NGS  EP300  were performed.    Results  Eight patients were found to carry  EP300  mutations. Phenotypic characteristics included: intellectual disability (generally mild), postnatal growth retardation, infant feeding problems, psychomotor and language delay and typical facial dysmorphisms (microcephaly, downslanting palpebral fissures,  columella  below the  alae nasi , and prominent nose). Broad thumbs and/or halluces were common, but angulated thumbs were only found in two patients. We identified across the gene novel mutations, including large deletion, frameshift mutations, nonsense, missense and splicing alterations, confirming de novo origin in all but one (the mother, possibly underdiagnosed, has short and broad thumbs and had learning difficulties).    Conclusions  The clinical evaluation of our patients corroborates that clinical features in  EP300  are less marked than in  CREBBP  patients although it is difficult to establish a genotype-phenotype correlation although. It is remarkable that these findings are observed in a RSTS-diagnosed cohort; some patients harbouring  EP300  mutations could present a different phenotype. Broadening the knowledge about  EP300 -RSTS phenotype may contribute to improve the management of patients and the counselling to the families.

Rubinstein-Taybi 2 associated to novel EP300 mutations: deepening the clinical and genetic spectrum