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

Abstract

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.

Keywords: Broad thumbs; EP300; EP300-RSTS-phenotype; EP300-Rubinstein-Taybi; EP300-mutations; Intellectual disability; RSTS; RSTS-2.

Fig. 1

Photographs of face, hands and feet of EP300 patients: #11 (a), #27 (b), #42 (c), #45 (d), #67 (e). For patient #45 photographs showing normal thumbs and halluces of the proband, short and broad but not angulated thumbs of her mother and her grandmother as well as detail of mother’s talon cusp at an upper incisor are shown

Fig. 2

Schematic representation of p300 protein and EP300 gene, including their functional and structural domains and their localization. Distribution of the variants found in EP300 gene in our cohort are showed. Symbols represent the mutation types as indicated. The different domains of the p300 protein are represented with different colours, and the exon codifying these domains are showed in the same colour: pink (NLS, nuclear localization signal), green (TAZ1, transcriptional-adaptor zinc-finger domain 1), purple (KIX, kinase inducible domain of CREB interacting domain), orange (Br, bromodomain), yellow (HAT, histone acetyltransferase domain), blue (ZZ, bromodomain), green (TAZ2, transcriptional-adaptor zinc-finger domain 2), light pink (IBiD, IRF3-binding domain). Numbers indicate aminoacid position in the protein and the exon in the gene