First case report of inherited Rubinstein-Taybi syndrome associated with a novel EP300 variant

Abstract

Background: Rubinstein-Taybi syndrome (RSTS; OMIM #180849, #613684) is a rare autosomal dominant genetic condition characterized by broad thumbs and halluces, facial dysmorphism, short stature and variable degree of intellectual disability. RSTS is associated with mutations in CREBBP and EP300 genes in 50-60% and 5-8% of cases, respectively. The majority of cases are de novo heterozygous mutations.

Case presentation: Here we describe a familial RSTS case, associated with a novel EP300 mutation. The proband was a 9 years old female, with mild learning difficulties. Her mother, who also had learning difficulties, was found to have short and broad thumbs. MLPA and panel-based NGS of CREBBP and EP300 were performed. A novel heterozygous frameshift mutation in exon 31 of the EP300 gene (c.7222_7223del; p.(Gln2408Glufs*39)) was found in both.

Conclusions: This case represents the first case of inherited EP300-RSTS. The location of the frameshift deletion not affecting HAT domain and PHD finger, could explain the mild phenotype and the well-preserved intelligence. These patients are mildly affected, and this case highlights the possible missed diagnosis. We would recommend molecular testing of apparently healthy parents, and in the case of inherited mutations, of all adult first degree relatives at risk.

Keywords: Case report; EP300; Familial-RSTS; Inheritance; RSTS; Rubinstein-Taybi syndrome.

Fig. 1

Images showing classical RSTS features of patient including thickened and low hanging columella (a, b), and detail of mother’s talon cusp at an upper incisor (c). Photographs showing normal thumbs and halluces of the proband (d, e), short and broad but not angulated thumbs of her mother (f, g) and her grandmother (h, i)