Abstract
The Rubinstein-Taybi syndrome (RSTS) is a rare congenital developmental disorder characterized by a typical facial dysmorphism, distal limb abnormalities, intellectual disability, and many additional phenotypical features. It occurs at between 1/100,000 and 1/125,000 births. Two genes are currently known to cause RSTS, CREBBP and EP300, mutated in around 55% and 8% of clinically diagnosed cases, respectively. To date, 500 pathogenic variants have been reported for the CREBBP gene and 118 for EP300. These two genes encode paralogs acting as lysine acetyltransferase involved in transcriptional regulation and chromatin remodeling with a key role in neuronal plasticity and cognition. Because of the clinical heterogeneity of this syndrome ranging from the typical clinical diagnosis to features overlapping with other Mendelian disorders of the epigenetic machinery, phenotype/genotype correlations remain difficult to establish. In this context, the deciphering of the patho-physiological process underlying these diseases and the definition of a specific episignature will likely improve the diagnostic efficiency but also open novel therapeutic perspectives. This review summarizes the current clinical and molecular knowledge and highlights the epigenetic regulation of RSTS as a model of chromatinopathy.
Highlights
Rubinstein-Taybi syndrome (RSTS; OMIM #180849, OMIM #613684), formerly called thumb syndrome and hallux larges, is a rare neurodevelopmental genetic abnormality whose incidence is currently estimated between 1/100,000 and 1/125,000 births [1]
New generation sequencing techniques have improved the understanding of the genetic heterogeneity of the syndrome and widened the phenotypic spectrum of RSTS by encompassing the broader field of chromatinopathies rendering phenotype/genotype correlations more complex (Figure 6)
The emergence of multi-omics approaches, the integration of transcriptomic data coupled to DNA and histone modification profiles, and the development of patient-derived cellular models will likely contribute to a better definition of a specific epigenetic signature to the syndrome
Summary
Rubinstein-Taybi syndrome (RSTS; OMIM #180849, OMIM #613684), formerly called thumb syndrome and hallux larges, is a rare neurodevelopmental genetic abnormality whose incidence is currently estimated between 1/100,000 and 1/125,000 births [1]. The transmission is autosomal dominant and the vast majority of cases (~99%) occur sporadically de novo a few familial cases have been reported [2,3,4] This syndrome is well-defined phenotypically and is characterized primarily by post-natal growth retardation, characteristic facial dysmorphia, large thumbs and hallux, and intellectual deficit [5,6]. Pathogenic variants in two highly evolutionarily conserved genes have been implicated in the etiology of RSTS: the CREBBP gene encoding the cAMP response elementbinding protein (CREB) binding protein (NM_600140) located in 16p13.3 [12] and the EP300 gene encoding the EA1-associated protein p300 (NM_602700) located in 22q13 [13] These two genes are ubiquitously expressed and encode acetyltransferases with a major role in histone acetylation and chromatin remodeling involved notably in neuronal plasticity and cognition [13,14]. The Rubinstein-Taybi syndrome is a developmental disorder whose physiopathology is based primarily on an epigenetic mechanism, belonging thereby to the group of “Chromatinopathies” defined as Mendelian disorders of the epigenetic machinery, as reviewed in [15]
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