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Master Thesis

Expérience bordelaise sur le syndrome de Rubinstein-Taybi : corrélations phénotype/génotype et identification de gènes candidats

Abstract : The Rubinstein-Taybi syndrome (RSTS) is a rare congenital developmental disorder characterized by typical facial dysmorphism and distal limbs abnormalities with intellectual disability and many additional features. Two genes are currently known to cause RSTS, CREBBP and EP300 respectively mutated in 55% and 8% of clinically diagnosed cases. Both paralogs play a major role in chromatin remodeling and encode for transcriptional co-activators interacting with many proteins. The clinical heterogeneity of this syndrome leads to difficulties to establish phenotype/genotype correlations. The first aim of our work was to search phenotype/genotype correlations between the clinical presentation of the patients and the types of mutations found in both genes. Starting from the cohort of 255 mutated patients followed in Bordeaux, we have focused our study on the phenotypes of patients caused by large deletions or missense mutations for which correlations are discussed. We demonstrate that CREBBP large deletion cause a classical RSTS phenotype regardless of the size of the deletion or neighboring genes in contrast to patients with EP300 large deletions for whom the phenotype is found "diluted" and not suggestive of RSTS. Analyses of missense mutations confirm that mutations of CREBBP KAT domain cause a typical phenotype with variable severity of RSTS. We show that it is the same for the CREBBP bromodomain, as well as for mutations affecting the EP300 KAT domain. We have conducted, using whole exome sequencing, a preliminary study of patients with no mutation identified, to better understand the genetic heterogeneity of the syndrome. We suggest MLLT1 as potential candidate gene in the genetic determinism of RSTS according to its interaction with CREBBP and EP300 and its role in chromatin remodeling. The further analysis of the phenotypes of all patients with and without identified mutations in our cohort will better clarify the nosological boundaries of RSTS. Subsequently, whole exome sequencing in all negative patients, compatible with RSTS, should then allow us to better understand this heterogeneity.
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Master Thesis
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Contributor : Bu Carreire Université de Bordeaux <>
Submitted on : Friday, September 8, 2017 - 11:41:09 AM
Last modification on : Friday, October 27, 2017 - 1:15:46 AM


  • HAL Id : dumas-01584062, version 1



Julien Van-Gils. Expérience bordelaise sur le syndrome de Rubinstein-Taybi : corrélations phénotype/génotype et identification de gènes candidats. Médecine humaine et pathologie. 2016. ⟨dumas-01584062⟩



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