Characterization of 14 novel deletions underlying Rubinstein–Taybi syndrome: an update of the CREBBP deletion repertoire

Abstract

Rubinstein–Taybi syndrome (RSTS) is a rare, clinically heterogeneous disorder characterized by cognitive impairment and several multiple congenital anomalies. The syndrome is caused by almost private point mutations in the CREBBP (~55 % of cases) and EP300 (~8 %) genes. The CREBBP mutational spectrum is variegated and characterized by point mutations (30–50 %) and deletions (~10 %). The latter are diverse in size and genomic position and remove either the whole CREBBP gene and its flanking regions or only an intragenic portion. Here, we report 14 novel CREBBP deletions ranging from single exons to the whole gene and flanking regions which were identified by applying complementary cytomolecular techniques: fluorescence in situ hybridization, multiplex ligation-dependent probe amplification and array comparative genome hybridization, to a large cohort of RSTS patients. Deletions involving CREBBP account for 23 % of our detected CREBBP mutations, making an important contribution to the mutational spectrum. Genotype–phenotype correlations revealed that patients with CREBBP deletions extending beyond this gene did not always have a more severe phenotype than patients harboring CREBBP point mutations, suggesting that neighboring genes play only a limited role in the etiopathogenesis of CREBBP-centerd contiguous gene syndrome. Accordingly, the extent of the deletion is not predictive of the severity of the clinical phenotype

Rubinstein–Taybi syndrome: New neuroradiological and neuropsychiatric insights from a multidisciplinary approach

“…Genetic tests were performed and found conclusive for 21 out of 23 patients. Twenty patients were carriers of different CREBBP mutations: 17 are described in our previous studies (Bentivegna et al, ; Rusconi et al, ; Spena et al, ) and three are unreported (Table ). One patient showed an EP300 mutation (Negri et al, ), and one was a carrier of a genomic imbalance of chromosome 3 (Gervasini et al, ).…”

Fetal phenotype of Rubinstein‐Taybi syndrome caused by CREBBP mutations

“…All fetuses have been examined in a fetopathology unit in French University Hospitals (cases [1][2][3][4][5][6][7][8][9]. In case 4, the pregnancy was obtained after in vitro fertilization (IVF).…”

“…CREBBP and extending at chromosome 16p13.3, whereas EP300 mutation-bearing patients display milder symptoms. 2,7,8 The diagnosis of RSTS is generally not suspected during antenatal period, with only three prenatal cases reported on ultrasound examination and postnatal molecular characterization of two of them. [9][10][11] We report nine fetuses for which the diagnosis of RSTS was established after autopsy and molecular characterization.…”

Stress and the Emerging Roles of Chromatin Remodeling in Signal Integration and Stable Transmission of Reversible Phenotypes

“…In humans, single exon or whole gene mutations in cbp flanking regions do not cause a differential diagnosis of RTS, suggesting that these flanking regions are complementary but not critical in the etiology of a clinical phenotype (Rusconi et al, 2015). Anatomically, RTS individuals show structure abnormalities related to deficits in activity dependent development and neural plasticity (Korzus et al, 2004), and display delayed myelination, neural dysgenesis, including cortical abnormalities and a thin corpus callosum and cognitive dysfunction early in life (Roelfsema and Peters, 2007; Lee et al, 2015).…”