TY - JOUR
T1 - Characterization of 14 novel deletions underlying Rubinstein–Taybi syndrome: an update of the CREBBP deletion repertoire
AU - Piccione, Maria
AU - Prontera, Paolo
AU - Curtisova, Vaclava
AU - Gasparini, Paolo
AU - Biamino, Elisa
AU - Negri, Gloria
AU - Rusconi, Daniela
AU - Picinelli, Chiara
AU - Stangoni, Gabriela
AU - Colapietro, Patrizia
AU - Fischetto, Rita
AU - Spena, Silvia
AU - Salviati, Leonardo
AU - Gervasini, Cristina
AU - Selicorni, Angelo
AU - Milani, Donatella
AU - Finelli, Palma
AU - Magnani, Cinzia
AU - Cavaliere, Maria Luigia
AU - Silengo, Margherita Cirillo
AU - Ferrero, Giovanni Battista
AU - Larizza, Lidia
AU - Sorasio, Lorena
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
UR - http://hdl.handle.net/10447/183914
M3 - Article
VL - 134
SP - 613
EP - 626
JO - Human Genetics
JF - Human Genetics
SN - 0340-6717
ER -