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

• Published in: Human genetics Vol. 134; no. 6; pp. 613 - 626
• Main Authors: Rusconi, Daniela, Negri, Gloria, Colapietro, Patrizia, Picinelli, Chiara, Milani, Donatella, Spena, Silvia, Magnani, Cinzia, Silengo, Margherita Cirillo, Sorasio, Lorena, Curtisova, Vaclava, Cavaliere, Maria Luigia, Prontera, Paolo, Stangoni, Gabriela, Ferrero, Giovanni Battista, Biamino, Elisa, Fischetto, Rita, Piccione, Maria, Gasparini, Paolo, Salviati, Leonardo, Selicorni, Angelo, Finelli, Palma, Larizza, Lidia, Gervasini, Cristina
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2015; Springer; Springer Nature B.V
• Subjects: Adolescent; Adult; Base Sequence; Biomedical and Life Sciences; Biomedicine; Child; Child, Preschool; Childrens health; Cohort Studies; CREB-Binding Protein - genetics; Female; Gene Function; Gene mutation; Genes; Genetic disorders; Genetics; Genomics; Human Genetics; Humans; Infant; Infant, Newborn; Intensive care; Male; Maternal & child health; Metabolic Diseases; Middle Aged; Molecular Medicine; Mutation; Original Investigation; Point Mutation; Proteins; RNA polymerase; Rubinstein-Taybi Syndrome - genetics; Sequence Deletion; Italy; Congenital Heart Defect; Deletion Size; Contiguous Gene Syndrome; Intellectual Disability; Hallux Valgus
• DOI: 10.1007/s00439-015-1542-9
• ISSN: 0340-6717

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.