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.
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Acknowledgments
We are grateful to the patients’ families for participating in this study and to the Italian RSTS Association “Una Vita Speciale” and Associazione Studio Malformazioni (ASM onlus) for supporting this study. We thank Dr. Franca Rossella for her technical support. We thank the Galliera Genetic Bank for establishing lymphoblastoid cell lines through the Italian Telethon project GTF4003. This research was approved by the Ethical Clinical Research Committee of the clinical centers involved in patient recruitment and clinical evaluation. Written informed consent was obtained from the patients’ parents.
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439_2015_1542_MOESM1_ESM.tiff
Molecular flowchart applied to our RSTS cohort. Molecular flowchart applied to our cohort by combining different techniques. The number of patients tested and identified carriers of CREBB deletions/point mutations or EP300 mutations are provided. (TIFF 1141 kb)
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Rusconi, D., Negri, G., Colapietro, P. et al. Characterization of 14 novel deletions underlying Rubinstein–Taybi syndrome: an update of the CREBBP deletion repertoire. Hum Genet 134, 613–626 (2015). https://doi.org/10.1007/s00439-015-1542-9
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DOI: https://doi.org/10.1007/s00439-015-1542-9