Abstract
Rubinstein–Taybi syndrome (RSTS) is a distinct dominant disorder characterized by short stature, typical face, broad angulated thumbs and halluces, and mental retardation. The RSTS can be caused by chromosomal microdeletions and molecular mutations in the CREBBP gene; however, relatively few mutations have been reported to date. Here, we aimed to determine the rate of point mutations and other small molecular lesions in true RSTS and possible mild variants, by using genomic DNA sequencing. A consecutive series of patients including 17 patients from our previous study was investigated. We identified 19 causative mutations of CREBBP in a total of 45 patients representing three different diagnostic groups: (a) 17 mutations in 30 patients with unequivocal RSTS (detection rate 56.6%), (b) two mutations in eight patients with features suggestive of RSTS (“moderate or incomplete RSTS”, detection rate 25%), and (c) no mutation in seven patients with undiagnosed syndromes and isolated features of RSTS. In general, the mutations were distributed without hot spots and most were unique; however, three recurrent mutations (R370X, R1664H, and N1978S) were identified. Furthermore, we detected 15 different intragenic polymorphisms, including two non-synonymous coding polymorphisms, L551I and Q2208H. We report not only the highest detection rate (56.6%) of CREBBP mutations in patients with RSTS to date, but also the second missense mutation (N1978S) in a patient with moderate or incomplete RSTS. Previous studies have identified cytogenetic deletions in the CREBBP gene in eight to 12% of patients and very recently, Roelfsema et al. reported EP300 gene mutations in three of 92 (3.3%) patients with either true RSTS or different syndromes resembling RSTS. Our 56.6% detection rate of molecular mutations in CREBBP in patients with unequivocal RSTS supports the new concept that RSTS is a genetically heterogeneous disorder and furthermore, indicates that RSTS may be caused by gene/s other than CREBBP in up to 30% of cases.
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Acknowledgements
We would like to thank the patients and their families for contributing to this study, and our clinical colleagues for referring patients and clinical data, especially Prof Gabriele Gillessen-Kaesbach (University of Essen, Germany; patient 25), Professor Josef Kofer (Masaryk Hospital, Usti nad Labem, Czech Republic, patient 30), Professor Hans-Dieter-Rott (University of Erlangen, Germany; patient 33), Professor Marius Bembea and Dr. Cristina Skrypnyk (University of Oradea, Romania; patient 34), and Dr. Helen Hughes (North Wales Clinical Genetics Service, Rhyl, UK; patient 35). We would also like to thank Professor Peter Meinecke (Altonaer Kinderkrankenhaus, Hamburg, Germany) for interpreting the MCPP of patient 28, and Dr. Andreas Rump and Ms. Alice Schindler for comments. This work was supported in part by a grant (Ba 1397/5-1) from the Deutsche Forschungsgemeinschaft.
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Bartsch, O., Schmidt, S., Richter, M. et al. DNA sequencing of CREBBP demonstrates mutations in 56% of patients with Rubinstein–Taybi syndrome (RSTS) and in another patient with incomplete RSTS. Hum Genet 117, 485–493 (2005). https://doi.org/10.1007/s00439-005-1331-y
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DOI: https://doi.org/10.1007/s00439-005-1331-y