Human Genetics

, Volume 117, Issue 5, pp 485–493

DNA sequencing of CREBBP demonstrates mutations in 56% of patients with Rubinstein–Taybi syndrome (RSTS) and in another patient with incomplete RSTS

  • Oliver Bartsch
  • Stefanie Schmidt
  • Marion Richter
  • Susanne Morlot
  • Eva Seemanová
  • Glenis Wiebe
  • Sasan Rasi
Original Investigation

DOI: 10.1007/s00439-005-1331-y

Cite this article as:
Bartsch, O., Schmidt, S., Richter, M. et al. Hum Genet (2005) 117: 485. doi:10.1007/s00439-005-1331-y

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.

Keywords

CREB binding proteinRubinstein–Taybi syndromeSmall molecular mutations

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Oliver Bartsch
    • 1
    • 2
  • Stefanie Schmidt
    • 2
  • Marion Richter
    • 2
  • Susanne Morlot
    • 3
  • Eva Seemanová
    • 4
  • Glenis Wiebe
    • 5
  • Sasan Rasi
    • 2
  1. 1.Institut für Humangenetik, KlinikumUniversität MainzMainzGermany
  2. 2.Institut für Klinische Genetik, Medizinische FakultätTechnische Universität DresdenDresdenGermany
  3. 3.Humangenetische PraxisGermany
  4. 4.Institute of Medical Biology and Genetics, 2nd Medical SchoolCharles UniversityPrague 5Czech Republic
  5. 5.Max Planck Institute of Molecular Cell Biology and GeneticsGermany