title: Diagnostic analysis of the Rubinstein-Taybi syndrome: five cosmids should be used for microdeletion detection and low number of protein truncating mutations.
abstract: Rubinstein-Taybi syndrome (RTS) is a malformation syndrome characterised by facial abnormalities, broad thumbs, broad big toes, and mental retardation. In a subset of RTS patients, microdeletions, translocations, and inversions involving chromosome band 16p13.3 can be detected. We have previously shown that disruption of the human CREB binding protein (CREBBP or CBP) gene, either by these gross chromosomal rearrangements or by point mutations, leads to RTS. CBP is a large nuclear protein involved in transcription regulation, chromatin remodelling, and the integration of several different signal transduction pathways. Here we report diagnostic analysis of CBP in 194 RTS patients, divided into several subsets. In one case the mother is also suspect of having RTS. Analyses of the entire CBP gene by the protein truncation test showed 4/37 truncating mutations. Two point mutations, one 11 bp deletion, and one mutation affecting the splicing of the second exon were detected by subsequent sequencing. Screening the CBP gene for larger deletions, by using different cosmid probes in FISH, showed 14/171 microdeletions. Using five cosmid probes that contain the entire gene, we found 8/89 microdeletions of which 4/8 were 5' or interstitial. This last subset of microdeletions would not have been detected using the commonly used 3' probe RT1, showing the necessity of using all five probes.
authors.affiliation: Departments of Human and Clinical Genetics, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: Petrij
authors.forename: H G
authors.initials: HG
authors.lastname: Dauwerse
authors.forename: R I
authors.initials: RI
authors.lastname: Blough
authors.forename: R H
authors.initials: RH
authors.lastname: Giles
authors.forename: J J
authors.initials: JJ
authors.lastname: van der Smagt
authors.forename: R
authors.initials: R
authors.lastname: Wallerstein
authors.forename: P D
authors.initials: PD
authors.lastname: Maaswinkel-Mooy
authors.forename: C D
authors.initials: CD
authors.lastname: van Karnebeek
authors.forename: G J
authors.initials: GJ
authors.lastname: van Ommen
authors.forename: A
authors.initials: A
authors.lastname: van Haeringen
authors.forename: J H
authors.initials: JH
authors.lastname: Rubinstein
authors.forename: H M
authors.initials: HM
authors.lastname: Saal
authors.forename: R C
authors.initials: RC
authors.lastname: Hennekam
authors.forename: D J
authors.initials: DJ
authors.lastname: Peters
authors.forename: M H
authors.initials: MH
authors.lastname: Breuning
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D050882:CREB-Binding Protein; D003360:Cosmids; D004252:DNA Mutational Analysis; D017353:Gene Deletion; D005822:Genetic Vectors; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics*; D012415:Rubinstein-Taybi Syndrome / Q000175:diagnosis / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D009687:Nuclear Proteins; D015534:Trans-Activators; D050882:CREB-Binding Protein; C494363:CREBBP protein, human