Diagnostic analysis of the Rubinstein-Taybi syndrome: five cosmids should be used for microdeletion detection and low number of protein truncating mutations
- Fred Petrija,b,
- Hans G Dauwersea,
- Ruthann I Bloughc,
- Rachel H Gilesa,
- Jasper J van der Smagta,
- Robert Wallersteine,
- Petra D Maaswinkel-Mooyd,
- Clara D van Karnebeekf,
- Gert-Jan B van Ommena,
- Arie van Haeringena,
- Jack H Rubinsteinc,
- Howard M Saalc,
- Raoul C M Hennekamf,
- Dorien J M Petersa,
- Martijn H Breuninga
- aDepartments of Human and Clinical Genetics, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands, bDepartment of Clinical Genetics, Erasmus University, Rotterdam, The Netherlands, cCincinnati Center for Developmental Disorders, Children's Hospital Medical Center, Cincinnati, USA, dDepartment of Paediatrics, Leiden University Medical Center, Leiden, The Netherlands, eDepartment of Pediatrics, New York University School of Medicine, New York, USA, fDepartments of Human Genetics and Paediatrics, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
- Dr Peters
- Revised 1 October 1999
- Accepted 18 October 1999
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 orCBP) 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 entireCBP 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 theCBP 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.
- Rubinstein-Taybi syndrome (RTS)
- CREB binding protein (CBP/CREBBP)
- protein truncation test (PTT)
- microdeletion
