1. ¹Laboratoire de Génétique Humaine, Développement et Cancer (EA 3669), Université Victor Segalen Bordeaux 2, Bordeaux, France
2. ²Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France
3. ³Pôle Génotypage-Séquençage de Bordeaux, Bordeaux, France
4. ⁴Institut Bergonié, Bordeaux, France

Correspondence: Professor B Arveiler, Laboratoire de Génétique Humaine, Développement et Cancer (EA3669), Université Victor Segalen Bordeaux 2, 146 Rue Léo Saignat, 33076 Bordeaux, France. Tel: +33 5 57 57 11 63; Fax: +33 5 56 98 33 48; E-mail: benoit.arveiler@u-bordeaux2.fr

⁵These authors contributed equally to the work

Received 27 November 2006; Revised 17 March 2007; Accepted 4 April 2007; Published online 2 May 2007.

Abstract

The Rubinstein–Taybi syndrome (RTS) is a rare autosomal-dominant disease associated with 10–15% of cases with 16p13.3 microdeletions involving the CREB-binding protein gene (CREBBP). We used array-comparative genomic hybridization and Quantitative multiplex fluorescent-PCR (QMF-PCR) to search for dosage anomalies in the 16p13.3 region and the CREBBP gene. We first constructed a microarray covering 2 Mb that carries seven BAC and 34 cosmid clones, as well as 26 low-molecular-weight probes (1000–1500 bp) that are spread along the CREBBP gene. To increase further the resolution inside the CREBBP gene, we used QMF-PCR assays providing a 7 kb resolution. The deletions characterized in this work extended between as little as 3.3 kb and 6.5 Mb. Some deletions were restricted to just a few exons of CREBBP, some deleted either the 5' or the 3' end of the gene plus adjacent genomic segments, others deleted the whole gene away. We also identified a duplication of exon 16. We showed that CREBBP dosage anomalies constitute a common cause of RTS. CREBBP high-resolution gene dosage search is therefore highly recommended for RTS diagnosis. No correlation was found between the type of deletion and the patients' phenotype. All patients had typical RTS, and there was no particular severity associated with certain alterations.