Spectrum of CREBBP gene dosage anomalies in Rubinstein-Taybi syndrome patients.
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.
Stef
Marianne
M
Laboratoire de Génétique Humaine, Développement et Cancer (EA 3669), Université Victor Segalen Bordeaux 2, Bordeaux, France.
Simon
Delphine
D
Mardirossian
Béatrice
B
Delrue
Marie-Ange
MA
Burgelin
Ingrid
I
Hubert
Christophe
C
Marche
Michèle
M
Bonnet
Françoise
F
Gorry
Philippe
P
Longy
Michel
M
Lacombe
Didier
D
Coupry
Isabelle
I
Arveiler
Benoît
B
D001483:Base Sequence; D050882:CREB-Binding Protein / Q000235:genetics*; D018628:Gene Dosage; D006801:Humans; D012415:Rubinstein-Taybi Syndrome / Q000235:genetics*; D017384:Sequence Deletion
D050882:CREB-Binding Protein; C494363:CREBBP protein, human