Variation in Microdeletions of the Cyclic AMP-responsive Element-binding Protein Gene at Chromosome Band 16p13.3 in the Rubinstein-Taybi Syndrome

Most reported microdeletions of the CREB-binding protein (CBP) gene in the Rubinstein-Taybi syndrome (RTS) were detected by fluorescence in situ hybridization (FISH) with a single cosmid probe specific to the 3' region of the gene. In order to test the hypothesis that the rate of microdeletion-positive cases would be greater if the entire gene was evaluated, we performed FISH on 66 patients with an established diagnosis of RTS, using a panel of five cosmids that span the CBP gene. Five of 66 patients had deletions by FISH (9%), consistent with those rates reported in various series that ranged between 3-25%. Among our cases, different deletions were observed; one was deleted for the 5' but not the 3' region of the CBP gene (case 055). Other deletions included a total CBP deletion extending from the 5' through the 3' region (case 017), a deletion of all but the 5' region (cases 006 and 060), and an interstitial deletion in the 3' region (case 028). Fine breakpoint mapping with additional cosmid and yeast artificial chromosome (YAC) constructs was performed on these patients. The findings of a partial 5' deletion and of interstitial deletions of the CBP gene add to the known spectrum of mutations of this gene in RTS and demonstrate the need for evaluation of the entire CBP gene region for deletions rather than only the 3' region in RTS patients. These results further suggest that the true rate of microdeletion across the CBP gene detectable by FISH has yet to be established firmly. No phenotypic differences between partial deletion, complete deletion, and nondeletion patients were observed, supporting a haploinsufficiency model for RSTS.