Rubinstein-Taybi syndrome (RTS, MIM 180849) is a multiple malformation syndrome characterized by growth retardation, developmental delay, and dysmorphic features, including down-slanting palpebral fissures, a beaked nose, broad thumbs, and halluces. Mutations in the gene encoding the CREB-binding protein gene (CREBBP, also known as CBP) on chromosome 16p13.3 were identified in 1995. Recently, we developed a mutation analysis protocol using denaturing high-performance liquid chromatography (DHPLC) and identified heterozygous CREBBP mutations in 12 of 21 RTS patients. To test whether exonic deletions represent a common pathogenic mechanism, we assessed the copy number of all the coding exons using a recently developed method, the multiplex PCR/liquid chromatography assay (MP/LC). By using MP/LC, we performed screening for CREBBP exonic deletions among 25 RTS patients in whom no point mutations or small insertions/deletions were identified by DHPLC screening. We identified four classic RTS patients with deletions encompassing multiple exons (14-16, 5-31, 1-16, and 4-26). We conclude that large deletions including several exons are a relatively frequent cause of RTS, and that MP/LC is an effective method for detecting these deletions.
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