Dissection of the VCFS phenotype--Palatal anomalies

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Velocardiofacial syndrome (VCFS) is a multiple malformation syndrome that is associated with a deletion of chromosome 22q11 in the majority of patients. The VCFS phenotype includes a broad range of features, but is most commonly characterized by the tetrad of palatal anomalies, congenital heart defects, cognitive impairment and a typical facial appearance. Individuals with VCFS usually exhibit only a subsets of these features, and the specific nature of any given feature may differ between individuals. For example, palatal anomalies are observed in approximately 50% of patients with VCFS and include overt cleft palate, submucous cleft palate, bifid uvula and velopharyngeal dysfunction. It was originally hypothesized that differences in the size of the chromosome 22q11 deletion would explain the observed variability in the VCFS phenotype. However, deletion size has not proven to be a strong phenotypic predictor, indicating that other factors-such as individual differences in genetic background and/or exposure history-must contribute to the observed variability in the VCFS phenotyped. Studies to identify specific factors that influence the VCFS phenotype will require extensive, systematically collected data from several hundred patients. We are uniquely poised to conduct studies of this nature, since the requisite data will be available through the proposed program project. The proposed project will capitalize on these data to identify the factors that influence the palatal phenotype in patients with VCFS. A comprehensive approach, integrating molecular and clinical data from patients with VCFS, will be employed to identify these factors. The proposed analyses will greatly increase our understanding of the factors that influence the palatal phenotype in patients with VCFS, and will lay the foundation for similar analyses of other phenotypic features of this syndrome.