MOLECULAR AND CYTOGENETIC DELINEATIONS OF 22Q11 DELETIONS

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The population of patients at-risk for VCFS and 22q11.->11.23 is extremely large. Therefore, a rapid DNA-based screening method to detect individuals at high risk for deletions will be required. We propose to develop and apply a multiplex PCR-based screening assay using highly polymorphic DNA markers. Individuals at risk for deletions will be further screened by fluorescence in situ hybridization (FISH) utilizing 22q11.2-specific cosmid clones which span and flank the VCFS critical region. Utilization of simultaneous hybridization of multiple probes to interphase nuclei will help us to estimate the extent of deletions for selected individuals. We will test the hypothesis that difference in the size, location, parent or origin, and etiology of the deletions within 22q11 account for the phenotypic variability observed between affected members of families may result from change in the size of an inherited deletion during meiosis. To test this hypothesis, we will correlate the size and location of the deletions with the clinical findings (Core A), the genes discovered (Project 1) and their expression pattern (Project 2). We will compare the size of deletions in multiple affected family members and test for imprinting effects by determining the parent of origin in patients with deletions. Finally, we propose that 22q11 may rearrange by centromeric exchange with other acrocentric chromosomes. We will examine the prevalence of such "cryptic translocation" as a mechanism associated with 22q11.2 deletions. Finally, we propose that isolated features of the VCFS phenotype, especially cleft palate and/or VIP, may be caused by abnormalities of a single gene in the VCFS-deletion region. To test this hypothesis we will test a cohort of isolated cleft palate patients for the presence of deletions and examine the evidence for the presence of a cleft palate locus in 22q11.21->22q11.23 by examining locus associations in cleft palate patients or families.