MOLECULAR MECHANISMS AND GENOTYPE-PHENOTYPE IN VCFS/DGS

The goal of this program is to understand the molecular basis of velo- cardio-facial syndrome (VCFS)/DiGeorge syndrome (DGS). VCFS/DGS is a congenital anomaly disorder associated with hemizygous deletions of chromosome 22q11. We have two scientific goals for this project. The first goal is to determine the molecular basis of the common 3 Mb deletion in patients with VCFS/DGS. We constructed to determine the molecular basis of the common 3 Mb deletion in patients with VCFS/DGS. We constructed high resolution physical maps in the form of overlapping BAC/PAC/cosmid clones of the regions of breakage on 22q11. Examination of these sequences revealed that the chromosome breakpoints in patients with the deletion occur within a 250 kb low copy repeat that we designated LCR22. We will test the hypothesis that the degree of homology between LCR22s dictates the frequency of recombination between them. This will be accomplished by cloning and sequencing the site(s) of chromosome breakage on 22qll. We will also identify sequence polymorphisms in individuals or particular haplotypes that may confer susceptibility to 22q11 rearrangements. Eight related LCR22s span the 22q11 region and there is evidence that they may also mediate rearrangements associated with other diseases. The proposed studies will serve as a model for understanding the basis of these other rearrangement disorders. We hypothesize that VCF/DGS is a contiguous gene disorder. The second goal of the project is to characterize the genes within the large 3 Mb deletion and identify functional polymorphisms that contribute to the phenotypes associated with the disorder. The second goal of the project is to characterize the genes within the large 3 Mb deletion and identify functional polymorphisms that contribute to the phenotypes associated with the disorder. The genes that will be subjected to detailed genotype/phenotype studies will be identified in Projects 2 and 3. Our VCFS/DGS patient population is our greatest resource. Both sets of studies depend on the quality of this population.