MOLECULAR MECHANISMS AND GENOTYPE-PHENOTYPE IN VCFS/DGS

The long term goal of this program is to understand the molecular basis of velo-cardio-facial syndrome (VCFS) and DiGeorge syndrome (DGS). The main clinical features of VCFS include congenial heart defects, craniofacial anomalies and learning disabilities. The clinical features of DGS include the anomalies of VCFS and in addition, includes thymus aplasia and hypoparathyroidism. Because VCFS and DGS share phenotypic features and are also both associated with overlapping chromosomal deletions with 22q11, they may share the same etiology. The precise molecular basis for VCFS and DGS is not understood. We hypothesize that haploinsufficiency-of a single gene within 22q11 is responsible for the etiology of the developmental anomalies of VCFS/DGS. Some of the other clinical features, not directly attributed to a developmental defect, may be due to haploinsufficiency of other genes within 2q11. The goal of this project is to define the deletions that occur in VCFS/DGS. Towards this goal, we have constructed a physical map of the 22q11 region. We have found that a common proximal and distal chromosomal breakpoint occurs in VCFS patients. As part of this project, we will clone the breakpoint junction to understand the mechanism for the deletion. Deletions/translocations that occur in VCGS/DGS patients have been used to define a critical region of 500 kb. Based upon current estimates of gene density, 15 genes may be present within this 500 kb critical region. We have performed hybridization selection to isolate genes within the critical region. We and others have isolated 8 genes within this region, and several of these are novel. Our strategy centers around using our patients to further narrow the critical region. We will isolate the full length cDHAs corresponding to the gene(s) that are expressed during development, as established in Project 2.