The majority of velo-cardio-facial syndrome (VCFS) patients have been shown to have microdeletions of 22q11.2. The region deleted is large and is likely to code for several contiguous genes. To begin to understand how hemizygosity of this chromosomal segment gives rise to multiple defects, including cleft palate and the characteristic craniofacial dysmorphia seen in VCFS, this region must be carefully analyzed and the genes identified. To accomplish this we propose to use our detailed physical map of the region to isolate overlapping cloned genomic DNA fragments from YAC and cosmid libraries. DNA samples from a selected subsets of VCFS patients will be used to narrow the critical region. In particular, the breakpoint of deleted patient who present with isolated features of VCFS, such as cleft palate, VPI or craniofacial dysmorphia, will findings. Multiple methods will be used to identify genes in region. These methods will include mapping of newly isolated chromosome 22-specific genes, directly selecting for cDNA which map to the VCFS critical region using YACs and cosmids and computer analysis of the DNA sequence obtained from large scale sequencing of the VCFS critical region. Coding regions identified in this manner will be confirmed and full-length cDNAs isolated by hybridization or PCR-based strategies. The pattern of expression of these genes will be determined using RT-PCR of cDNA isolated from various human tissues. Murine genes which are developmentally expressed at the appropriate time and place will be mapped in humans to determine if any are homologous to genes in the VCFS critical region. The identification and characterization of the gene(s) responsible for VCFS should greatly increase our understanding of the etiology of this developmental disorder and will also contribute to our understanding of normal craniofacial development.
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