The microdeletion of 22q11.2 associated with over 90 percent of the cases of DiGeorge syndrome, referred to as the DiGeorge Critical Region (DGCR), is highly variable in size and does not predict severity of phenotype. Within the DGCR is a 200-250 kb segment common to all deleted patients designated the minimal DiGeorge Critical Region (MDGCR), suggesting that at least some genes relevant to the DGS phenotype reside in this region. To test this hypothesis, the investigators assembled a cosmid and BAC contig of mouse chromosome 16 and established a region of synteny with the MDGCR (Galili et al., 1997). This has been extended to include regions syntenic to most of the 2.5 Mb DGCR, and contains 25 or the 26 known genes within the human DGCR. Synteny between mouse and human DGCR is almost complete with respect to gene content, order and intron/exon composition, and includes six genes of potential importance to outflow tract morphogenesis. The approach to determining the role of these and other genes to outflow tract morphogenesis is based upon the hypothesis that: (1) the DiGeorge phenotype is the result of a change in copy number of one or more genes within the DGCR; (2) the critical morphogenetic event(s) may depend upon the coordinated expression of more than one gene; (3) the variable severity of DGS phenotypes is the result of changes in expression of different combinations of genes as well as variable genetic backgrounds; (4) within the MDGCR is at least one gene critical to some aspect of early heart morphogenesis. The goals are, therefore to evaluate the morphogenetic function of individual genes using reagents and sequence data generated over the past four years, use animals transgenic for overlapping BACs and cosmids to evaluate the morphogenetic role of multiple genes in the context of their """"""""native"""""""" genetic environment within the DGCR, and explore the role of new genes the investigators have identified by representational difference analysis and with the yeast 2-hybrid system in early heart morphogenesis and subsequent role in congenital outflow tract abnormalities within """"""""non-deleted"""""""" patients.
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