Genetic Basis of Birth Defects in 22q11 Deletion Syndrome

DESCRIPTION (provided by applicant): Mouse genomic engineering for 22q11.2 rearrangement disorders The 22q11.2 deletion syndrome (22q11DS), also known as velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS), is one of the most common microdeletion disorders in humans, occurring in 1/4,000 live births. Over 90% of patients have a typical 3 Mb (million base pair) deletion, while some have smaller deletions within. The characteristic clinical features include cardiovascular defects, immune, and craniofacial anomalies as well as psychiatric illness and mild mental retardation. Although a handful of candidate genes have been identified and pursued on their own, there is significant evidence that additional genes contribute to the overall phenotype. For example, a gene in the proximal (centromeric) half of the 3 Mb region, termed TBX1, and distal half, termed CRKL have been found to genetically interact for cardiovascular development. Recently, it was found that non-overlapping deletions within the 3 Mb region have been identified in association with the syndrome, suggesting that haploinsufficiency of different genes can contribute to related congenital malformations. Several genes in the proximal 1.5 Mb region are candidates for neurocognitive deficits, but genes in the distal half have not been pursued as of yet. Finally, the disorder occurs with variable expressivity, possibly due to sequence variation in genes on the remaining allele. Understanding gene functions and interactions would provide insights into the molecular pathogenesis of VCFS/DGS. Our hypothesis is that haploinsufficiency of contiguous gene(s) within the 22q11.2 region is responsible for the overall phenotype of the disorder. The genes on 22q11.2 are conserved on mouse chromosome 16. A 1.5 Mb deletion comprising the proximal half of the 22q11.2 region was generated and characterized, but a deletion that is equivalent to the 3 Mb deletion was not made, largely due to past ambiguities in the mouse gene map. In Specific Aim 1, we will use the Cre/loxP system (MICER) to create a deletion that includes most of the genes hemizygous in humans with the typical 3 Mb deletion. These mice should recapitulate the human condition. In Specific Aim 2, we will compare the phenotypes between mice with the 1.5 Mb deletion that was previously generated, Tbx1 and Crkl mice. The studies in Aim 2 will directly test our hypothesis. The next goal would be to perform genotype phenotype correlations by creation of additional alleles with overlapping smaller deletions and duplications and this will be done in the future. We are also interested in modeling the reciprocal 3 Mb duplication syndrome, dup(22)(q11.2, q11.2) and the mice with the duplication can serve this purpose. PUBLIC HEALTH RELEVANCE: We propose to generate a mouse model of velo-cardio-facial/DiGeorge syndrome to test the hypothesis that it results from haploinsufficiency of contiguous genes on 22q11.2.