The 22q11.2 deletion syndrome (22q11DS, aka velo-cardio-facial syndrome/DiGeorge syndrome) is a congenital anomaly disorder characterized by learning disabilities, craniofacial malformations, immune deficiencies, hypocalcemia and cardiac outflow tract defects. It occurs in 1/2-4,000 live births. Most affected individuals have the same 3 Mb deletion, suggesting that haploinsufficiency of gene(s) in the deleted interval is responsible for its etiology. One of the strongest candidate genes is TBX1, a T-box containing transcription factor, expressed in the pharyngeal apparatus during embryonic development. The disorder is fully penetrant but the expressivity is variable. One of the greatest challenges in this field is to determine the basis for its varied expressivity. Stochastic, environmental and genetic factors likely modify the phenotype. Evidence for genetic factors or modifiers, derives from genetic studies in animal models in the form of phenocopies, gene interactions and genetic background effects of Tbx1 null mutations. The major goal of this research program is to identify genetic modifiers for 22q11DS by performing genotype-phenotype correlations in human subjects with the typical deletion. Part of the difficulty in studying a rare disorder, is to obtain sufficient numbers of well-defined study subjects. We propose to solve this problem by creating a 22q11.2 consortium, thereby combining resources. Five hundred cases with the 3 Mb deletion have already been ascertained and another set of 500 with the 3 Mb deletion will be collected as part of this program. We will perform a whole genome association study on the DNA from 300 cases divided equally among those with significant heart defects and without, using Illumina 300,000 HapMap SNP arrays. A biological replication on 700 cases and a joint statistical analysis will be performed. We will re-stratify the patient set for other clinical malformations. A candidate gene approach will be undertaken in parallel, to assess genes in the genetic pathway of TBX1 in 1,000, 22q11DS individuals with the 3 Mb deletion, using the Illumina custom 1,536-plex SNP arrays. It is likely that modifiers for the salient malformations in the syndrome may confer susceptibility to sporadic birth defects with unknown etiologies.
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