?s abstract) The process of cardiac development is extraordinarily complex requiring precise coordination of gene expression. Conotruncal development is an essential step in cardiogenesis, and disturbances in this process can result in severe life-threatening congenital cardiac defects. Such malformations are present in 85 percent of patients with velocardiofacial/DiGeorge syndrome (VCFS) and are the major cause of morbidity and mortality in these patients. Detectable deletions of chromosome 22q11.2 are found in approximately 90 percent of these patients and are estimated to occur at an extremely high frequency in the general population (1/3,000-4,000 live births), making them a significant health concern. The molecular mechanisms by which the deletion occurs is largely unknown. This proposal seeks to examine the genetic mechanisms of the most frequent human microdeletion syndrome. Recent data from our laboratory and others have shown the existence of large low copy repeats in the 22q11 deletion interval. We hypothesize that the location of the low copy repeats near the deletion endpoints(DEPs) plays a significant role in the mechanism of deletion formation. Using our extensive patient cohort for haplotype reconstruction, we will analyze sequences flanking the repeats and trace de novo deleted alleles in parental and granparental meioses. We will also determine whether inter- or intra- chromosomal events predominate and if the sex of the parent of origin affects the mechanism of deletion formation. Additionally, we have recently described a novel 22q11.2 deletion, in a patient with outflow tract defects and VCFS. This patient is deleted for a different set of genes than those thought to result in the conotruncal phenotype associated with VCFS. Using this unique resource we will identify and examine the genes present in the novel deletion interval, and assess their potential contribution to conotruncal development. Here we describe a five-year training program in which the applicant will acquire the skills and experience required of an independent physician scientist. The primary focus throughout the grant period, will be to provide broad and in-depth training in the areas of genomic structure and instability which lead to human disease, and genetic mechanisms involved in the developmental patterning of the heart. These studies will utilize the expertise of the mentors, and will enable the candidate to transition into an investigator capable of directing future studies of the molecular basis of development and human genetic disease.
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| Saitta, Sulagna C; Harris, Stacy E; Gaeth, Ann P et al. (2004) Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion. Hum Mol Genet 13:417-28 |
