22q11.2 deletion--Mechanisms and consequences

Children'S Hospital Of Philadelphia, Philadelphia PA

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Abstract

Velocardiofacial syndrome (VCFS) is one of several disorders caused by a deletion of 22q11.2. The deletion occurs at an extremely high frequency in the general population (1/3,000-4,000 live births). The prevalence of these de novo 22q11.2 deletions indicates an extremely high "mutation" rate within this genomic region (approximately 2.5 x 10/-4). Little attention has been paid to elucidating the mechanism which gives rise to this "genomic disorder." Thus, we will investigate the cytogenetic mechanism(s) and genomic configuration which predispose 22q11.2 to frequent deletional events. Although a minority of patients have variant deletion endpoints (DEPs), there is a large (>2.3 Mb) typically deleted region (TDR) in over 85% of patients. The DEPs cluster such that there are a typical proximal and distal DEP as well as two variant distal DEPs. The region which comprises the deletion interval contains at least 4 large blocks of duplicated DNA sequence which appear to coincide with the location of the DEPs. In this proposal, we will examine the hypothesis that the location, organization and orientation of the duplicated regions in the vicinity of the DEPs play a significant role in the mechanism and consequences of deletion formation. In Aim 1, we will position the 22q11.2 DEPs by FISH in additional patients with the 22q11.2 deletion syndrome to determine whether the two variant DEPs we have identified are the only ones that recur. In Aim II we will utilize DNA microarray technology to create a "chip" designed to detect atypical deletions and dosage differences in patients and their parents. In Aim III, we will isolate, sequence and characterize 22q11.2. In Aim IV we will examine the similarity between 22q11.2 DEPs for different individuals with the typical 22q11.2 deletion (TDR) to determine whether the proximal and distal DEPs are tightly clustered molecularly on 22q11.2 and gain insights into the mechanisms responsible for the frequent large deletion events. Further, we will examine the similarity between the different distal DEPs to determine whether the basis for the deletion can be determined. In Aim V, by haplotype reconstruction, we will examine the meiotic mechanism responsible for the generation of the standard and the variant deletions to determine whether they are inter- or intra-chromosomal events and the role, if any, that the sex of the individuals in whom the deletion occurred plays in the meiotic event.