Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome:genomic organization and deletion endpoint analysis

The 22q11.2 deletion syndrome, which includes DiGeorge and velocardiofacial syndromes (DGS/VCFS), is the most common microdeletion syndrome. The major ity of deleted patients share a common 3 Nib hemizygous deletion of 22q11.2 . The remaining patients include those who have smaller deletions that are nested within the 3 Mb typically deleted region (TDR) and a few with rare d eletions that have no overlap with the TDR. The identification of chromosom e 22-specific duplicated sequences or low copy repeats (LCRs) near the end- points of the 3 Mb TDR has led to the hypothesis that they mediate deletion s of 22q11.2. The entire 3 Mb TDR has been sequenced, permitting detailed i nvestigation of the LCRs and their involvement in the 22q11.2 deletions. Se quence analysis has identified four LCRs within the 3 Mb TDR. Although the LCRs differ in content and organization of shared modules, those modules th at are common between them share 97-98% sequence identity with one another. By fluorescence in situ hybridization (FISH) analysis, the end-points of f our variant 22q11.2 deletions appear to localize to the LCRs, Pulsed-field gel electrophoresis and Southern hybridization have been used to identify r earranged junction fragments from three variant deletions. Analysis of junc tion fragments by PCR and sequencing of the PCR products implicate the LCRs directly in the formation of 22q11.2 deletions. The evolutionary origin of the duplications on chromosome 22 has been assessed by FISH analysis of no n-human primates. Multiple signals in Old World monkeys suggest that the du plication events may have occurred at least 20-25 million years ago.