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Human Molecular Genetics, 2000, Vol. 9, No. 4 489-501
© 2000 Oxford University Press

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

Tamim H. Shaikh1,+, Hiroki Kurahashi1,+, Sulagna C. Saitta1, Anna Mizrahy O’Hare1, Ping Hu4, Bruce A. Roe4, Deborah A. Driscoll1,2,3, Donna M. McDonald-McGinn1, Elaine H. Zackai1,2, Marcia L. Budarf1,2 and Beverly S. Emanuel1,2,§

1Division of Human Genetics and Molecular Biology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA, Departments of 2Pediatrics and 3Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA and 4Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA

The 22q11.2 deletion syndrome, which includes DiGeorge and velocardiofacial syndromes (DGS/VCFS), is the most common microdeletion syndrome. The majority of deleted patients share a common 3 Mb 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 deletions that have no overlap with the TDR. The identification of chromosome 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 deletions of 22q11.2. The entire 3 Mb TDR has been sequenced, permitting detailed investigation of the LCRs and their involvement in the 22q11.2 deletions. Sequence analysis has identified four LCRs within the 3 Mb TDR. Although the LCRs differ in content and organization of shared modules, those modules that are common between them share 97–98% sequence identity with one another. By fluorescence in situ hybridization (FISH) analysis, the end-points of four variant 22q11.2 deletions appear to localize to the LCRs. Pulsed-field gel electrophoresis and Southern hybridization have been used to identify rearranged junction fragments from three variant deletions. Analysis of junction 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 non-human primates. Multiple signals in Old World monkeys suggest that the duplication events may have occurred at least 20–25 million years ago.

+ These authors contributed equally to this work

§ To whom correspondence should be addressed at: The Children’s Hospital of Philadelphia, 1002 Abramson Research Center, 3516 Civic Center Boulevard, Philadelphia, PA 19104, USA. Tel: +1 215 5903856; Fax: +1 215 590 3764; Email: beverly@mail.med.upenn.edu


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