Human Molecular Genetics, 1999, Vol. 8, No. 7 1157-1167
© 1999 Oxford University Press
Article |
A common molecular basis for rearrangement disorders on chromosome 22q11
Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA, 1Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 391, New York City, NY 10021, USA, 2Child Development Rehabilitation Center, Oregon Health Science University, 707 Southwest Gaines Road, Portland, OR 97201, USA and 3Center for the Diagnosis, Treatment and Study of Velo-Cardio-Facial Syndrome, State University of New York Health Science Center, New York, NY 13210, USA
The chromosome 22q11 region is susceptible to rearrangements that are associated with congenital anomaly disorders and malignant tumors. Three congenital anomaly disorders, cat-eye syndrome, der(22) syndrome and velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) are associated with tetrasomy, trisomy or monosomy, respectively, for part of chromosome 22q11. VCFS/DGS is the most common syndrome associated with 22q11 rearrangements. In order to determine whether there are particular regions on 22q11 that are prone to rearrangements, the deletion end-points in a large number of VCFS/DGS patients were defined by haplotype analysis. Most VCFS/DGS patients have a similar 3 Mb deletion, some have a nested distal deletion breakpoint resulting in a 1.5 Mb deletion and a few rare patients have unique deletions or translocations. The high prevalence of the disorder in the population and the fact that most cases occur sporadically suggest that sequences at or near the breakpoints confer susceptibility to chromosome rearrangements. To investigate this hypothesis, we developed hamster–human somatic hybrid cell lines from VCFS/DGS patients with all three classes of deletions and we now show that the breakpoints occur within similar low copy repeats, termed LCR22s. To support this idea further, we identified a family that carries an interstitial duplication of the same 3 Mb region that is deleted in VCFS/DGS patients. We present models to explain how the LCR22s can mediate different homologous recombination events, thereby generating a number of rearrangements that are associated with congenital anomaly disorders. We identified five additional copies of the LCR22 on 22q11 that may mediate other rearrangements leading to disease.
a To whom correspondence should be addressed. Tel: +1 718 430 4273; Fax: +1 718 430 8778; Email: morrow{at}aecom.yu.edu
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