A common molecular basis for rearrangement disorders on chromosome 22q11

The chromosome 22q11 region is susceptible to rearrangements that are assoc iated with congenital anomaly disorders and malignant tumors. Three congeni tal anomaly disorders, cat-eye syndrome, der(22) syndrome and velo-cardio-f acial syndrome/DiGeorge syndrome (VCFS/DGS) are associated with tetrasomy, trisomy or monosomy, respectively, for part of chromosome 22q11, VCFS/DGS i s the most common syndrome associated with 22q11 rearrangements. In order t o determine whether there are particular regions on 22q11 that are prone to rearrangements, the deletion end-points in a large number of VCFS/DGS pati ents were defined by haplotype analysis. Most VCFS/DGS patients have a simi lar 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 trans locations. The high prevalence of the disorder in the population and the fa ct that most cases occur sporadically suggest that sequences at or near the breakpoints confer susceptibility to chromosome rearrangements. To investi gate 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 inters titial duplication of the same 3 Mb region that is deleted in VCFS/DGS pati ents, We present models to explain how the LCR22s can mediate different hom ologous 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 rearrangemen ts leading to disease.