A common molecular basis for rearrangement disorders on chromosome 22q11

TLDR

The 22q11 region is prone to rearrangements linked to congenital anomaly disorders such as VCFS/DGS, cat‑eye syndrome, and der() syndrome, with VCFS/DGS being the most common, and its high sporadic prevalence suggests breakpoint‑proximal sequences confer susceptibility. To determine whether particular regions on 22q11 are prone to rearrangements, the authors defined deletion endpoints in many VCFS/DGS patients by haplotype analysis and developed hamster‑human somatic hybrid cell lines to test the hypothesis that breakpoints occur within low‑copy repeats (LCR22s). The study used haplotype mapping, hybrid cell lines, and identification of an interstitial duplication family to show that breakpoints lie within LCR22s, and presented models explaining how these repeats mediate homologous recombination events that generate diverse rearrangements. Most VCFS/DGS patients share a 3 Mb deletion, some have a nested 1.5 Mb deletion, a few have unique deletions or translocations, and five additional copies of LCR22 were identified that may mediate other disease‑associated rearrangements.

Abstract

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() 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.