Molecular mechanisms and diagnosis of chromosome 22q11.2 rearrangements

Abstract

Several recurrent, constitutional genomic disorders are present on chromosome 22q. These include the translocations and deletions associated with DiGeorge and velocardiofacial syndrome and the translocations that give rise to the recurrent t(11;22) supernumerary der(22) syndrome (Emanuel syndrome). The rearrangement breakpoints on 22q cluster around the chromosome-specific segmental duplications of proximal 22q11, which are involved in the etiology of these disorders. While the deletions are the result of nonallelic homologous recombination (NAHR) between low copy repeats or segmental duplications within 22q11, the t(11;22) is the result of rearrangement between palindromic AT-rich repeats on 11q and 22q. Here we describe the mechanisms responsible for these recurrent rearrangements, discuss the recurrent deletion endpoints that are the result of NAHR between chromosome 22q specific low copy repeats as well as present current diagnostic approaches to deletion detection.

Fig. 1

An ideogram of chromosome 22 indicating the position of the low copy repeats (LCRs) in 22q11.2. The chromosome bands involved in the rearrangements of 22q11 are as indicated. Boxes indicate the position of the LCRs. Filled boxes (LCRs through D) are those that have been documented to be involved in numerous recurrent rearrangements. In brackets are indicated the recurrent nested deletions of chromosome 22q11.2. Open boxes (LCRs E through H) indicate LCRs that have only rarely been implicated in rearrangements. The proximal and distal breakpoints for the marker chromosomes seen in association with the cat eye syndrome and the t(11;22) breakpoint region are also noted.

Fig. 2

A schematic depiction of low copy repeats (LCRs) that mediate genomic instability on chromosome 22. The 22q11 region is enlarged, represented by the blue line with arrows at both ends, and is drawn from centromere (left) to telomere (right). The complex modular LCRs that characterize this region are represented by the multicolored vertical rectangular boxes, each color representing a stretch of DNA sequence repeated in multiple LCRs. The BCRL module is depicted by a royal blue box that is present in all of the LCRs except LCR-B. Zigzag lines represent the locations of multiple recurrent breakpoints including those for the deletions seen in the 22q11.2 deletion syndrome patients, the duplications seen in the Cat Eye syndrome, and the translocations involving 22q. Light blue horizontal rectangles on the lower portion of the diagram indicate the extent of the prevalent, recurrent LCR-mediated 22q deletions seen in the 22q11.2 deletion syndrome. It has been demonstrated that palindromic AT rich repeats in the white “gap” indicated in LCR-B of 22q11 can form hairpins and cruciforms that mediate translocations between chromosome 22 and several other partner chromosomes. Concept and design courtesy of Tamim H. Shaikh, Ph.D.

Fig. 3

Diagrammatic representation of the TDR on 22q11.2q and deletion size in 300 patients. The orientation of the region is centromere (left) to telomere (right). LCRs-A, -B, -C, and -D are indicated as filled boxes. The small, hatched box between markers S22S36 and D22S75 indicates the proximal deletion endpoint (A′) of several variant deletions not deleted for cosmid c103a2. The cosmids used as FISH probes for deletion sizing are indicated with asterisks. Above the line are the markers from chromosome 22q contained within the cosmid clones.

Fig. 4

Graphical representation of HDMLPA data. Shown above the representation of chromosome 22 are the FISH probes (cosmids) used in the laboratory designated either by cosmid address or locus name. The MLPA probes (orange rectangles, existing MLPA PO23 loci; yellow rectangles, new MLPA loci) are shown in map order based upon data derived from the UCSC genome browser. All MLPA loci were tested in all samples. Copy number for MLPA probes is indicated by color (grey = disomic, 2 copies; red = hemizygous deletion). The 22q11.2 deletions studied are shown as samples 1–10: (1,2) CH99-023 and CH02-125 with 3 Mb LCR-A to LCR-D deletions. Patient 2 has an extended deletion. (3,4) CH06-198, DO6-231 with LCR-B to LCR-D deletions. (5,6) 06-006997 and 07000363 with a distal variant of LCR-B to LCR-D deletions. (7) 06-006837 an atypical deletion. (8) 06-004115 a LCR-C to LCR-D deletion. (9) CH98-018 a LCR-D to LCR-E deletion, (10) 07-0000553 a LCR-D to LCR-F deletion.