Segmental Duplications And 22q112 Rearrangement Disorders

The establishment of physical maps of chromosome 22 made it possible to determine the position of the common recurrent breakpoints associated with chromosome 22q11.2 rearrangement disorders (Fig. 1). Probes used to screen filters containing large genomic insert bacterial artificial chromosome (BAC) clones identified clones mapping to several locations on 22q11.2 including clones in the vicinity of the breakpoints. LCRs have been noted already on 22q11.2 over 16 years ago (Heisterkamp and Groffen [78]) and in the general vicinity of VCFS/DGS locus over 10 years ago (37), but the connection between them was not made until integrated physical maps were generated (9,26).

Interchromosomal recombination events lead to the 22q11.2 deletion and a reciprocal duplication, both associated with congenital anomalies. Using microsatellite genetic markers and screening more than 150 VCFS/DGS patients and their unaffected family members, it was possible to narrow the region containing the common recurrent 1.5- and 3-Mb deletions (23). Further analysis of the breakpoints occurring in VCFS/DGS and CES patients suggested that they occurred in the same regions (38). More recently, the constitutional t(11;22) breakpoint on 22q11.2 was placed in the vicinity of the distal deletion breakpoint in VCFS/DGS patients with the nested 1.5 Mb deletion (34).

Blocks of region-specific segmental duplications or LCR22-2, LCR22-3a and LCR22-4; also known as LCR22-A, -B, and -D, respectively were found to map to the three regions of breakage, associated with VCFS/DGS, CES, and der(22) syndrome, all 1.5 Mb apart, implicating them in their etiology (Fig. 1) (9,24,25-27,34). The LCR22-2 and LCR22-4 are more than 240 kb in size and more than 99% identical in sequence. This suggested that misalignment of nonallelic copies of the homologs could occur during meiosis and through the mechanism of nonallelic homologous recombination (NAHR) resulting in a deletion.

Both intrachromosomal and interchromosomal unequal crossover events were found to be responsible for the 3-Mb deletion (Fig. 2) (26,38,39). This was determined by performing haplotype analysis with microsatellite markers, of three generations, the patient, parents, and grandparents. For interchromosomal events, which are more predominant (Baumer et al. [38]; Siatta et al. [39]), there should be individuals with the reciprocal duplication, dup(22)(q11.2q11.2). An analogous mechanism has been described for chromosome 17p11.2 for Smith-Magenis syndrome (SMS) (40). Indeed, interchromosomal unequal recombination events between two misaligned chromosomes 22 during meiosis resulted in a reciprocal duplication, dup(22)(q11.2)(11.2), (Fig. 2) (11,12,26). Unrelated dup(22)(q11.211.2) patients had been ascertained based on suspicion that they had VCFS/DGS. Dup(22)(q11.2q11.2) disorder is associated with some clinical findings occurring in VCFS/DGS, but also with other features which are distinct including characteristic facial features with mild craniofacial anomalies, hearing loss, and urogenital malformations (9,11,12).

Thus, based on mechanisms proposed, a newly recognized genetic syndrome was identified. Interestingly, unlike for VCFS/DGS which are characterized by deletions between LCR22-2 and LCR22 (LCR22-A-D), the size of the duplications vary in size, extending to more distal LCR22s (11) suggesting that larger duplications are more tolerated than larger deletions or that the mechanism for deletion and duplication may involve other sequences within LCR22s.

Unequal crossing over

Unequal crossing over

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