Genomic disorders on 22q11

Abstract

The 22q11 region is involved in chromosomal rearrangements that lead to altered gene dosage, resulting in genomic disorders that are characterized by mental retardation and/or congenital malformations. Three such disorders-cat-eye syndrome (CES), der(22) syndrome, and velocardiofacial syndrome/DiGeorge syndrome (VCFS/DGS)-are associated with four, three, and one dose, respectively, of parts of 22q11. The critical region for CES lies centromeric to the deletion region of VCFS/DGS, although, in some cases, the extra material in CES extends across the VCFS/DGS region. The der(22) syndrome region overlaps both the CES region and the VCFS/DGS region. Molecular approaches have revealed a set of common chromosome breakpoints that are shared between the three disorders, implicating specific mechanisms that cause these rearrangements. Most VCFS/DGS and CES rearrangements are likely to occur by homologous recombination events between blocks of low-copy repeats (e.g., LCR22), whereas nonhomologous recombination mechanisms lead to the constitutional t(11;22) translocation. Meiotic nondisjunction events in carriers of the t(11;22) translocation can then lead to offspring with der(22) syndrome. The molecular basis of the clinical phenotype of these genomic disorders has also begun to be addressed. Analysis of both the genomic sequence for the 22q11 interval and the orthologous regions in the mouse has identified >24 genes that are shared between VCFS/DGS and der(22) syndrome and has identified 14 putative genes that are shared between CES and der(22) syndrome. The ability to manipulate the mouse genome aids in the identification of candidate genes in these three syndromes. Research on genomic disorders on 22q11 will continue to expand our knowledge of the mechanisms of chromosomal rearrangements and the molecular basis of their phenotypic consequences.

Figure 1

Rearrangements on 22q11. A multitude of germline rearrangements on 22q11 (boxed) are associated with congenital anomaly disorders. VCFS/DGS is associated with interstitial hemizygous deletions; a family has been reported with an interstitial duplication of the same interval that is deleted in patients with VCFS/DGS (Edelmann et al. 1999b). Der(22) syndrome occurs in offspring of unaffected carriers of the constitutional t(11;22) translocation; patients with der(22) syndrome have a partial trisomy for 22pter-q11 and 11q23-qter. Patients with CES harbor a bisatellited supernumerary chromosome 22 that results in a partial tetrasomy.

Figure 2

LCR22s in mediation of chromosomal rearrangements. LCR22 designations have been described elsewhere (Dunham et al. 1999). The proximal endpoints for the 1.5- and 3-Mb VCFS/DGS deletions occur in LCR22-2, and the distal endpoints occur in LCR22-3a and LCR22-4, respectively. The constitutional t(11;22) translocation disrupts LCR22-3a. Three CES-duplication endpoints—those for types I, IIa, and IIb—are shown. Deletions (white boxes), partial trisomies (i.e., three copies; gray boxes), and partial tetrasomies (i.e., four copies; black boxes) are depicted.

Figure 3

Map of human 22q11 region and orthologous regions in mouse. The relative order of genes (circles) on the 22q11 region (HSA22) and orthologous genes on MMU6 (for CES) and MMU16 (for VCFS/DGS) are shown. The arrows between the human and mouse maps indicate orientation. Deletions that have been generated in MMU16, to generate mouse models of VCFS/DGS, are indicated by a solid blue line below MMU16. BAC transgenic lines that harbor human genes in the distal half of the 1.5-Mb region that is deleted in patients with VCFS/DGS have also been generated, to overexpress sets of genes for genetic complementation studies; the genes included in these lines are indicated at the bottom of the figure.