The inv dup(22), or CES chromosome, is associated with the clearly delineated disorder cat eye syndrome or CES (MIM #115470). This syndrome is characterized by a variety of congenital defects including ocular coloboma, anal atresia, preauricular tags/pits, heart defects (particularly the relatively rare total anomalous pulmonary venous return or TAPVR), kidney and skeletal defects, dysmorphic facial features, and mild mental retardation. Cat eye syndrome is highly variable in severity and the number of features expressed, even within families, can range from severe to essentially normal. Cat eye syndrome is rare, with an estimated frequency in the range of 1/ 50,000 to 1/150,000 live births.
The typical CES karyotype is 47,+idic(22)(pter! q11.2), resulting in the presence of four copies of the CES critical region or CESCR. However, interstitial duplications of 22q11.2 have also been associated with CES.[16-18] Because of the small sample size of interstitial duplications and the extreme variability of the syndrome, it is unclear whether three copies of the region give a less severe phenotype than four.
The CESCR does not overlap with the DGS/VCFS deletion syndrome of 22q11, and thus they are not reciprocal syndromes (Fig. 2). However, the CES chromosome exists in several discrete sizes, some of which do include the DGS/VCFS critical region. The CES region extends ~ 3 Mb from the centromere and is present in two copies in all inv dup(22). Some CES chromosomes also contain one or two copies of the adjacent 3-Mb region deleted in DGS/VCFS. The recurrent CES breakpoint regions occur in the same intervals as the proximal and distal 3-Mb VCFS/DGS deletion breakpoints.[20,21] Thus a Type I CES chromosome is symmetrical with two proximal breakpoints and no DGS/VCFS material (Fig. 2). Type II CES chromosomes contain one proximal and one distal breakpoint (Type IIa, asymmetrical) or two distal breakpoints (Type lib, symmetrical), resulting in an additional one or two copies of the VCFS/DGS region. Interestingly, most reported Type II inv dup(22)s are asymmetrical, whereas most reported inv dup(15)s are symmetrical. An additional, less-frequent 22q11 breakpoint exists in the middle of the DGS/VCFS, which can also be used as a distal breakpoint.1-22-1 All three breakpoint regions, each 1.5 Mb apart, harbor a similar low-copy repeat or LCR22. The size of the inv dup(22) does not appear to have an obvious correlation to the severity of the phenotype, despite the fact that dosage-sensitive gene(s) must be present in the DGS/VCFS region. However, the sample size of this study was small (10 patients).
The CESCR was further defined by studying a child with an unusual supernumerary double-ring chromosome 22 and all major physical features of CES. The duplication extended from the centromere to the gene ATP6E, a distance of approximately 2 Mb (Fig. 2). Fourteen transcripts have been identified in the CESCR, as well as 12 mouse homologues in the region of conserved synteny on murine chromosome 6.[25,26] It is not yet known whether one or multiple genes are involved in CES. Unlike the inv dup(15), the study of the inv dup(22) is not complicated by the presence of imprinting.[27-29]
Like the inv dup(15), there are also inv dup(22)s that are associated with normal phenotype. These chromosomes presumably do not contain euchromatin, although their cytogenetic appearance is often not distinguishable from the CES chromosome. This is especially problematic when an inv dup(22) is found during prenatal testing, as there are currently no commercial fluorescence in situ hybridization (FISH) probes available to distinguish between the benign and CES chromosomes.
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