Inv Dup22

The consequence of inv dup(22) for clinical phenotype is in one way simpler than that for the inv dup(15) since chromosome 22 does not appear to be influenced by genomic imprinting. No convincing sex bias has been seen in chromosome 22 rearrangements (37), and three cases of maternal uniparental disomy 22 have shown normal phenotype (38-40). However, the remarkable phenotypic variation of the associated syndrome results in diagnostic problems of its own.

inv dup(22)(q11) is associated with cat eye syndrome (CES), which is characterized by abnormalities ofthe eye, heart, anus, kidneys, skeleton, gastrointestinal tract, and face (41-43). Patients may show mild mental retardation, but many are within the normal intelligence quotient (IQ) range. The syndrome derives its name from ocular coloboma, although only about half of CES patients show this feature. Preauricular skin tags or pits are the most constant feature. The CES phenotype is surprisingly variable, ranging from apparently normal to multiple severe and life-threatening malformations. The incidence of CES has been estimated to be 1/50-150,000 (OMIM 115470). Because some patients are mildly affected, there are numerous cases of inheritance of the CES chromosome, sometimes through multiple generations (44).

Although the CES chromosome is often stable, it is not uncommon to detect mosaicism (42). There are also cases where the inv dup(22) has shown instability within a family, resulting in secondary rearrangements (45). The parental origin of few inv dup(22)s has been determined. By comparing Q-banded polymorphisms, two cases were shown to originate from both maternal homologs (46). A similar analysis identified a third case of maternal origin, but from the same chromosome 22 homolog (47). Thus, both intra- and interchromosomal recombination can be involved in the production of inv dup(22).

The 22q11 region has a variety of chromosomal rearrangements that are mediated by LCRs (reviewed in ref. 48). Most prominent is the common deletion associated with DiGeorge syndrome/velocardiofacial syndrome (DGS/VCFS). The majority of DGS/VCFS deletions localize between LCR22-2 and LCR22-4, spanning approx 3 Mb (Fig. 3). A small percentage of deletions occur between LCR22-2 and LCR22-3a, spanning approx 1.5 Mb. CES chromosomes also appear to break at these LCRs (9,49).

An inv dup(22) is formed from breakpoints in two chromatids. In a type I CES chromosome, both breakpoints are at LCR22-2, only the CES region (proximal to LCR22-2) is included and the inv dup(22) is symmetrical (9). In type II CES chromosomes, the DGS/VCFS region is also included in the duplication. Type II chromosomes can be symmetrical, with both breakpoints in LCR22-4 and two additional copies of the DGS/VCFS region (type IIb), or asymmetrical, with breakpoints at LCR22-2 and LCR22-4 and with only one extra copy of the DGS/VCFS region (type IIa). A case has also been found with at least one breakpoint at LCR22-3a (50).

The CES phenotype results from overexpression of dosage sensitive genes in the CES critical region. The critical region for CES was determined by the analysis of an unusual patient with a relatively stable, supernumerary double r(22) (51). This child had all major physical

Fig. 3. Composition of various inv dup(22)s associated with cat-eye syndrome (CES). The inv dup(22) breakpoints coincide with the location of the of low copy repeats associated with DGS/VCFS deletions. Type I and lib chromosomes are symmetrical duplications, with the latter containing the DGS/VCFS critical region as well as the CES region. Type lia chromosomes are asymmetrical, with only one extra copy of the DiGeorge syndrome/velocardiofacial syndrome region, but two extra copies of the CES region. There is also one reported case of a CES chromosome with a LCR22-3a breakpoint, although in this case the location of the second breakpoint is not clear (50, case 2).

Fig. 3. Composition of various inv dup(22)s associated with cat-eye syndrome (CES). The inv dup(22) breakpoints coincide with the location of the of low copy repeats associated with DGS/VCFS deletions. Type I and lib chromosomes are symmetrical duplications, with the latter containing the DGS/VCFS critical region as well as the CES region. Type lia chromosomes are asymmetrical, with only one extra copy of the DiGeorge syndrome/velocardiofacial syndrome region, but two extra copies of the CES region. There is also one reported case of a CES chromosome with a LCR22-3a breakpoint, although in this case the location of the second breakpoint is not clear (50, case 2).

features of CES, although development could not be assessed as the child died at 17 days. The ring contained approx 2 Mb of proximal 22q11 from the centromere to a region distal to the ATP6E gene. A typical inv dup(22) contain at least an additional 1 Mb. The first 1-1.5-Mb from the 22 centromere contain pericentromeric repeats that are unlikely to contain active and unique genes (52). Thus, the majority, if not all, of the genes in the CES critical region lie within an approx 700-kb interval that contains at least 14 predicted or known genes (52). The gene or genes causative for CES features has yet to be determined. Candidates identified include a secreted growth factor predicted to have adenosine deaminase activity (CECR1) (53,54), and a transcription factor involved in chromatin remodeling (55).

A proportion of CES chromosomes have one or two copies of the DGS/VCFS region in additional to four copies of the CES region. Duplications of the DGS/VCFS region have been associated recently with variable symptoms including learning disabilities, cognitive and behavioral abnormalities, palate defects, hearing loss, heart defects, growth deficiency, developmental and motor delays, and urogenital anomalies (56). This likely represents only a spectrum of the microduplication 22q11.2 syndrome, because the patients were ascertained during testing specific for the DGS/VCFS deletion. In any case, one would assume that the addition of extra copies of the DGS/VCFS region would worsen the phenotype of CES, but this has not been observed. However, because only 10 CES patients have been characterized in this way (9), this lack of correlation is likely to be because of the extreme variability of the overall syndrome masking more subtle changes brought on by additional copies of the DGS/VCFS

multicopy/ mosaic familial 1 de novo?

multicopy/ mosaic familial 1 de novo?

Fig. 4. Prenatal identification of small marker chromosomes—a diagnostic predicament. Prenatally identified small marker chromosomes (SMCs) involving chromosomes 15 and 22 have partially predictable outcomes. The phenotypic outcome for a fetus with an SMC can depend on its molecular composition, whether the SMC is familial or de novo, and whether it is present in multiple copies or only in some cells. Overall, molecular and cytogenetic tests have been or are being developed that should unequivocally identify the extra material present in the SMC.

Fig. 4. Prenatal identification of small marker chromosomes—a diagnostic predicament. Prenatally identified small marker chromosomes (SMCs) involving chromosomes 15 and 22 have partially predictable outcomes. The phenotypic outcome for a fetus with an SMC can depend on its molecular composition, whether the SMC is familial or de novo, and whether it is present in multiple copies or only in some cells. Overall, molecular and cytogenetic tests have been or are being developed that should unequivocally identify the extra material present in the SMC.

region. Only the analysis of a much larger cohort of CES patients will determine whether a correlation exists between phenotype and the size of the CES chromosome.

CES is usually associated with the inv dup(22), however interstitial duplications have also been reported (57-59). Again, because of phenotypic variability and problems of ascertaining mild cases, it is not yet clear whether three copies of the CES region produce less susceptibility to malformations than four copies. Interestingly, the father and grandfather of the child with the supernumerary double r(22) both had a single supernumerary r(22) and appeared normal, stressing the variability of this syndrome even within families (51).

There is also a class of inv dup(22) associated with a normal phenotype (3,60,61). These chromosomes are often familial, and presumably contain no dosage-sensitive genes. The size in comparison to CES chromosomes has not been determined yet, and no commercial probe exists to differentiate the two. The cytogenetic appearance of these small inv dup(22)s is not always helpful in distinguishing them from CES chromosomes. This makes the prenatal discovery of an inv dup(22) a serious genetic counseling dilemma.

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