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From: Genomic Disorders: The Genomic Basis of Disease Edited by: J. R. Lupski and P. Stankiewicz © Humana Press, Totowa, NJ
22 inv dup(15) and inv dup(22)
Heather E. McDermid, P h D and Rachel Wevrick, P h D
C
ONTENTSINTRODUCTION
SMALL MARKER CHROMOSOMES
INV DUP SMALL MARKER CHROMOSOMES INV DUP(15)
INV DUP(22) SUMMARY
REFERENCES
INTRODUCTION
The presence of a small supernumerary marker chromosome (SMC) in a karyotype creates a diagnostic dilemma, because the resulting duplications/triplications may cause abnormal development, depending on the location and size of the extra material. The most common SMC is the inv dup(15), the effect of which varies with size of triplication as well as the parent of origin. inv dup(22) is associated with the highly variable cat eye syndrome. Both are thought to be caused by U-type recombination between neighboring low-copy repeats (LCRs), result- ing in both symmetric and asymmetric bisatellited dicentric supernumerary chromosomes.
Studies are underway to associate the abnormal features of each syndrome with specific genes in the duplicated regions.
SMALL MARKER CHROMOSOMES
SMCs, detected prenatally or postnatally, have presented a diagnostic dilemma since the birth of cytogenetics nearly 50 years ago. SMCs, also referred to as extra structurally abnormal chro- mosomes, are present in addition to the normal chromosome complement, usually not identifi- able by standard staining techniques, and typically smaller than the smallest autosome (1–4).
In a landmark study of almost 400,000 amniocenteses, 0.04% had an SMC of cytogeneti- cally unidentifiable origin (reviewed in ref.1). The incidence of SMCs at live birth has been variously reported as 0.05% (2) and 0.07% (3). SMCs can also exist as rings and occasionally may be present in multiple copies per cell. Mosaicism has been seen in 59% of all SMC cases, but is higher (69%) for SMCs derived from nonacrocentric chromosomes (4). In any case, the presence of an SMC may lead to an imbalance for whatever genes are duplicated in the SMC.
When studied using fluorescence in situ hybridization (FISH), the chromosomal origin of most SMCs can be identified by the presence of chromosome-specific α-satellite DNA (although commercial satellite probes to differentiate chromosomes 13 from 21 and 14 from 22 are not available). More recent variants of the FISH technique, such as spectral karyotyping, centromere-specific multicolor FISH, and subcentromeric multicolor-FISH have allowed finer identification, the latter technique determining the presence of specific subcentromeric euchromatin (5–7). SMCs derived from chromosome 15 can also be identified by specific staining with DAPI, a DNA-binding dye.
In a study of 112 autosomal SMCs ascertained both prenatally and postnatally, 68% were derived from acrocentric autosomes, and of those, 51% were derived from chromosome 15 (35% of all SMCs) (4). The risk of an abnormal phenotype associated with the 32% of SMCs that are nonacrocentric-derived has been calculated as approx 28%, whereas SMCs derived from acrocentric autosomes, excluding chromosome 15, carry a lower risk (approx 7%) of abnormal phenotype (8). Correlations between the SMC origin and phenotype have been attempted (7,8). SMCs derived from chromosome 15 are associated with defined risk and distinct phenotype, depending on their genetic composition. As described below, imprinting of the proximal region of the chromosome 15 long arm also alters gene dosage effects. Specific SMCs derived from chromosome 22 cause a distinct phenotype, the cat eye syndrome (OMIM 115470).
INV DUP SMALL MARKER CHROMOSOMES
SMCs containing two copies of a centromere, arranged in an apparent mirror image sym- metry around a central axis, have been referred to as isodicentric (idic), pseudoisodicentric (psu dic) or, more correctly, inverted duplication (inv dup) (Fig. 1). The best studied, recurrent inv dup SMCs are derived from chromosomes 15 or 22. These chromosomes are bisatellited because of an acrocentric p-arm on each end. They also contain two centromeres, usually separated by at least several megabases of euchromatin. Such chromosomes are often stable, presumably because one centromere is inactivated (hence the term pseudoisodicentric). An inv dup SMC associated with an otherwise normal karyotype results in a total of four copies of the excess region, and is therefore a triplication or partial tetrasomy.
inv dup SMCs have been referred to as isodicentric, but this term is appropriate only if the duplications on each side are symmetrical (Fig. 1). inv dup chromosomes have been found often to be asymmetrical, with one side of the chromosome considerably larger than the other.
This results in a total of four copies of some regions and only three copies of others (9).
inv dup SMCs can also originate from the other acrocentric chromosomes, but with less frequency and are associated with a less well-defined phenotype than that for chromosomes 15 and 22. Nonacrocentric chromosomes are also a source for inv dup SMCs. These may contain noα-satellite DNA and yet are stable, providing an opportunity to address the question of centromeric function in the absence of the DNA normally present at centromeres (10). These unusual inv dup SMCs are C-band negative, yet have a G-banded primary constriction, which acts as an active kinetochore and reacts with CENP-C antibodies (11). It is presumed that these SMCs activate noncentromeric sequences that function as neocentromeres.
It has long been suggested that inv dup chromosomes are derived from a “U-type” rather than the normal “X-type” exchange between nonsister or sister chromatids at meiosis I (12,13).
Mediated by LCRs on chromosomes 15 or 22, a U-type exchange between repeats in opposite
orientation would lead to a dicentric SMC as well as an acentric fragment composed of two copies of the rest of each chromatid. The acentric fragment would be lost, whereas the SMC would be retained through nondisjunction and inactivation of one centromere. Each LCR in chromosome 22q11 is composed of complex blocks of repeats (14). LCR2 and LCR4, in which most rearrangements occur, contain shared repeat blocks in both the same and opposite orien- tations, which facilitate U-type exchanges. If a U-type exchange occurs between elements of the same LCR (allelic), the resulting inv dup chromosome would essentially be symmetrical.
A U-type exchange between similar elements of different LCRs (nonallelic) would produce an asymmetric SMC. Asymmetric inv dup SMCs could also result from a paracentric inversion of a region between LCRs, followed by recombination within the inversion loop (15). This would similarly result in a dicentric SMC and an acentric fragment that is lost.
INV DUP(15)
inv dup chromosomes derived from chromosome 15 account for approx 35% of SMCs (4), and, after trisomy 21, are the most common autosomal chromosomal aberration (16). Although the phenotype associated with the inv dup(15) itself can be variable, uniparental disomy or deletion of the normal chromosome 15 can accompany the inv dup chromosome with addi- tional clinical consequences (17,18). The presence of abnormalities on the “normal” chromo- somes 15, the size of the inv dup(15), and the parental origin of the chromosomal abnormalities all affect the severity of the outcome. This information is critical in the context of genetic counseling, particularly in the setting of prenatal ascertainment of a de novo inv dup(15).
Because of their relatively common frequency, chromosome 15 rearrangements have pro- vided a rich source of information for the study of chromosomal abnormalities. The presence of a set of LCRs on the proximal long arm of chromosome 15 predisposes this region to a Fig. 1. Structure of bisatellited and dicentric inv dup chromosomes. These chromosomes can have a symmetrical duplication (A) or be asymmetrical, where one side of the duplication is larger than the other (B). In an asymmetric inv dup, the region nearest the centromere is present in two extra copies (light gray), whereas the more distal region is present in only one extra copy (dark gray).
heterogeneous group of inter- and intrachromosomal rearrangements (19,20). The nonallelic copies of these LCRs can misalign during meiosis, and the resulting nonallelic homologous recombination or unequal crossover event gives rise to structurally abnormal chromosomes.
The LCRs are present in the breakpoint regions involved in the rearrangements, and are named in ascending order from the most centromeric, as break point (BP)1 to BP5 (Fig. 2).
The chromosomal disorders Prader-Willi syndrome (PWS; OMIM 176270) and Angelman syndrome (AS; OMIM 105830) most commonly involve a deletion of the genetic material between BP2 and BP3A/3B, with PWS deletions occurring on the paternally derived chromo- some, and AS deletions occurring on the maternally derived chromosome (19,20) (Fig. 2).
Although both syndromes include developmental delay, PWS individuals typically have a neonatal failure to thrive and hyperphagic obesity, among other neurodevelopmental findings (21), whereas AS individuals typically have seizures and absent speech (22). The difference between the phenotypes is owing to the presence of imprinted genes in the deletion region, which are expressed on only one chromosome in a manner dependent on parent of origin. The paternally expressed genes responsible for PWS are clustered toward the centromeric end of the BP2-BP3A/3B deletion region. Four of the PWS candidate genes, MKRN3, NDN (necdin), MAGEL2, and SNURF/SNRPN, are protein-coding and expressed in the nervous system during development (23–26). Another PWS candidate gene encodes a functional RNA, the imprinting Fig. 2. Examples of various types of inv dup(15)s. Chromosome 15q11-q14 contains a set of genes that are expressed only from the paternally inherited allele (black diamonds, Prader-Willi syndrome [PWS]
candidate genes), from the maternal allele in a tissue-specific fashion (white diamonds, including the Angelman syndrome [AS] gene UBE3A) or from both alleles (not imprinted, gray diamonds). Rear- rangements of chromosome 15q11-q14 generally involve a set of low-copy repeats labeled BP1 through BP5; the PWS/AS interstitial deletions typically occur between BP2 and BP3A/3B. inv dup(15) chro- mosomes can involve any of the breakpoint regions, and can be symmetrical or asymmetrical, as in the bottom example. inv dup(15)s that contain material telomeric to BP2 (shaded gray) are associated with an adverse outcome. The centromere is represented by the black circle toward the left.
center transcript (27). This transcript also contains a set of small nucleolar RNAs as well as acting as an antisense RNA for a more telomeric gene, UBE3A. In tissues in which the imprint- ing center transcript is active, this antisense regulation imparts paternal allele-specific gene silencing of UBE3A. Chromosomal deletions or other types of mutations that inactivate the maternal allele of UBE3A causes AS.
In addition to deletions, unequal recombination events can give rise to rare interstitial duplications and triplications, and to the more common inv dup(15). Maternally derived inter- stitial duplications of 15q11-q14 give rise to a phenotype, characterized by various types of intellectual impairment, which is distinct from the deletion syndromes, whereas paternally derived interstitial duplications are significantly less likely to be associated with abnormal phenotype (28). There is at least one case where a paternally derived interstitial duplication was not associated with an adverse outcome, whereas the same duplication causes severe abnor- malities upon maternal transmission (29). De novo inv dup(15)(q11-q14) chromosomes also show a parent of origin bias, being almost exclusively maternal in origin (30), and are associ- ated with late maternal age (4,31). This emphasizes the fact that the parental origin and size of the duplication region are important in predicting clinical outcome.
The smallest inv dup(15)s contain no duplicated material from the PWS/AS deletion region between BP2 and BP3 and carry a low risk of adverse outcome, despite the presence of at least four protein coding genes in the region centromeric to BP2 (32,33) (Fig. 2). The largest interstitial and supernumerary duplications contain extra copies of the chromosomal material extending distally to the PWS/AS BP3 region, and are associated with dysmorphic features, severe developmental delay, autism, seizures, strabismus, and abnormal dermatoglyphics (28).
inv dup(15)s, because of their derivation from an imprinted region, can present an unusual situation in terms of gene activity. A PWS or AS phenotype has been found in individuals who, in addition to the inv dup(15), carry either a deletion or uniparental disomy for chromosome 15, leading to the parent of origin phenotypes associated with loss of one parental copy of imprinted genes (17,18).
The inv dup(15)s carrying duplicated PWS/AS region material are categorized according to the breakpoints involved, with examples given in Fig. 2. Several groups have identified the repeat regions involved in inv dup(15)s and interstitial duplications, using FISH, somatic cell hybrids and array comparative genomic hybridization to detect the dosage and position of single genomic sequences (16,19,20,34,35). At high resolution, some inv dup(15)s that were thought to be symmetrical are in fact asymmetrical, and involve recombination between two different BP repeat clusters (35). The most common of the larger inv dup(15)s involves BP4 and BP5, whereas most of the remainder are the result of a symmetrical BP3 to BP3 rearrange- ment. Individuals with this latter class of inv dup(15) carry one paternally derived and three maternally derived copies of the PWS/AS region, whereas individuals carrying the BP4:BP5 inv dup(15)s carry this genetic material plus additional copies of maternally inherited genes distal to the PWS/AS region (35). Clear phenotypic differences among these latter classes, if they exist, have yet to emerge. A dosage effect associated with inv dup(15)s is evident, how- ever, with reports of individuals with hexasomy for 15q11-q14 at the severe end of the phe- notypic spectrum (36).
The high frequency of chromosomal rearrangements is undoubtedly related to the presence of the “BP” LCRs (Fig. 2), but rearrangements appear to arise from a variety of recombina- tional mechanisms. Reciprocal recombination events of the PWS/AS deletion region likely cause interstitial duplications involving the same LCRs. Studies using probes located near the
chromosome 15 centromere suggest that aberrant U-type exchange resulting in inv dup(15) can occur between sister chromatids, or between homologous chromosomes either during or after recombination (34). The development of informative markers closer to the centromere of chromosome 15 and sequencing of the breakpoints will facilitate further analyses of the struc- ture and mechanism of origin of these structurally abnormal chromosomes.
INV DUP(22)
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 abnor- malities of the 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 mater- nal 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 chromo- somes 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
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, devel- opmental and motor delays, and urogenital anomalies (56). This likely represents only a spec- trum 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 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 IIb chromosomes are symmetrical duplications, with the latter containing the DGS/VCFS critical region as well as the CES region. Type IIa 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).
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 dis- covery of an inv dup(22) a serious genetic counseling dilemma.
SUMMARY
inv dup chromosomes 15 and 22, along with recurrent deletions and duplications, appear to be the inevitable consequence of the presence of LCRs relatively close to the centromere of Fig. 4. Prenatal identification of small marker chromosomes—a diagnostic predicament. Prenatally identified small marker chromosomes (SMCs) involving chromosomes 15 and 22 have partially predict- able outcomes. The phenotypic outcome for a fetus with an SMC can depend on its molecular compo- sition, 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 unequivo- cally identify the extra material present in the SMC.
acrocentric chromosomes 15 and 22. Formation of an inv dup chromosome results in a com- bination of duplication and triplication of variable regions, depending on the LCRs involved and whether the chromosome is symmetrical or asymmetrical. The phenotypic consequences of such rearrangements also vary with the LCR used.
The finding of an acrocentric-derived inv dup chromosome or other SMC at prenatal diag- nosis presents a diagnostic dilemma (Fig. 4). Identification of the chromosomal origin of the SMC can be achieved using centromere-specific FISH probes, although the commercially available probe for chromosomes 13/21 and 14/22 does not distinguish the two. Chromosome painting, or more complex molecular cytogenetic methods can now identify the extraneous material, and additional analysis is then required to determine the size of the SMC. Prediction of clinical outcome remains problematic, especially for inv dup(22). Overall, further investi- gation of the frequency and clinical outcomes of the more commonly occurring SMCs should enable the development of algorithms for genetic counseling after cytogenetic identification of an SMC.
REFERENCES
1. Warburton D. De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. Am J Hum Genet 1991;49:995–1013.
2. Buckton KE, Spowart G, Newton MS, Evans HJ. Forty four probands with an additional “marker” chromo- some. Hum Genet 1985;69:353–370.
3. Gravholt CH, Friedrich U. Molecular cytogenetic study of supernumerary marker chromosomes in an unselected group of children. Am J Med Genet 1995;56:106–111.
4. Crolla JA, Youings SA, Ennis S, Jacobs PA. Supernumerary marker chromosomes in man: parental origin, mosaicism and maternal age revisited. Eur J Hum Genet 2005;13:154–160.
5. Haddad BR, Schrock E, Meck J, et al. Identification of de novo chromosomal markers and derivatives by spectral karyotyping. Hum Genet 1998;103:619–625.
6. Nietzel A, Rocchi M, Starke H, et al. A new multicolor-FISH approach for the characterization of marker chromosomes: centromere-specific multicolor-FISH (cenM-FISH). Hum Genet 2001;108:199–204.
7. Starke H, Nietzel A, Weise A, et al. Small supernumerary marker chromosomes (SMCs): genotype-phenotype correlation and classification. Hum Genet 2003;114:51–67.
8. Crolla JA. FISH and molecular studies of autosomal supernumerary marker chromosomes excluding those derived from chromosome 15: II. Review of the literature. Am J Med Genet 1998;75:367–381.
9. McTaggart KE, Budarf ML, Driscoll DA, Emanuel BS, Ferreira P, McDermid HE. Cat eye syndrome chromo- some breakpoint clustering: identification of two intervals also associated with 22q11 deletion syndrome breakpoints. Cytogenet Cell Genet 1998;81:222–228.
10. Depinet TW, Zackowski JL, Earnshaw WC, et al. Characterization of neo-centromeres in marker chromosomes lacking detectable alpha-satellite DNA. Hum Mol Genet 1997;6:1195–1204.
11. Amor DJ, Choo KH. Neocentromeres: role in human disease, evolution, and centromere study. Am J Hum Genet 2002;71:695–714.
12. Van Dyke DL, Weiss L, Logan M, Pai GS. The origin and behavior of two isodicentric bisatellited chromo- somes. Am J Hum Genet 1997;29:294–300.
13. Schreck RR, Breg WR, Erlanger BF, Miller OJ. Preferential derivation of abnormal human G-group-like chromosomes from chromosome 15. Hum Genet 1997;36:1–12.
14. Babcock M, Pavlicek A, Spiteri E, et al. Shuffling of genes within low-copy repeats on 22q11 (LCR22) by Alu- mediated recombination events during evolution. Genome Res 2003;13:2519–2532.
15. Emanuel BS, Shaikh TH. Segmental duplications: an ‘expanding’ role in genomic instability and disease. Nat Rev Genet 2001;2:791–800.
16. Wandstrat AE, Schwartz S. Isolation and molecular analysis of inv dup(15) and construction of a physical map of a common breakpoint in order to elucidate their mechanism of formation. Chromosoma 2000;109:498–505.
17. Spinner NB, Zackai E, Cheng SD, Knoll JH. Supernumerary inv dup(15) in a patient with Angelman syndrome and a deletion of 15q11-q13. Am J Med Genet 1995;57:61–65.
18. Robinson WP, Wagstaff J, Bernasconi F, et al. Uniparental disomy explains the occurrence of the Angelman or Prader-Willi syndrome in patients with an additional small inv dup(15) chromosome. J Med Genet 1993;30:756–760.
19. Christian SL, Fantes JA, Mewborn SK, Huang B, Ledbetter DH. Large genomic duplicons map to sites of instability in the Prader- Willi/Angelman syndrome chromosome region (15q11-q13). Hum Mol Genet 1999;8:1025–1037.
20. Amos-Landgraf JM, Ji Y, Gottlieb W, et al. Chromosome breakage in the Prader-Willi and Angelman syn- dromes involves recombination between large, transcribed repeats at proximal and distal breakpoints. Am J Hum Genet 1999;65:370–386.
21. Gunay-Aygun M, Schwartz S, Heeger S, O’Riordan MA, Cassidy SB. The changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria. Pediatrics 2001;108:E92.
22. Clayton-Smith J, Laan L. Angelman syndrome: a review of the clinical and genetic aspects. J Med Genet 2003;40:87–95.
23. Lee S, Walker CL, Wevrick R. Prader-Willi syndrome transcripts are expressed in phenotypically significant regions of the developing mouse brain. Gene Expr Patterns 2003;3:599–609.
24. Jong MT, Gray TA, Ji Y,et al. A novel imprinted gene, encoding a RING zinc-finger protein, and overlapping antisense transcript in the Prader-Willi syndrome critical region. Hum Mol Genet 1999;8:783–793.
25. MacDonald HR, Wevrick R. The necdin gene is deleted in Prader-Willi syndrome and is imprinted in human and mouse. Hum Mol Genet 1997;6:1873–1878.
26. Gray TA, Saitoh S, Nicholls RD. An imprinted, mammalian bicistronic transcript encodes two independent proteins. Proc Natl Acad Sci USA 1999;96:5616–5621.
27. Runte M, Huttenhofer A, Gross S, Kiefmann M, Horsthemke B, Buiting K. The IC-SNURF-SNRPN transcript serves as a host for multiple small nucleolar RNA species and as an antisense RNA for UBE3A. Hum Mol Genet 2001;10:2687–2700.
28. Bolton PF, Dennis NR, Browne CE, et al. The phenotypic manifestations of interstitial duplications of proximal 15q with special reference to the autistic spectrum disorders. Am J Med Genet 2001;105:675–685.
29. Cook EH Jr, Lindgren V, Leventhal BL, et al. Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am J Hum Genet 1997;60:928–934.
30. Mignon C, Malzac P, Moncla A, et al. Clinical heterogeneity in 16 patients with inv dup 15 chromosome:
cytogenetic and molecular studies, search for an imprinting effect. Eur J Hum Genet 1996;4:88–100.
31. Maraschio P, Zuffardi O, Bernardi F, et al. Preferential maternal derivation in inv dup(15): analysis of eight new cases. Hum Genet 1981;57:345–350.
32. Chai JH, Locke DP, Greally JM, et al. Identification of four highly conserved genes between breakpoint hotspots BP1 and BP2 of the Prader-Willi/Angelman syndromes deletion region that have undergone evolu- tionary transposition mediated by flanking duplicons. Am J Hum Genet 2003;73:898–925.
33. Huang B, Crolla JA, Christian SL, et al. Refined molecular characterization of the breakpoints in small inv dup(15) chromosomes. Hum Genet 1997;99:11–17.
34. Wandstrat AE, Leana-Cox J, Jenkins L, Schwartz S. Molecular cytogenetic evidence for a common breakpoint in the largest inverted duplications of chromosome 15. Am J Hum Genet 1998;62:925–936.
35. Wang NJ, Liu D, Parokonny AS, Schanen NC. High-resolution molecular characterization of 15q11-q13 rearrangements by array comparative genomic hybridization (array CGH) with detection of gene dosage. Am J Hum Genet 2004;75:267–281.
36. Mann SM, Wang NJ, Liu DH, et al. Supernumerary tricentric derivative chromosome 15 in two boys with intractable epilepsy: another mechanism for partial hexasomy. Hum Genet 2004;115:104–111.
37. Morrow B, Goldberg R, Carlson C, et al. Molecular definition of the 22q11 deletions in velo-cardio-facial syndrome. Am J Hum Genet 1995;56:1391–1403.
38. Kirkels VG, Hustinx TW, Scheres JM. Habitual abortion and translocation (22q;22q): unexpected transmission from a mother to her phenotypically normal daughter. Clin Genet 1980;18:456–461.
39. Palmer CG, Schwartz S, Hodes ME. Transmission of a balanced homologous t(22q;22q) translocation from mother to normal daughter. Clin Genet 1980;17:418–422.
40. Schinzel AA, Basaran S, Bernasconi F, Karaman B, Yuksel-Apak M, Robinson WP. Maternal uniparental disomy 22 has no impact on the phenotype. Am J Hum Genet 1994;54:21–24.
41. Schinzel A, Schmid W, Fraccaro M, et al. The “cat eye syndrome”: dicentric small marker chromosome probably derived from a no.22 (tetrasomy 22pter to q11) associated with a characteristic phenotype. Report of 11 patients and delineation of the clinical picture. Hum Genet 1981;57:148–158.
42. Berends MJ, Tan-Sindhunata G, Leegte B, van Essen AJ. Phenotypic variability of Cat-Eye syndrome. Genet Couns 2001;12:23–34.
43. Rosias PR, Sijstermans JM, Theunissen PM, et al. Phenotypic variability of the cat eye syndrome. Case report and review of the literature. Genet Couns 2001;12:273–282.
44. Luleci G, Bagci G, Kivran M, Luleci E, Bektas S, Basaran S. A hereditary bisatellite-dicentric supernumerary chromosome in a case of cat-eye syndrome. Hereditas 1989;111:7–10.
45. Urioste M, Visedo G, Sanchis A, et al. Dynamic mosaicism involving an unstable supernumerary der(22) chromosome in cat eye syndrome. Am J Med Genet 1994;49:77–82.
46. Magenis RE, Sheehy RR, Brown MG, et al. Parental origin of the extra chromosome in the cat eye syndrome:
evidence from heteromorphism and in situ hybridization analysis. Am J Med Genet 1988;29:9–19.
47. Tupler R, Hoeller A, Pezzolo A, Maraschio P. Maternal derivation of inv dup (22) and clinical variation in cat- eye syndrome. Ann Genet 1994;37:153–155.
48. McDermid HE, Morrow BE. Genomic disorders on 22q11. Am J Hum Genet 2002;70:1077–1088.
49. Edelmann L, Pandita RK, Spiteri E, et al. A common molecular basis for rearrangement disorders on chromo- some 22q11. Hum Mol Genet 1999;8:1157–1167.
50. Crolla JA, Howard P, Mitchell C, Long FL, Dennis NR. A molecular and FISH approach to determining karyotype and phenotype correlations in six patients with supernumerary marker(22) chromosomes. Am J Med Genet 1997;72:440–447.
51. Mears AJ, el-Shanti H, Murray JC, McDermid HE, Patil SR. Minute supernumerary ring chromosome 22 associated with cat eye syndrome: further delineation of the critical region. Am J Hum Genet 1995;57:
667–673.
52. Footz T.K, Brinkman-Mills P, Banting GS, et al. Analysis of the cat eye syndrome critical region in humans and the region of conserved synteny in mice : a search for candidate genes at or near the human chromosome 22 pericentromere. Genome Res 2001;11:1053–1070.
53. Riazi MA, Brinkman-Mills P, Nguyen T, et al. The human homolog of insect-derived growth factor, CECR1, is a candidate gene for features of cat eye syndrome. Genomics 2000;64:277–285.
54. Maier SA, Podemski L, Graham SW, McDermid HE, Locke J. Characterization of the adenosine deaminase- related growth factor (ADGF) gene family in Drosophila. Gene 2001;280:27–36.
55. Banting GS, Barak O, Ames TM, et al. CECR2, a protein involved in neurulation, forms a novel chromatin remodeling complex with SNF2L. Hum Mol Genet 2005;14:513–524.
56. Ensenauer RE, Adeyinka A, Flynn HC, et al. Microduplication 22q11.2, an emerging syndrome: clinical, cytogenetic, and molecular analysis of thirteen patients. Am J Hum Genet 2003;73:1027–1040.
57. Reiss JA, Weleber RG, Brown MG, Bangs CD, Lovrien EW, Magenis RE. Tandem duplication of proximal 22q: a cause of cat-eye syndrome. Am J Med Genet 1985;20:165–171.
58. Knoll JH, Asamoah A, Pletcher BA, Wagstaff J. Interstitial duplication of proximal 22q: phenotypic overlap with cat eye syndrome. Am J Med Genet 1995;55:221–224.
59. Lindsay EA, Shaffer LG, Carrozzo R, Greenberg F, Baldini A. De novo tandem duplication of chromosome segment 22q11-q12: clinical, cytogenetic, and molecular characterization. Am J Med Genet 1995;56:296–299.
60. Brondum-Nielsen K, Mikkelsen M. A 10-year survey, 1980-1990, of prenatally diagnosed small supernumer- ary marker chromosomes, identified by FISH analysis. Outcome and follow-up of 14 cases diagnosed in a series of 12,699 prenatal samples. Prenat Diagn 1995;15:615–619.
61. Engelen JJ, Tuerlings JH, Albrechts JC, Schrander-Stumpel CT, Hamers AJ, De Die-Smulders CE. Prenatally detected marker chromosome identified as an i(22)(p10) using (micro)FISH. Genet Couns 2000;11:13–17.
