Chapter 22 / inv dup(15) and inv dup(22) 315 22 inv dup(15) and inv dup(22) Heather E. McDermid, PhD and Rachel Wevrick, PhD CONTENTS INTRODUCTION 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. From: Genomic Disorders: The Genomic Basis of Disease Edited by: J. R. Lupski and P. Stankiewicz © Humana Press, Totowa, NJ 315 316 Part IV / Genomic Rearrangements and Disease Traits 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 no α-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 Chapter 22 / inv dup(15) and inv dup(22) 317 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). 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 318 Part IV / Genomic Rearrangements and Disease Traits 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. 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.