Inv Dup15

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 additional clinical consequences (17,18). The presence of abnormalities on the "normal" chromosomes 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 provided 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. 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). Rearrangements 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) chromosomes 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.

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). Rearrangements 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) chromosomes 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 chromosome, 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 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 imprinting 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 interstitial 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 abnormalities 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 associated 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 rearrangement. 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, however, with reports of individuals with hexasomy for 15q11-q14 at the severe end of the phenotypic 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 structure and mechanism of origin of these structurally abnormal chromosomes.

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