Cryptic Inversion At 8p23

The finding that a Y chromosome inversion was the basis for a recurrent translocation (18) was at first considered peculiar to the sex chromosomes. Further relevance of these data emerged following our studies (21) reporting that some recurrent chromosome rearrangements at 8p occur as a consequence of an 8p submicroscopic paracentric inversion present in the parent transmitting the abnormal chromosome. At that time, we already knew that the recurrent inv dup(8p) rearrangement, an inverted duplication of the chromosome 8 short arm associated with deletion of the very distal 8p (8p23.2-pter), was not the primary product of an abnormal recombination but instead was produced by the breakage of a dicentric chromosome 8qter-8p23.1::8p23.1-8qter (22) leading to the formation of an inv dup(8p) and, though formally not demonstrated, to a chromosome 8 deleted for part of its short arm (8p-) (Fig. 2). In the dicentric chromosome the two duplicated regions are separated by a small single copy region (Fig. 3). The fact that the original inv dup (8p) was a dicentric chromosome led us to hypothesize that

Fig. 1. Mechanism of the Xp/Yp translocation at the basis of XX males and XY females. (Top) Recombination between the Xp and Yp chromosome normally occurs at the pseudo-autosomal region 1 (PAR). PRKX gene lies on the X chromosome approx 1 Mb centromeric to PAR. On the Y chromosome theSRY gene is just centromeric to PAR. PRKY, homologous to PRKX, lies about 4.5 Mb centromeric to PAR and is included within a polymorphic inversion region (yellow region) of 3 Mb. In noninverted subjects PRKX and PRKY have opposite orientation, thus preventing any possible recombination event. In subjects with inverted PRKX and PRKY acquire the same orientation (Bottom), thus, allowing an ectopic recombination. The result is the transposition of SRY on the Xp chromosome and the absence of SRY on the Y chromosome.

Fig. 1. Mechanism of the Xp/Yp translocation at the basis of XX males and XY females. (Top) Recombination between the Xp and Yp chromosome normally occurs at the pseudo-autosomal region 1 (PAR). PRKX gene lies on the X chromosome approx 1 Mb centromeric to PAR. On the Y chromosome theSRY gene is just centromeric to PAR. PRKY, homologous to PRKX, lies about 4.5 Mb centromeric to PAR and is included within a polymorphic inversion region (yellow region) of 3 Mb. In noninverted subjects PRKX and PRKY have opposite orientation, thus preventing any possible recombination event. In subjects with inverted PRKX and PRKY acquire the same orientation (Bottom), thus, allowing an ectopic recombination. The result is the transposition of SRY on the Xp chromosome and the absence of SRY on the Y chromosome.

the reciprocal analphoid chromosome might be present in some subjects who acquired of a neocentromere. From a literature review we were able to identify two of such cases where the analphoid chromosome was a supernumerary marker that was mosaic with a normal cell line. Molecular definition of this marker (+der[8p]) demonstrated that it was exactly the reciprocal of the dicentric chromosome 8 and that both rearrangements were mediated by a pair of olfactory receptor (OR)-gene clusters mapping to 8p23.1 (21) (Figs. 3 and 4). The refined distance between the two clusters (the single-copy region) is approx 3.5 Mb. We reasoned that, according to the classical cytogenetics, the production of two reciprocal rearrangements, one dicentric and the other acentric, could only result following a crossover within a paracentric inversion. We, thus, studied by fluorescent in situ hybridization the apparently normal chromosomes 8 in the parent-of-origin of several inv dup(8p)s (thus far 16 cases) and of one case of+der(8p) and discovered that a heterozygous paracentric inversion with the same breakpoints of the dicentric and the acentric chromosomes was present in all of them. The presence of the

Fig. 2. The dicentric chromosome resulting from nonallelic homologous recombination can undergo a breakage at the level of the second centromere or a more proximal breakage, leading to an inv dup(8)s and a del(8p). Note that the inv dup(8p)s may differ according to the duplication size.
Fig. 3. Cryptic paracentric inversion between the two pairs of olfactory receptor (OR) gene clusters mapping to 8p23.1. Non-allelic homologous recombination results in a dicentric and an acentric recombinant chromosome. The single copy region is delimited by the two OR gene clusters (red arrows).

inversion also explained a highly unlikely crossover pattern at 8p23 observed in members of some Centre d'Etude du Polymorphisme Humain families (23) that showed apparent triple recombination events in a very short region. Studies on normal populations revealed that the 8p23 inversion is present in the heterozygous state in 26% of the European population (21) and in 39% of the Japanese population (24). Thus, the inversion represents a genomic polymorphism that,

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