Reproductive risks for paracentric inversion heterozygotes: Inversion or insertion? That is the question

What is the risk of a liveborn child with a recombi-nant arising from a paracentric inversion in one of the parents? The standard textbooks state that this risk is negligible and that, in general, there is no indication for prenatal diagnosis for carriers of paracentric inversions [Gardner and Sutherland, 1996; Connor and Ferguson-Smith, 1993]. Various reviews [e.g., Callen et al., 1985; Madan, 1988], including one of 184 cases [Madan, 1995], have con®rmed that the risk is very low. On the other hand, a large review of 446 cases of paracentric inversions by Pettenati et al. [1995] gives the risk of viable recombinants as 3.8%. Such contradicting infor-mation can pose a dilemma for the genetic counselor. The following summary of the controversy, a re-examination of the recombinants reported to have arisen from the paracentric inversions and some useful suggestions for distinguishing between paracentric inversions and intrachromosomal paracentric inser-tions, may be helpful. The conclusions of the article by Pettenati et al. [1995] have been contested in letters to the editor. Warburton and Twersky [1997] warn against poten-tially misleading information in this article, which gives a very high risk of congenital abnormalities associated with balanced paracentric inversions. Sutherland et al. [1995] pointed out that in calculating the risk of recombinants, Pettenati et al. illegitimately included cases that were reported as intrachromosomal insertions by the original authors, and they failed to correct for ascertainment bias. In their reply, Pettenati and Rao [1995] justi®ed including cases of recombi-nants that arose from insertions because, in practice, it is dif®cult to distinguish inversions from insertions. Indeed, inversions are not always distinguishable from insertions, especially if there is a very small segment between the original site and the new site of the inserted segment (Fig. 1). There are a number of examples in the published reports. One case that was reported as an insertion was initially thought to be an inversion [Webb et al., 1988]. There are three other cases of recombinants that were initially presented in poster abstracts as having arisen from a paracentric inversion [Kelly et al., 1979; Alderdice et al., 1980; Haapala et al., 1983]. The ®rst two were reinterpreted and were ®nally published as having arisen from insertions [Alderdice et al., 1983; Wyandt et al., 1980], and the third was never published. There are several more examples shown in Table I. Table I shows 13 cases of recombinants reported to date as having arisen from a paracentric inversion in one of the parents. Of these, only two, possibly three, could be expected to arise from a paracentric inversion. Several different unusual and sometimes complicated mechanisms have been invoked to explain the remain-ing 10 cases. In at least six of these, however, a much simpler alternative explanation based on classical cytogenetic principles could be found for the recombi-nant by interpreting the rearrangement in the parent as an insertion instead of an inversion (see Table I for details, and Madan and Menko [1992] for diagrams of recombination in insertions). The only two classical recombinants arising from paracentric inversions in Table I [Mules and Stamberg, 1984; Worsham et al., 1989] arose from a large inversion, had a genetic imbalance that was compatible with livebirth, and formed a stable dicentric by an extremely rare phenomenon of suppression of one of the centromeres [Gardner and Sutherland, 1996]. From the above-mentioned published correspon-dence [Pettenati and Rao, 1995; Sutherland et al., 1995], it appears that all parties agree that more research is necessary at the molecular level. There is already some new evidence emerging from molecular studies in meiosis that the risk of recombinants may not always be proportional to the length of the inversion, as was previously thought [Brown et al., 1998; Cheng et al., 1999]. However, there is, as yet, no evidence to suggest that monocentric recombinants with small deletions or duplications can arise from true paracentric inversions. Until such time, as Sutherland