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 theparents? The standard textbooks state that this risk isnegligible and that, in general, there is noindication forprenatal diagnosisfor carriers ofparacentric 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 conﬁrmed that the risk is very low. On theother hand, a large review of 446 cases of paracentricinversions by Pettenati et al. [1995] gives the risk ofviable 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 havearisen from the paracentric inversions and some usefulsuggestions for distinguishing between paracentricinversions 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, whichgives a very high risk of congenital abnormalitiesassociated with balanced paracentric inversions.Sutherland et al. [1995] pointed out that in calculatingthe risk of recombinants, Pettenati et al. illegitimatelyincluded cases that were reported as intrachromosomalinsertions by the original authors, and they failed tocorrect for ascertainment bias. In their reply, Pettenatiand Rao [1995] justiﬁed including cases of recombi-nants that arose from insertions because, in practice, itis difﬁcult to distinguish inversions from insertions.Indeed, inversions are not always distinguishablefrom insertions, especially if there is a very smallsegment between the original site and the new site ofthe inserted segment (Fig. 1). There are a number ofexamples in the published reports. One case that wasreported as an insertion was initially thought to be aninversion [Webb et al., 1988]. There are three othercases of recombinants that were initially presented inposter abstracts as having arisen from a paracentricinversion [Kelly et al., 1979; Alderdice et al., 1980;Haapala et al., 1983]. The ﬁrst two were reinterpretedand were ﬁnally published as having arisen frominsertions [Alderdice et al., 1983; Wyandt et al., 1980],and the third was never published. There are severalmore examples shown in Table I.Table I shows 13 cases of recombinants reported todate as having arisen from a paracentric inversion inone of the parents. Of these, only two, possibly three,could be expected to arise from a paracentric inversion.Several different unusual and sometimes complicatedmechanisms have been invoked to explain the remain-ing 10 cases. In at least six of these, however, a muchsimpler alternative explanation based on classicalcytogenetic principles could be found for the recombi-nant by interpreting the rearrangement in the parentas an insertion instead of an inversion (see Table I fordetails, and Madan and Menko [1992] for diagrams ofrecombination in insertions). The only two classicalrecombinants arising from paracentric inversions inTable I [Mules and Stamberg, 1984; Worsham et al.,1989] arose from a large inversion, had a geneticimbalance that was compatible with livebirth, andformed a stable dicentric by an extremely rarephenomenon 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 moreresearch is necessary at the molecular level. There isalready some new evidence emerging from molecularstudies in meiosis that the risk of recombinants maynot always be proportional to the length of theinversion, as was previously thought [Brown et al.,1998; Cheng et al., 1999]. However, there is, as yet, noevidence to suggest that monocentric recombinantswith small deletions or duplications can arise from trueparacentric inversions. Until such time, as Sutherland