Reply to Callen

Abstract

To the Editor:In our recent article in the Journal (Yang et al. 1997xMolecular analysis of deletion (17)(p11.2p11.2) in a family segregating a 17p paracentric inversion: implications for carriers of paracentric inversions. Yang, SP, Bidichandani, SI, Figuera, LE, Juyal, RC, Saxon, PJ, Baldini, A, and Patel, PI. Am J Hum Genet. 1997; 60: 1184–1193PubMedSee all ReferencesYang et al. 1997), we showed that an interstitial deletion of 17p11.2 had arisen after meiotic recombination in a carrier of an apparently balanced paracentric inversion (PAI; with breakpoints at 17p11.2 and 17p13.3). Considering all the cytogenetic and molecular evidence, especially the facts that (a) the breakpoints of the proband's interstitial deletion “flanked” the proximal breakpoint of the paternal PAI (the proximal Smith-Magenis syndrome (SMS) markers were deleted in spite of not being inverted), (b) some markers involved in the PAI were not deleted (the PMP22 locus), and (c) the position of the recombination in paternal meiosis was mapped within the immediate vicinity of the resulting deletion, we proposed a model of unequal crossing-over at the base of an inversion loop.In response to our article, Callen has raised an interesting point. He proposes an alternate explanation, wherein pairing at meiosis, followed by recombination between an insertion-bearing and the normal chromosome 17 homologue could result in the interstitial chromosomal deletion observed in the proband. We agree that a within-arm direct or inverted insertion is an important differential diagnosis in cases of suspected paracentric inversions, given the significantly enhanced risk of chromosomal imbalance associated with the former. However, although within-arm insertions (direct or inverted) can result in deletion or duplication of the inserted sequence (Gardner and Sutherland 1996xGardner, RJM and Sutherland (eds), GR. See all ReferencesGardner and Sutherland 1996), they cannot result in a concurrent deletion of noninserted sequences (proximal SMS markers) and sparing of inserted sequences (PMP22 markers).Taken together, the data seem to favor our hypothesis of an unequal crossing-over at meiosis, as proposed in our article. However, it should be noted that we have yet to formally exclude Callen's proposal—or even the possibility that the deletion arose de novo as a result of a slightly more proximal (unequal) recombination in 17p11.2.