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Interpretation of molecular results in segmental uniparental disomy

In this journal, Giovannoni et al. recently reported on a 5.5-year-old boy with progressive familial intrahepatic cholestasis of type 2 due to a homozygous c.2494C>T/p.R832C transition in exon 21 of the ABCB11 gene. Familial investigations revealed the mutation only in the father, but not in the mother. As in the mother a mutation in the primer binding site, mosaicism and a large deletion could be excluded, paternal uniparental isodisomy was assumed. Analyses of microsatellites and single nucleotide polymorphisms spread over the entire chromosome 2 demonstrated paternal inheritance around the mutation but biparental inheritance for other markers. The authors discuss uniparental disomy (UPD), which describes the inheritance of both homologues of a pair of chromosomes from only one parent, but the molecular results appear not to be completely thought through and the rarity and the impact of the results are not adequately appreciated from a genetic point of view. First of all, the results clearly indicate that UPD in this patient is only segmental. Excluding all markers which are neither informative for biparental inheritance nor for isodisomy or heterodisomy due to their homozygosity for the same allele in both parents (n = 7), 17 fullyinformative markers and 25 semi-informative markers remain (Table 1). Before interpreting the results one should keep in mind that formation of interstitial segmental UPD is complex and might be either exclusively mitotic or a combination of meiotic and mitotic events (Fig. 1). For interstitial heterodisomy, a meiosis I or meiosis II non-disjunction followed by a mitotic double recombination and a subsequent loss of the uniparental homologue involved in the recombinations must have occurred (Fig. 1a). In contrast, interstitial uniparental isodisomy arises from a 46,XX or 46,XY zygote by concurrent or back to back mitotic double recombination and subsequent cell separation (Fig. 1b). Only by the latter can UPD be demonstrated by routine laboratory investigations. Otherwise, molecular results neutralize one another. The hypothesis of mitotic formation is supported by the lack of additional symptoms caused by mosaicism which would be likely a consequence of a trisomic zygote as well as by a minimum of one case with mosaic interstitial segmental paternal isodisomy. In contrast, for terminal segmental UPD, a meiotic formation by meiotic recombination and non-disjunction followed by a second mitotic recombination and lastly loss of one homologue is also possible. Both events must occur in an early postzygotic cell division, as otherwise mosaicism would superpose the laboratory and clinical phenotype of segmental UPD. In the case reported by Giovannoni et al., the 42 fullyand semi-informative markers indicate minimal regions of biparental inheritance from 2pter up to rs887941 on 2p11.2, or even rs880872 on 2q11.2, and from D2S1384 or even rs2241340, both located on 2q31.1 up to 2qter. Both breakpoints are poorly determined. Particularly, the proximal breakpoint should have been determined more exactly. For interpretation regarding the mechanism of formation, it might be relevant whether the centromere is within or outside the uniparental region. According to the arguments above, in 2q, the alleles of D2S2381 and D2S2284 should also be inherited biparentally and not paternally heterodisomically. In 2p, the marker rs880872, as well as in 2q, the two markers rs2287622 and rs2241340, do not allow to distinguish paternal isodisomy from biparental inheritance. Therefore and as a whole, segmental UPD extends at least from D2S113 to rs853772 (~72.5 Mb), but perhaps even from rs880872 to rs2287622 (~87 Mb). Surprisingly, within the undoubtedly uniparental region, one marker (D2S1399) shows paternal heterodisomy or biparental inheritance. This raises the question whether there is a typing error for this marker, a postzygotic mutation expanding the number of repeats from 136 to 140 in one paternal allele of D2S1399, or yet a small region of paternal uniparental heterodisomy, or even more unlikely of biparental inheritance. In all scenarios, each of the events occurs independently but necessarily most likely back to back. Per se, the more events that are necessary the more unlikely the scenario is. Therefore, in the patient reported by Giovannoni et al., the additional events which should have produced a switch of isodisomic and heterodisomic bs_bs_banner