Meiotic outcomes of three-way translocations ascertained in cleavage-stage embryos: refinement of reproductive risks and implications for PGD

Abstract

Our study provides an analysis of the outcome of meiotic segregation of three-way translocations in cleavage-stage embryos and the accuracy and limitations of preimplantation genetic diagnosis (PGD) using the fluorescence in situ hybridization technique. We propose a general model for estimating reproductive risks for carriers of this class of complex chromosome rearrangement. The data presented describe six cycles for four couples where one partner has a three-way translocation. For male heterozygotes, 27.6% of embryos were consistent with 3:3 alternate segregation resulting in a normal or balanced translocation chromosome complement; 41.4% were consistent with 3:3 adjacent segregation of the translocations, comprising 6.9% reflecting adjacent-1 and 34.5% adjacent-2 segregation; 24.1% were consistent with 4:2 nondisjunction; none showed 5:1 or 6:0 segregation; the probable mode could not be ascertained for 6.9% of embryos due to complex mosaicism or nucleus fragmentation. The test accuracy for male heterozygotes was estimated to be 93.1% with 100% sensitivity and 75% specificity. With 72.4% prevalence, the predictive value was estimated to be 91.3% for an abnormal test result and 100% for a normal test result. Two of four couples had a healthy baby following PGD. The proportion of normal/balanced embryo could be significantly less for female heterozygotes, and our model indicates that this could be detrimental to the effectiveness of PGD. A 20% risk of live-born offspring with an unbalanced translocation is generally accepted, largely based on the obstetric history of female heterozygotes; we suggest that a 3% risk may be more appropriate for male carriers.

Chromothripsis: potential origin in gametogenesis and preimplantation cell divisions. A review

“…The advent of efficient techniques for fast in situ chromosomal detection and precise genome analysis has contributed to improve our understanding of CCR formation and etiology (3,4). Today, several laboratories propose preimplantation genetic diagnosis (PGD) procedures for couples with CCRs, thus offering an alternative to prenatal diagnosis and pregnancy termination (5)(6)(7)(8). The occurrence of CCRs also constitutes a feature of numerous cancers (9).…”

The influence of balanced complex chromosomal rearrangements on preimplantation embryonic development potential and molecular karyotype

“…E. Vanneste et al reported a couple in which the husband was an exceptional CCRs carrier with two PGT cycles, who had 4 balanced or normal embryos and 12 abnormal embryos [14] . Paul et al reported 4 couples, including 3 males and 1 female three-way rearrangements carriers with 6 PGT cycles, who had 6 euploid embryos and 31 aneuploid embryos [10] . Hu L et alreported 7 couples, including 5 couples with three-way rearrangements, who 6 had 3 balanced or normal embryos, 31 abnormal embryos and one embryo of amplification failure, and 1 couple with double two-way translocations, who had no balanced or normal embryos and 12 abnormal embryos [1] .…”

“…Therefore, recurrent spontaneous abortion, arrested intrauterine pregnancy (aIUP), fetal malformation and infertility often happen. In addition, male BCCR can also be observed as oligoasthenoterazoospermia and infertile [7,10] . It has been reported that the odds of balanced or normal embryos in couples with BCCR are <6% [1] .Preimplantation genetic testing(PGT) is performed before embryo transfer, and a small portion of cells will be aspirated for comprehensive chromosome screening to analyze embryos identified as balanced or normal for transplantation.…”

Familial 3-Way Balanced Translocation Causes 1q43&#x2192;qter Loss and 10q25.2&#x2192;qter Gain in a Severely Affected Male Toddler

“…Constitutional complex chromosomal rearrangements (CCRs) are relatively rare events [e.g., Berend et al, 2002;Scriven et al, 2014] that typically involve 2 or more chromosomes with at least 3 breakpoints and can result in normal or abnormal phenotypes depending on whether they entail imbalances, disrupt coding or regulatory regions, or somehow disturb the euchromatic neighborhood [Fukami et al, 2017]. CCRs often arise through well-known errors in replication or recombination that ultimately lead to the "accumulation" of DNA defects.…”

“…Familial CCRs often represent a challenge for genetic counseling since each rearrangement and its segregation are unique, leading to distinct reproductive risks for carriers. Healthy carriers with impaired reproduction might transmit the balanced CCR which may lead to an unbalanced karyotype [Pellestor et al, 2011, Rivera andDominguez, 2012;Scriven et al, 2014;Tulay et al, 2015]. Such imbalances may occur in one or more of the rearranged chromosomes and lead to phenotypes specific to one or more syndromes or unspecific phenotypes [e.g., Neira et al, 2012;Rivera and Dominguez, 2012].…”