EP472: Deriving risk estimates for balanced rearrangement carriers utilizing PGT-SR data

Abstract

Parental balanced rearrangements (PBRs) are identified in approximately 4% of couples with recurrent pregnancy loss compared to 0.2% in the general population. PBR carriers are typically healthy, as little or no chromosomal material is lost or gained; however, they are at increased risk of creating unbalanced embryos that can result either in miscarriage or in the birth of a child with health problems and/or birth defects. Currently, most couples carrying PBRs are counseled based on risk estimates from either gamete studies (sperm/ova) or rates of miscarriage and/or abnormal live births. Preimplantation genetic testing for structural rearrangements (PGT-SR) can be performed for many types of PBRs, with detection dependent on the specific chromosome breakpoints and the testing technology used. Using data from PGT-SR cycles can generate risk estimates that are more informative for the IVF community regarding success rates for PBR couples. Trophectoderm biopsies were analyzed using a modified FAST-SeqS NGS-based PGT method and bioinformatics pipeline, which detects whole chromosome and segmental aneuploidies (≥10Mb), most types of polyploidy, and many instances of single chromosome uniparental isodisomy. A retrospective analysis of all embryo biopsies from patients with an identified PBR from September 2015 to March 2021 was performed to analyze rates of abnormalities derived from the PBR [derivative chromosomes and whole-chromosome aneuploidy of the involved chromosome(s)]. A total of 238 patients, with 380 PGT-SR cycles, were analyzed. The largest cohort, carrying reciprocal translocations, included 172 patients with 280 cycles (50.6% maternal, 49.4% paternal). The observed rates of derivative abnormalities were similar between the two groups (58.51% maternal vs. 50.41% paternal). Robertsonian translocations were documented in 50 patients with 81 cycles (48.0% maternal, 52.0% paternal). Unlike reciprocal translocations, we observed a clear increase in derivative abnormalities from maternally-derived rearrangements (36.4% vs. 18.2%), with the most striking difference seen with rob(14;21) carriers (n=9; 36.4% maternal vs. 3.1% paternal). Finally, sixteen patients (19 cycles) carried inversions, with eleven pericentric and five paracentric inversions represented. Similar to Robertsonian translocations, we observed an increase in derivative abnormalities when the pericentric inversion was maternally-derived (34.4% vs. 17.7%). Unexpectedly, a single paternally-derived paracentric inversion, inv(3)(q26.1q29), produced 37.5% blastocyst-stage derivative-abnormal embryos. Overall, as expected from the literature, derivative-abnormal rates from PBRs are highest for reciprocal translocation carriers, followed by Robertsonian translocations and inversions. While gamete studies have shown a higher rate of abnormalities in maternally-derived translocations, our abnormal rates were similar between the two parent-of-origin groups. In contrast, there is a clear parent-of-origin effect for both Robertsonian translocations and inversions. In all PBR types, abnormal rates are lower than those observed in gametes, likely due to decreased viability of abnormal embryos even before the blastocyst stage. These rates, derived from the largest published cohort to date, can be a valuable tool in counseling patients with PBRs regarding the potential success of their IVF journey.