Segmental aneuploid hotspots identified across the genome concordant on reanalysis

Abstract

The aim of this study was to characterize a large set of full segmental aneuploidies identified in trophectoderm (TE) biopsies and evaluate concordance in human blastocysts. Full segmental aneuploid errors were identified in TE biopsies (n=2,766) from preimplantation genetic testing for aneuploid (PGT-A) cycles. Full segmental deletions (n=1,872; 66.1%) presented twice as many times as duplications (n=939; 33.9%), mapped more often to the q-arm (n=1,696; 61.3%), than the p-arm (n=847; 31.0%), or both arms (n=223; 8.1%; P<0.05), and were 8 times more likely to include the distal end of a chromosome than not (P<0.05). Additionally, 37 recurring coordinates (each≥10 events) were discovered across 17 different chromosomes, which were also significantly enriched for distal regions (P=4.1x10−56). Blinded concordance analysis of 162 dissected blastocysts validated the original TE PGT-A full segmental result for a concordance of 96.3% (n=156); remaining dissected blastocysts were identified as mosaic (n=6; 3.7%). Origin of aneuploid analysis revealed full segmental aneuploid errors were mostly paternally derived (67%) in contrast to whole chromosome aneuploid errors (5.8% paternally derived). Errors from both parental gametes were observed in 6.5% of aneuploid embryos when multiple whole chromosomes were affected. The average number of recombination events was significantly less in paternally derived (1.81) compared to maternally derived (3.81) segmental aneuploidies (P<0.0001). In summary, full segmental aneuploidies were identified at hotspots across the genome and were highly concordant upon blinded analysis. Nevertheless, future studies assessing reproductive potential of full (non-mosaic) segmental aneuploid embryos are critical to rule out potential harmful reproductive risks.

Insights into embryonic chromosomal instability: mechanisms of DNA elimination during mammalian preimplantation development

“…This mis-repair leads to DNA damage and segmental errors that may still impact implantation potential, resulting in a higher likelihood of miscarriage and reduced live birth rate if transferred ( Zore et al, 2019 ). Several studies have now shown that segmental aneuploidy is more often mitotic in origin, mostly paternally-derived, and tends to occur within distinct chromosomal regions ( Chavez et al, 2012 ; Babariya et al, 2017 ; McCarty et al, 2022 ; Palmerola et al, 2022 ). Regardless of whether whole and/or partial chromosomes are affected, the DNA will become subjected to further damage due to the fragility of the NE that encapsulates the mis-segregated material, which can have significant consequences for embryo development.…”