P-557 Origin of segmental aneuploidy in preimplantation development: Studying >100 IVF embryos reveal novel mechanisms akin to cancer cells with a possible intrachromosomal effect

Study question What are the mechanisms underlying segmental aneuploidy (SA) in preimplantation human embryos, and to what extent is there concordance between germ cell layers? Summary answer Segmental aneuploidy (SA) in IVF embryos predominantly arises from paternal meiotic errors, exhibiting deletion-duplications, inversions, and chromothripsis-like mechanisms, with rare SA concordance observed What is known already Segmental aneuploidy (SA) involves the gain or loss of chromosomal segments rather than entire chromosomes, leading to significant embryonic consequences such as implantation failure, spontaneous abortion, and congenital abnormalities. Identified in about 7% of aneuploid biopsies during preimplantation genetic testing for aneuploidy (PGT-A) and preimplantation genetic testing for structural rearrangements (PGT-SR), SA arises from chromosomal breakage and recombination during meiosis or early cleavage. These structural abnormalities disrupt gene dosage, potentially resulting in non-disjunction events or abnormal recombination, which affect normal embryonic development. Understanding SA mechanisms is crucial for improving outcomes in both natural conception and assisted reproductive technologies (ART). Study design, size, duration This single-centre retrospective study examined 101 blastocysts identified as aneuploid with segmental aneuploidy (SA) via a validated NGS-based PGT-A protocol. The protocol enables precise identification of the parental origin of SA (paternal or maternal) by integrating genotyping data with chromosomal copy number variation analysis. This method enhances understanding of SA mechanisms and their implications, contributing valuable insights into embryonic development and improving assisted reproductive technology (ART) outcomes. Participants/materials, setting, methods The participants in this study were couples undergoing IVF cycles with PGT-A from 2020–2024. Ethical approval was secured from IRAS (#294909) and HFEA licence (#R0208). Segmental aneuploidy (SA) was identified in embryos post-PGT-A. Participants provided cheek swabs for parental DNA analysis, and embryo biopsies included samples from the inner cell mass (ICM) and two trophectoderm (TE) biopsies. This approach enabled comprehensive analysis of SA origin and patterns in the context of preimplantation development. Main results and the role of chance In our analysis of a cohort exceeding 100 cases of segmental aneuploidy (SA), we examined both two trophectoderm (TE) biopsies and the inner cell mass (ICM) from each embryo. We frequently observed complex SA aneuploidies characterized by combinations of deletions, duplications, inversions, isochromosomes, and ring chromosomes, often localized to a single chromosome, with a notable prevalence of paternal errors. Interestingly, while mosaicism typically suggests post-zygotic origins, evidence from our data indicates meiotic origins for some cases, supporting the concept of “SA rescue,” where specific chromosomes can be restored to euploidy—a phenomenon not commonly associated with whole chromosome aneuploidy. Furthermore, unlike the typical concordance seen in whole chromosome aneuploidy, perfect concordance of SA abnormalities among the three sampled regions was rare. We identified an “intrachromosomal effect,” where additional SA abnormalities on the same chromosome were maintained across the biopsies, possibly related to chromothripsis. These observed patterns bear resemblance to chromosomal instability seen in cancer, leading to the hypothesis that tumor-like mechanisms might influence SA development during preimplantation human embryogenesis. Overall, while the study’s design minimizes chance influences, variability in SA manifestations calls for cautious interpretation of these complex genetic phenomena. Limitations, reasons for caution Limitations of this study include its retrospective and single-centre design, which may affect generalizability. The use of cheek swabs for parental DNA analysis might not capture full genetic variability, and biases could arise from sample handling and mosaicism. Further multicentre research is needed to validate the findings. Wider implications of the findings This study helps us inform future PGT strategies, it highlights the need to screen for (and, where possible reduce) chromosome breakage/DNA damage in IVF cases. It provides novel insight into the mechanisms of chromosome behaviour in early human development. It introduces novel concepts hitherto unreported in this context. Trial registration number No