A context-specific evaluation of polygenic embryo screening in best-prognosis preimplantation genetic testing cycles

In best-prognosis preimplantation genetic testing (PGT) cycles-defined by the availability of multiple transferable embryos-can polygenic embryo screening (PES) provide meaningful, context-dependent stratification that may influence embryo prioritization?

In a sister-pair breast cancer validation cohort, the polygenic risk score (PRS) showed modest predictive performance, and when applied retrospectively to embryos, differences in modelled susceptibility were context-dependent, primarily influenced by the number of available embryos, parental polygenic risk profile, the limited discriminative power of the PRS, and the presence of disease-related monogenic variants.

The use of PES as an embryo-ranking tool within PGT remains controversial. Its potential utility depends on embryo availability and clinical context, yet empirical evaluations in real-world PGT settings remain limited.

This retrospective study combined (i) family-based validation using 184 affected-unaffected sisters, and (ii) embryo-level analysis of 310 PGT for monogenic disorders (PGT-M) cycles comprising 1722 embryos. Simulation modelling estimated differences in modelled embryo-level PRS percentile ranking under varying clinical and genetic scenarios.

Family-based performance of a breast cancer PRS was evaluated using affected and unaffected sister pairs. Embryo genotype data from PGT-M cycles were used to model PES under varying conditions, including the number of transferable embryos, the presence of pathogenic monogenic variants, and parental PRS percentile strata.

Within-family PRS discrimination was modest: sisters in the top 10% of the PRS distribution had 4.07-fold higher breast cancer odds than their siblings (95% CI: 1.55-6.33). In the PGT-M cohort, 55% of cycles produced ≥3 transferable embryos, with a median within-cycle spread of approximately 25 PRS percentiles. In BRCA1/2-related cycles, PRS did not introduce distinct risk strata but revealed dispersion in modelled susceptibility among embryos sharing the same monogenic background. Embryo PRS distributions were concordant with parental profiles: 71% of embryos from couples with parental PRS ≥80th percentile were classified as high-PRS, compared with 7% when at least one parent was ≤20th percentile. Simulation analyses indicated that PRS-based embryo prioritization was associated with a 12-point lower mean embryo PRS percentile compared with morphology-based embryo prioritization in PGT-M cycles, attenuating to 10 points when PGT-A was incorporated. These differences reflect a statistical surrogate outcome only and do not demonstrate reduction in lifetime disease incidence or other clinical benefits.

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These findings derive from high-prognosis PGT-M cycles and may not generalize to other PGT settings. Current PRS models have modest performance and variable transferability across ancestries. The retrospective design, limited subgroup sizes, and modelling assumptions (e.g. aneuploidy and sex distribution) further constrain interpretation. The primary simulation outcome-PRS percentile shift-is a hypothesis-generating surrogate endpoint, not a clinical outcome; clinical benefit was not assessed or demonstrated. These findings should not be interpreted as supporting routine clinical implementation of PES; premature use may increase parental anxiety, inequitable access, and pressure to rank embryos using predictions that remain unvalidated at the embryo level.

This study provides an empirical framework for evaluating the current limits of PES within PGT. The observed PRS percentile shifts appear concentrated in best-prognosis cycles with multiple transferable embryos and elevated parental PRS, whereas little change is observed when embryo numbers are limited or risk is dominated by high-penetrance monogenic variants. These findings are hypothesis-generating and may inform future prospective research and ethical discussion, while underscoring that clinical utility and implementation require further validation within appropriately governed settings.

This study was funded by Major Scientific Program of CITIC Group (No. 2023ZXKYB34100), the Science Foundation of Hunan Province (Grant 2023JJ30422), and Health Research Project of Hunan Provincial Health Commission (grant number: W20243089).

The authors declare no conflicts of interest.