Pan-ethnic preconception screening: evidence from a large-scale programme in a genetically diverse population.

BACKGROUND

Preconception genetic screening is a key preventive strategy for identifying at-risk couples (ARCs) of inherited disorders and supporting informed reproductive decision-making. However, increasing population admixture and the widespread adoption of next-generation sequencing challenge the validity of ancestry-driven risk stratification.

METHODS

A total of 107 739 individuals participated in the national screening programme, including 51 722 couples and 4295 individuals tested independently, representing 33 ethnic groups. Under the sequential testing strategy, all women underwent initial screening, whereas male partners were tested only when a pathogenic variant (PV) was identified in the female partner. Consequently, carrier-status results were available for 76 317 individuals.

RESULTS

Among 76 317 individuals tested, 30 475 (39.9%) carried at least one PV. ARCs were identified in 1.15% of couples, reaching up to 10% in certain ethnic groups. Risk increased with shared ancestry, rising to 5.72% among same-ancestry couples versus 1.28% among mixed-ancestry couples (OR 4.69; 95% CI 3.70 to 6.01). Compared with ethnicity-based screening, the pan-ethnic targeted common variant (TCV) screening approach identified 11.9% more ARCs, with 26.8% of variants detected outside their historically associated populations. Postimplementation analyses also identified variants with limited yield, supporting periodic panel refinement.

CONCLUSION

The TCV approach improves carrier and ARC detection compared with ethnicity-based approaches and represents a practical screening model for genetically diverse populations. These findings support consideration of the TCV approach as a practical screening strategy in genetically diverse populations, with continuous panel refinement, inclusive reference datasets and targeted outreach to high-risk communities essential to maximising its population impact.