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

Area of Science:

• Medical Genetics
• Preventive Medicine
• Population Health

Background:

• Preconception genetic screening is vital for identifying at-risk couples (ARCs) and informing reproductive choices.
• Increasing population admixture and next-generation sequencing challenge traditional ancestry-driven risk stratification.

Purpose of the Study:

• To evaluate the effectiveness of a pan-ethnic targeted common variant (TCV) screening approach for identifying ARCs in a genetically diverse population.
• To compare the TCV approach with traditional ethnicity-based screening strategies.

Main Methods:

• A national screening program involving 107,739 individuals from 33 ethnic groups.
• Sequential testing strategy: initial screening for all women, with male partner testing contingent on female carrier status for pathogenic variants (PVs).
• Carrier status determined for 76,317 individuals.

Main Results:

• 39.9% of tested individuals carried at least one PV; ARCs identified in 1.15% of couples, up to 10% in specific ethnic groups.
• The TCV approach identified 11.9% more ARCs than ethnicity-based screening, with 26.8% of variants found outside historically associated populations.
• Risk of ARCs was significantly higher in same-ancestry couples (5.72%) compared to mixed-ancestry couples (1.28%).

Conclusions:

• The TCV approach is a practical and effective screening model for genetically diverse populations, outperforming ethnicity-based methods in carrier and ARC detection.
• Continuous refinement of screening panels, inclusive reference datasets, and targeted outreach are crucial for maximizing the population impact of TCV screening.
• Findings support the TCV approach for widespread consideration in preconception genetic screening programs.