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

Carrier screening for recessive pathogenic variants using a pan-ethnic targeted common variant approach, independent of self-reported ancestry.

A national preconception screening programme enrolled 107,739 individuals from 33 ethnic groups, including 51,722 couples and 4,295 individuals tested independently, under a sequential strategy in which male partners were tested only when a pathogenic variant was found in the female partner. Carrier status was available for 76,317 individuals, of whom 30,475 (39.9%) carried at least one pathogenic variant; at-risk couples were identified in 1.15% of couples, rising to 10% in some ethnic groups. Risk increased with shared ancestry: 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 approach identified 11.9% more at-risk couples, with 26.8% of variants detected outside their historically associated population. Post-implementation analyses also flagged variants with limited yield, supporting periodic panel refinement.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The number to remember in clinic is the 26.8% of variants detected outside their expected population of origin: it makes ancestry-driven triage hard to defend in an admixed population, even though it remains standard practice in many laboratories. The sequential strategy is an economically sensible compromise, but it precludes any estimate of male carrier frequencies and misses at-risk couples in which only the male partner carries a variant absent from the panel. The operational message is not to expand the variant list indefinitely but to curate it: the authors themselves identify variants with no yield, and the quality of reference datasets for under-represented groups remains the true limiting factor.

Analysis by Dr Thibaut Benquey