Equity in genome sequencing for rare disease diagnosis: a cross-sectional analysis of data from the UK 100,000 Genomes Project.

Dependence of prioritisation pipelines on poorly diversified allele frequency resources, corrected by ancestry-stratified allele frequency filters.

Automated pipelines narrow millions of variants per patient to a small subset for clinical review, relying on allele frequency resources that do not fully represent human genetic diversity. Among 29,405 rare disease probands in the UK 100,000 Genomes Project, the East African ancestry group had nearly three times more variants prioritised for clinical review than the European group (IRR 2.77, 95% CI 2.33-3.29), with other non-European groups also significantly higher. Diagnostic yield was similar across groups after adjustment, but prioritised variants were less likely to be recorded as diagnostic in East African (OR 0.32, 95% CI 0.22-0.46), West African (0.47, 0.39-0.57), South Asian (0.65, 0.58-0.73) and Middle Eastern (0.68, 0.54-0.86) groups. Applying ancestry-stratified allele frequency filters derived from an independent, diverse UK cohort (n = 33,724) removed 3.1% of prioritised variants overall and 24.3% in the East African group — including 29.5% of recorded variants of uncertain significance in that group — without loss of diagnostic sensitivity.

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

The number to remember is not the inequity, already documented, but the fact that a simple change of allele frequency filter removes a quarter of the review burden for one ancestry group with no loss of sensitivity: this is a correction implementable today in any prioritisation pipeline, with no new technology and no re-sequencing. The excess of variants of uncertain significance in non-European patients is not a biological fact but an artefact of our reference databases — paid for in interpretation time for the laboratory and in uncertainty returned to families. The prerequisite, a diverse reference cohort, remains out of reach for many centres, and that is the real work ahead.

Analysis by Dr Thibaut Benquey