Ensuring equity in reproductive carrier screening of CFTR with increasing population diversity

Carrier screening for cystic fibrosis (CF; CFTR gene) identifies individuals at risk of having affected children. Screening was originally developed for populations of European ancestry, in whom disease incidence is highest. Although current American College of Medical Genetics and Genomics (ACMG) guidelines endorse pan-ancestry screening using a 100-variant CFTR panel, it remains unclear whether targeted variant panels achieve equitable performance across ancestries.

Using national data from the Australian cystic fibrosis data registry (ACFDR; 3798 individuals), we assessed targeted CFTR assays relative to sequencing by estimating carrier screening sensitivity (proportion of CF-causing variants detected), yield (proportion of carriers detected) and post-test residual risk using modelling and international real-world data (RWD). Modelling incorporated pathogenic CFTR variant frequencies from CFTR2, gnomAD v4.1.0 (807,162 individuals) and ClinVar, across ten ancestry groups. RWD were derived from unselected carrier screening samples from >75 countries (362,000 individuals).

Panels of 25-50 variants initially captured ∼92-95% of CFTR variants in Australia, declining to ∼87-92% over ten years in parallel with demographic change. International RWD showed varying yields across self-reported ancestries: "Asian" (25-69%), "Black" (62-91%), "Middle Eastern" (51-55%), "Pacific Islander" (17-33%), "White (European)" (84-90%). Modelling demonstrated that equitable sensitivity and residual risk across ancestries requires ≥176 pan-ancestry variants, many recommended by expert panels and practice guidelines but absent from current ACMG recommendations.

Current CFTR variant panels remain calibrated primarily to variants common in European populations. Expanding panel content or transitioning to sequencing-based assays is necessary to ensure equitable carrier screening in increasingly diverse populations.