Comparing traditional and NGS-based screening strategies for thalassemia in a high-prevalence Hakka population: a population-based study

Abstract Thalassemia is one of the most common monogenic disorders in southern China, with the Hakka population exhibiting a distinct genetic profile. This study evaluated whether next-generation sequencing (NGS)-based universal screening offers advantages over traditional cascade screening in this specific population. We enrolled 91,857 reproductive-age individuals in Ganzhou, a high-prevalence Hakka region, comparing 37,500 participants who underwent traditional screening (2019–2021) with 54,357 who received NGS-based screening. NGS-based screening detected thalassemia carriers at a rate 4.74 times higher than traditional screening (15.05% vs. 3.18%), particularly identifying silent α-thalassemia and β ++ -thalassemia variants that were substantially under-detected by the traditional approach. Crucially, while traditional screening identified 98.7% of β‑high‑severity couples, it detected only 71.4% of α‑high‑severity couples and missed 28.6% of those at risk for Hb Bart’s hydrops fetalis, as well as 32.7% of couples at risk for severe non‑deletional Hb H disease. Traditional screening cost only USD 3.90 per person (versus USD 21.00 for NGS) and provided faster results (6.40 vs. 13.06 days). NGS-based universal screening provides a more accurate assessment of thalassemia burden and genotype diversity, offering critical advantages for prevention programs. Although traditional cascade screening is more cost-effective, its limited sensitivity for α-thalassemia variants leads to substantial underdetection. These findings underscore the need to tailor screening protocols to local epidemiological and genetic characteristics.