High efficiency of thalassemia prevention by next-generation sequencing: a real-world cohort study in two centers of China

The occurrence of severe thalassemia, an inherited blood disorder that is either blood-transfusion-dependent or fatal, can be mitigated through carrier screening. Here, we aim to evaluate the effectiveness and outcomes of pre-conceptional and early pregnancy screening initiatives for severe thalassemia prevention in a diverse population of 28,043 women. Using next-generation sequencing (NGS), we identify 4,226 (15.07%) thalassemia carriers across 29 ethnic groups and categorize them into high- (0.75%), low- (25.86%), and unknown-risk (69.19%) groups based on their spouses' screening results. Post-screening follow-up reveals 59 fetuses with severe thalassemia exclusively in high-risk couples, underscoring the efficacy of risk classification. Among 25,053 live births over 6 months of age, two severe thalassemia infants were born to unknown-risk couples, which was attributed to incomplete screening and late NGS-based testing for a rare variant. Notably, 64 rare variants are identified in 287 individuals, highlighting the genetic heterogeneity of thalassemia. We also observe that migrant flow significantly impacts carrier rates, with 93.90% of migrants to Chenzhou originating from high-prevalence regions in southern China. Our study demonstrates that NGS-based screening during pre-conception and early pregnancy is effective for severe thalassemia prevention, emphasizing the need for continuous screening efforts in areas with high and underestimated prevalence.