Genetic Spectrum of Hemoglobinopathies in Reproductive-Age Individuals from a Hospital-Based Cohort in Guangdong,...

Background: Hemoglobinopathies, including thalassemia and structural hemoglobin variants, are among the most prevalent inherited disorders worldwide and represent a major public health concern in southern China. Accurate characterization of both common and rare variants is essential for carrier screening, genetic counseling, and prevention. However, routine molecular screening is generally restricted to common pathogenic variants, potentially overlooking rare hemoglobinopathy subtypes. This study aimed to characterize the spectrum of hemoglobinopathies in a large hospital-based cohort of reproductive-age individuals from Guangdong, China, and to evaluate a genotype-phenotype discordance-guided secondary testing strategy. Methods: A retrospective hospital-based study was conducted in 71,676 reproductive-age individuals who underwent hemoglobinopathy screening at our hospital in Guangdong, China, between 2018 and 2024. Hematological and routine genetic analyses were performed in parallel. Cases exhibiting genotype-phenotype discordance were further investigated using tailored secondary molecular approaches selected according to specific hematological findings. Results: In this cohort, 10,412 hemoglobinopathies were identified. Thalassemia accounted for 10,217 cases (98.13%), including α-thalassemia (8026), β-thalassemia (2561), δβ-thalassemia (17), γ-thalassemia (10), and δ-thalassemia (4). Structural hemoglobin variants comprised 195 cases (1.91%). Among the 788 genotype-phenotype discordant cases, secondary analysis yielded a positive detection rate of 36.80% (290/788). Conclusions: This study provides large-scale hospital-based data on the distribution of hemoglobinopathies among reproductive-age individuals in Guangdong. Review of genotype-phenotype discordance improved the detection of rare variants beyond routine screening and may facilitate the development of tailored secondary testing strategies. Further studies are warranted to validate its clinical utility and applicability.