Genotype-Specific Hematologic Signatures Across α-Globin Defect Categories in α-Thalassemia.

Abstract

Alpha-thalassemia is a genetically and clinically heterogeneous hemoglobin disorder caused by deletions or mutations of the α-globin genes (HBA1 and HBA2) on chromosome 16. We aimed to evaluate the hematologic impact of single- and multiple-α-globin gene deletions and to characterize genotype-related laboratory phenotypes in α-thalassemia carriers. This retrospective study included 599 individuals aged 18-64 years: 229 in the genotype-negative comparison group and 370 genetically confirmed α-thalassemia carriers with diverse mutation profiles. Participants were categorized into five groups by genotype: Group I, genotype-negative comparison group; Group II, carriers of the -^3.7kb deletion; Group III, carriers of the Constant Spring (CS) mutation; Group IV, carriers of the --^SEA deletion; and Group V, individuals with compound or more severe genotypes, including -α^3.7/-α^4.2, --^SEA, and HbH-related genotypes. Significant intergroup differences were observed in hematologic parameters. The -α^3.7 and Hb Constant Spring groups had relatively preserved MCV and MCH values compared with the --^SEA and compound/HbH-related groups. The --^SEA group showed a microcytic erythrocytosis pattern, whereas the compound/HbH-related group showed the most pronounced hematologic disturbance. In conclusion, distinct α-globin genotype groups and defect categories are associated with markedly different hematologic phenotypes. Although the molecular mechanisms underlying these differences remain incompletely understood, deletional burden and genotype complexity appear to have clinically meaningful effects on red cell indices. Integrating molecular genotyping with hematologic profiling may therefore improve diagnostic interpretation and genotype-phenotype assessment in α-thalassemia.