The role of heterocellular hereditary persistence of fetal haemoglobin in β0-thalassaemia intermedia

Abstract

β0-thalassaemia intermedia (β0-TI) describes patients who lack β-globin synthesis yet manifest a non-transfusion-dependent form of β-thalassaemia. Co-inheritance of α-thalassaemia, certain variants of the β-like globin gene cluster and elevated fetal haemoglobin (HbF) production are all associated with β0-TI. However, the mild phenotypes of many β0-TI patients are unexplained. Genetically determined HbF levels in β-thalassaemia are difficult to assess because erythrocytes containing HbF (F cells) preferentially survive over erythrocytes without HbF. To evaluate the importance of genetically elevated HbF in β-thalassaemia, F-cell levels of 19 TI patients' relatives were compared with relatives of transfusion-dependent β-thalassaemia major patients and those of β-globin genotype-matched controls. The β-globin and α-globin genotypes, as well as their Gγ promoter were also examined. Using this approach, in all but one patient the mild phenotype was attributable to either α-globin genotype, γ-globin promoter polymorphism or inherited elevated F-cell levels. The findings of this study establish the F-cell levels required to modify the degree of disease severity significantly and demonstrate that F-cell level is a crucial parameter in the understanding of phenotypic variation in β-thalassaemia.