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

beta (o)-thalassaemia intermedia (beta (o)-TI) describes patients who lack beta -globin synthesis yet manifest a nontransfusion-dependent form of beta -thalassaemia. Co-inheritance of alpha -thalassaemia, certain variants of the beta -like globin gene cluster and elevated fetal haemoglobin (HbF) production are all associated with beta (o)-TI. However, the mild phenotypes of many beta (o)-TI patients are unexplained. Genetically determined HbF levels in beta -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 beta -thalassaemia, F-cell levels of 19 TI patients' relatives were compared with relatives of transfusion-dependent beta -thalassaemia major patients and those of beta -globin genotype-matched controls. The beta -globin and alpha -globin genotypes, as well as their (G)gamma promoter were also examined. Using this approach, in all but one patient the mild phenotype was attributable to either alpha -globin genotype, gamma -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 beta -thalassaemia.