Association of thalassaemia intermedia with a beta-globin gene haplotype

We have identified 14 Asian patients with homozygous β⁰ thalassaemia who had a mild clinical disorder related to an augmented production of haemoglobin F. None of their parents had an elevated level of Hb F. Restriction fragment length polymorphism analysis of the β-globin cluster of these patients and a control group of Asian thalassaemia major patients showed that 6/14 of the thalassaemia intermedia patients were homozygous for a particular 5' β-globin haplotype (- + - + +), in contrast to 1/42 of the thalassaemia major patients. Furthermore, the - + - + + β haplotype is also associated with amelioration of disease severity in β thalassaemia in an Italian population. This β haplotype is linked to a DNA sequence variation 5' (at position -158) to the (G)γ globin gene which can be detected by the presence (+) of an Xmn I restriction enzyme site. The possible role of the Xmn I-γ polymorphism in relation to this variant HPFH is discussed. We conclude that much of the observed clinical variability of β thalassaemia can now be explained by the inheritance of β thalassaemia chromosomes with different propensities for fetal haemoglobin production.