Beta‐thalassaemia intermedia: is it possible consistently to predict phenotype from genotype?

Eighty-seven patients with β thalassaemia of intermediate severity were investigated in our Unit to determine whether it is possible to consistently predict phenotypic severity from genotypic factors. The subjects were from the following ethnic backgrounds: Asian Indian (35.1%), Middle Eastern (24.3%), Mediterranean (21.6%), Northern European (14.9%) and South-East Asian/Chinese (4.1%). There was a wide spectrum of phenotypic severity; 49 had mild disease, 22 moderate and 16 severe disease. 22/87 patients had inherited only a single copy of a β-thalassaemia allele, of whom 11 had also co-inherited triplicated α genes (ααα/αα or ααα/ααα) and seven had dominantly inherited β thalassaemia. In four of the heterozygotes no explanation was found for the thalassaemia-intermedia phenotype. 65/87 patients were homozygous or compound heterozygous for 26 mutations (40 genotypes) which ranged from very mild β+ to β° thalassaemia alleles. All patients with two mild or very mild β+ thalassaemia alleles had mild to moderate disease. Although concurrent inheritance of extra α genes with heterozygous β thalassaemia results in thalassaemia intermedia, the disease is mild. Co-inheritance of α thalassaemia as a modulating factor was not evident in this cohort of patients. Presence of the in-cis Xmn I-Gγ site was a modulating factor but insufficient to explain the high fetal haemoglobin levels encountered. In conclusion, apart from the two categories of triplicated α genes with heterozygous β thalassaemia and inheritance of mild β+ thalassaemia alleles, it was not possible to consistently predict phenotype from α and β genotypes alone, due to the influence of modulating factors, some implicated (such as inheritance of HPFH determinants) and others as yet unidentified.