Molecular, haematological and clinical studies of the −101 C → T substitution of the β-globin gene promoter in 25 β-thalassaemia intermedia patients and 45 heterozygotes

We report the clinical, haematological, biosynthetic and molecular data of 25 double heterozygote β-thalassaemia intermedia patients and 45 β-thalassaemia heterozygotes with the C → T substitution at nucleotide position −101 from the Cap site, in the distal CACCC box of the β-globin gene promoter. This mutation is considered the most common amongst the silent β-thalassaemia mutations in Mediterranean populations. Of the 25 compound heterozygotes for the β−101 C → T and common severe β-thalassaemia mutations, all but one had mild thalassaemia intermedia preserving haemoglobin levels around 9.5 g/dl and haemoglobin F levels < 25%. The only transfused patient was characterized to have an additional α-globin gene.

Strict assessment of haematological and biosynthetic findings in the heterozygotes for the β−101 C → T mutation (excluding six cases with an α-globin gene defect) demonstrated that less than half of them had completely normal (silent) haematology; the remainder had either high haemoglobin A₂ values (in the range of 3.7–5.1%) and/or low red cells indices and/or raised haemoglobin F values. The α/non-α-globin chain synthesis ratios were generally raised, with mean 1.44 (1.07–2.10). Amongst the parents of the compound heterozygotes, who were not selected for molecular analysis following haematological screening, half of the cases were completely silent.

Interaction with severe β-thalassaemia mutations always resulted in the clinical phenotype of mild non-transfusion-dependent thalassaemia intermedia.