RELATIONSHIP BETWEEN THE SEVERITY OF BETA-THALASSEMIA SYNDROMES AND THE NUMBER OF ALLEVIATING MUTATIONS

Thalassaemia intermedia, defined as homozygous beta-thalassaemia in wh ich patients are not transfusion-dependent, covers a wide range of cli nical severity. It may arise because one or more genetic factors ameli orate the otherwise severe phenotype of thalassaemia major. Exactly wh ich and how many such mutations are necessary to produce a thalassaemi a intermedia phenotype is incompletely understood, although such infor mation would be useful both clinically and for prenatal diagnosis. We examined DNA from 28 patients with thalassaemia intermedia resident in London and 28 matched patients with thalassaemia major, for 3 types o f genetic modifying factors, namely; mild beta-thalassaemia mutations, the upstream XmnI G-gamma globin gene polymorphism, and alpha-globin gene deletions. The results show that the number of alleviating mutati ons present has a large influence on the phenotype of patients with ho mozygous beta-thalassaemias, A single alleviating mutation was present in 56% of thalassaemia intermedia subjects compared with 26% of thala ssaemia major subjects. Two alleviating mutations were present in 33% of thalassaemia intermedia subjects compared with 1 thalassaemia major subject. No patients with thalassaemia major had 3 alleviating mutati ons, in contrast to 11% of those with thalassaemia intermedia. Althoug h the findings did not account for the full range of phenotypic variat ion, such information is of potential value both in the clinical manag ement and the prenatal diagnosis of homozygous beta-thalassaemia.