The molecular basis of beta-thalassemia intermedia in southern China: genotypic heterogeneity and phenotypic diversity

Background: The clinical syndrome of thalassemia intermedia (TI) results from the beta-globin genotypes in combination with factors to produce fetal haemoglobin (HbF) and/or co-inheritance of alpha-thalassemia. However, very little is currently known of the molecular basis of Chinese TI patients. Methods: We systematically analyzed and characterized beta-globin genotypes, alpha-thalassemia determinants, and known primary genetic modifiers linked to the production of HbF and the aggravation of alpha/beta imbalance in 117 Chinese TI patients. Genotype-phenotype correlations were analyzed based on retrospective clinical observations. Results: A total of 117 TI patients were divided into two major groups, namely heterozygous beta-thalassemia (n = 20) in which 14 were characterized as having a mild TI with the Hb levels of 68-95 g/L except for five co-inherited alpha alpha alpha(anti-3.7) triplication and one carried a dominant mutation; and beta-thalassemia homozygotes or compound heterozygotes for beta-thalassemia and other beta-globin defects in which the beta(+)-thalassemia mutation was the most common (49/97), hemoglobin E (HbE) variants was second (27/97), and deletional hereditary persistence of fetal hemoglobin (HPFH) or delta beta-thalassemia was third (11/97). Two novel mutations, Term CD+32(A -> C) and Cap+39 (C -> T), have been detected. Conclusions: Chinese TI patients showed considerable heterogeneity, both phenotypically and genotypically. The clinical outcomes of our TI patients were mostly explained by the genotypes linked to the beta- and alpha-globin gene cluster. However, for a group of 14 patients (13 beta(0)/beta(N) and 1 beta(+)/beta(N)) with known heterozygous mutations of beta-thalassemia and three with homozygous beta-thalassemia (beta(0)/beta(0)), the existence of other causative genetic determinants is remaining to be molecularly defined.