Genetic interactions in thalassemia intermedia : analysis of beta-mutations, alpha-genotype, gamma-promoters, and beta-LCR hypersensitive sites 2 and 4 in Italian patients

In order to verify the genetic factors influencing the clinical expression of \u3b2-thalassemia we have studied 292 Italian patients, 165 with thalassemia intermedia and 127 with thalassemia major. The \u3b2-globin gene mutations were defined in all cases. The number of \u3b1-globin genes and the integrity of specific control regions of the \u3b2-globin cluster-\u3b3 promoters and \u3b2-locus Control Region (\u3b2-LCR)-were studied in selected cases. Homozygosity for mild mutations (group I) accounts for 24% of the intermedia patients and it is not represented among major patients. Forty-four percent of intermedia patients had combinations of mild/severe (group II) mutations and 32% had homozygosity or double heterozygosity for severe mutations (group III). Seventy-six percent of patients with thalassemia major were classified in group III and 24% in group II. Deletion type -\u3b1 3.7 thalassemia, assessed in a part of the cases, was found in 5% of thalassemia major and 19.5% of intermedia patients in groups II and III. Structural analysis of \u3b3 promoters and \u3b2-LCR HS2 and HS4 regions, carried out in order to look for alterations associated with Hb F increase, did not reveal new mutations. Only rare polymorphic changes were observed at the HS2 and HS4 level. The -158 (G)\u3b3C T change was found with an increased incidence in intermedia patients in groups II and III. A subset of 10 \u3b2-thalassemia heterozygotes with mild intermedia phenotype resulted from coinheritance of a triplicated \u3b1-locus. We have been unable to find a molecular basis for the benign clinical course in approximately 20% of patients with thalassemia intermedia. Other genetic or acquired factors must be hypothesized which ameliorate the clinical condition