Genetic interactions in thalassemia intermedia: Analysis of β‐Mutations, α‐Genotype, γ‐Promoters, and β‐LCR hypersensitive sites 2 and 4 in Italian patients

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Abstract
In order to verity the genetic factors influencing the clinical expression of β‐thalassemla we have studied 292 Kalian patients, 165 with thalassemia intermedia and 127 with thalassemia major. The β‐globin gene mutations were defined in all cases. The number of α‐globin genes and the integrity of specific control regions of the β‐globin cluster—γ promoters and β‐Locus Control Region (β‐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 end 24% in group II. Deletion type —α3.7 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 γ promoters and β‐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 γ C T change was found with an increased incidence in intermedia patients in groups II and III. A subset of 10 β‐thalassemia heterozygotes with mild intermedia phenotype resulted from coinheritance of a triplicated α‐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.