Relationship between Genotype and Phenotype: Thalassemia Intermediaa

Abstract

Thalassemia intermedia encompasses a number of clinical conditions ranging in severity from β‐thalassemia carrier state to transfusion‐dependent thalassemia major. The molecular bases of thalassemia intermedia, only partially defined, are very heterogeneous, but in general any factor able to reduce the globin‐chain imbalance results in a milder form of thalassemia. These factors are the presence of a silent or mild β‐thalassemia allele, associated with a high residual β‐globin production, and the coinheritance of α‐thalassemia or of genetic determinants that increase the γ‐chain production. Less frequent mechanisms are double heterozygosity for β‐thalassemia and triplicated α genes, and the presence of a hyperunstable hemoglobin variant. However, for a consistent number of β⁰‐thalassemia homozygotes with a thalassemia intermedia phenotype the modifying factor has not been defined yet. In contrast, there are simple β‐thalassemia carriers who, for unknown reasons, have an unusually severe clinical phenotype.