Genotype-phenotype correlations in beta-thalassemias

Abstract

In this paper we review the molecular basis of the marked heterogeneity of the thalassemia syndromes as well as the relative implications for carrier screening and prenatal diagnosis. The classical phenotype of heterozygous beta-thalassemia may be modified by a number of environmental and genetic interacting factors--among which the most relevant are: (1) coinheritance of alpha-thalassemia, which may normalize the red blood cell indices; (2) the presence of a mild beta-thalassemia mutation; (3) cotransmission of delta-thalassemia which may reduce the increase of HbA2 typical of heterozygous beta-thalassemia to normal values and (4) the presence of a silent mutation which can be defined only by imbalanced beta-globin chain synthesis. A number of molecular mechanisms are able to produce the non transfusion dependent attenuated forms of thalassemia syndromes referred to as thalassemia intermedia. The most common are homozygosity for mild beta-thalassemia mutations, coinheritance with homozygous beta-thalassemia of alpha-thalassemia or genetic determinants able to sustain a continuous production of HbF in adult life or the presence of heterozygosity for hyperunstable globin variants.