GENOTYPE-PHENOTYPE CORRELATIONS IN BETA-THALASSEMIAS

In this paper we review the molecular basis of the marked heterogeneit y of the thalassemia syndromes as well as the relative implications fo r carrier screening and prenatal diagnosis. The classical phenotype of heterozygous beta-thalassemia may be modified by a number of environm ental and genetic interacting factors-among which the most relevant ar e: (1) coinheritance of alpha-thalassemia, which may normalize the red blood cell indices; (2) the presence of a mild beta-thalassemia mutat ion; (3) cotrasmission of delta-thalassemia which may reduce the incre ase 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 mechani sms are able to produce the non transfusion dependent attenuated forms of thalassemia syndromes referred to as thalassemia intermedia. The m ost common are homozygosity for mild beta-thalassemia mutations, coinh eritance with homozygous beta-thalassemia of alpha-thalassemia or gene tic determinants able to substain a continuous production of HbF in ad ult life or the presence of heterozygosity for hyperunstable globin va riants.