Beta-thalassaemia

Abstract

A complete spectrum of genetic lesions affecting the beta-globin gene giving rise to a complete spectrum of phenotypic severity is described. Although most of the molecular lesions involve the structural beta gene directly, some down regulate the gene through in-cis effects at a distance while trans-acting factors are implicated in a few cases. The remarkable phenotypic diversity can be related ultimately to the degree of alpha-globin-beta-globin chain imbalance and arises from variability of mutations affecting the beta gene itself and from interactions with other genetic loci, such as the alpha- and gamma-globin genes. The presence of other interacting loci is implicated by their interactions in increasing gamma gene expression or by an increased proteolytic capacity of the erythroid precursors. It is hoped that observations from the genotype-phenotype relationship might form the basis for a comprehensive diagnostic database that will be useful not only for genetic counselling and prenatal diagnosis but also for providing prognostic information for decision making in bone marrow transplantation and gene therapy programmes in the future. However, it is clear from recent analyses that, apart from the two categories of triplicated alpha genes with heterozygous beta-thalassaemia and inheritance of mild beta(+)-thalassaemia alleles, it is still not possible to predict consistently phenotype from alpha and beta genotypes alone owing to the influence of the other modulating factors, some implicated (such as inheritance of hereditary persistence of fetal haemoglobin) and others as yet unidentified.