beta-thalassaemia

A complete spectrum of genetic lesions affecting the beta-globin gene givin g rise to a complete spectrum of phenotypic severity is described. Although most of the molecular lesions involve the structural beta gene directly, s ome down regulate the gene through in-cis effects at a distance while trans -acting factors are implicated in a few cases. The remarkable phenotypic di versity can be related ultimately to the degree of alpha-globin-beta-globin chain imbalance and arises from variability of mutations affecting the bet a gene itself and from interactions with other genetic loci, such as the al pha- and gamma-globin genes. The presence of other interacting loci is impl icated by their interactions in increasing gamma gene expression or by an i ncreased 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 g enetic counselling and prenatal diagnosis but also for providing prognostic information for decision making in bone marrow transplantation and gene th erapy programmes in the future. However, it is clear from recent analyses t hat, apart from the two categories of triplicated alpha genes with heterozy gous 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 factor s, some implicated (such as inheritance of hereditary persistence of fetal haemoglobin) and others as yet unidentified.