Phenotype-genotype relationships in monogenic disease: Lessons from the thalassaemias

The remarkable phenotypic diversity of the beta -thalassaemias reflects the heterogeneity of mutations at the beta -globin locus, the action of many s econdary and tertiary modifiers, and a wide range of environmental factors. It is likely that phenotype-genotype relationships will be equally complex in the case of many monogenic diseases. These findings highlight the probl ems that, might be encountered in defining the relationship between the gen ome and the environment in multifactorial disorders, in which the degree of heritability might be relatively low and several environmental agents are involved. They also emphasize the value of an understanding of phenotype-ge notype relationships in designing approaches to gene therapy.