Genetic and Molecular Analysis of Mild Forms of Homozygous β‐Thalassemia

Despite the remarkable progress that has been made in determining the molecular basis for many forms of thalassemia, relatively little is known about the mechanisms that underlie their phenotypic diversity. This is an important aspect of the thalassemia problem because, as well as providing a valuable opportunity to increase our understanding of molecular pathophysiology, it has major practical implications. For example, with the widespread application of prenatal diagnosis for the prevention of the thalassemias, it is becoming increasingly important to understand the molecular basis for the difference in the clinical course of patients who are apparently hornozygous for P-thalassemia. For although this condition is usually characterized by severe anemia and transfusion dependence from early life, in most populations there is a significant number of individuals who, although they appear to have received a pthalassemia gene from both parents, have a much milder clinical condition, a condition rather loosely termed /3-thalassemia intermedia. Clearly, if we are to develop more rational prenatal diagnosis programs, we shall have to learn how to anticipate these mild phenotypes. Here we shall review what is known about the factors that can modify the clinical course of homozygous 0-thalassemia. It is concluded that, although there are several complex genetic and environmental interactions involved, it may be possible to define a few of the most important genetic factors, at least in some populations.