INTRODUCTION

The β thalassemias and related disorders are characterized by a quantitative reduction in the production of β-globin chains of HbA. More than 200 β thalassemia alleles have now been characterized (http://globin.cse.psu.edu) involving mutations affecting any of the steps in the transcription of the β-globin gene, posttranscriptional processing of its pre-mRNA, or the translation of its mRNA into protein. The vast majority of simple β thalassemias are caused by point mutations within the gene or its immediate flanking sequences, although small deletions involving the β gene may also occur. If β-chain production is totally abolished by the mutation it is referred to as β0 thalassemia, whereas reduced output of β-chains (of normal structure) produces β+ thalassemia, with the mildest forms sometimes referred to as β++ or “silent” β thalassemia. These common forms of β thalassemias are inherited as haploinsufficient mendelian recessives.

Some structurally abnormal β-chain variants are also associated with quantitative deficiencies of β-globin chain production and have a phenotype of β thalassemia, in which case they are referred to as “thalassemic hemoglobinopathies,” for example, HbE (β26 Glu→Lys). In others, the β-globin variants are so unstable that they undergo very rapid postsynthetic degradation giving rise to a functional deficiency. These hyperunstable β-chain variants act in a dominant negative fashion, causing a disease phenotype even when present in the heterozygous state, and hence have been referred to as “dominantly inherited β thalassemia.” β Thalassemia mutations that segregate independently of the β-globin cluster have been described in occasional families.