Single-Tube Multiplex-PCR Screen for Anti-3.7 and Anti-4.2 α-Globin Gene Triplications

摘要

The coexistence of α-globin gene triplication (ααα) is an important modulator of the severity of β-thalassemia trait or β-thalassemia intermedia, exacerbating the phenotypic severity of β-thalassemia by causing more globin chain imbalance (1)(2). Typically, the inheritance of a single β-thalassemia allele is associated with mild anemia and hypochromic microcytic red cells. Compared with simple β-heterozygotes, co-inheritance of triplicated or quadruplicated α-globin genes in β-heterozygotes often leads to more significant anemia, splenomegaly, more pronounced red cell abnormalities, the presence of circulating normoblasts, higher hemoglobin F concentrations, and even the presence of inclusion bodies in erythroblasts (3)(4). Because the α- and β-globin gene clusters are physically unlinked and segregate independently, β-thalassemia carriers who also carry triplicated or quadruplicated α-globin genes have a 25% risk of having a similarly affected offspring, although their partners may be entirely normal.Triplicated α-globin genes appear to be ubiquitous and have been found in most populations (2). They result from misalignment and unequal crossover between the homologous X-, Y-, and Z-box segments of the α-globin gene cluster during meiosis (Fig. 1A? ). Generally, two types of triplicated alleles can be generated from an unequal crossover, αααanti3.7 and αααanti4.2. If the crossover occurs between the homologous Z2 and Z1 boxes, also referred to as a “rightward crossover”, this produces a ?α3.7 single-gene deletion allele and the reciprocal αααanti3.7 triplicated allele. However, if the crossover occurs between the X2 and X1 boxes (a “leftward crossover”), a ?α4.2 single-gene deletion allele and the reciprocal αααanti4.2 triplicated allele are generated (5).A Sri Lankan study of individuals with severe to moderate β-thalassemia revealed a 2% frequency of α-globin gene triplications (6), whereas a preliminary study in Hong Kong suggests that the frequency …