Diagnostic testing for α‐globin gene disorders in a heterogeneous North American population

Adult hemoglobin is a heterotetramer composed of two α-globin chains and two β-globin chains (α2 β2 ), each of which contains a heme molecule capable of binding oxygen and facilitating oxygen transport. The α-globin chains are expressed from duplicated genes within a tandem gene cluster located on chromosome region 16p13.3. High-level expression of the α-globin genes commences early in fetal development and continues throughout life. The α-thalassemia syndromes are among the most single-gene disorders, resulting from decreased synthesis of α-globin chains or synthesis of functionally abnormal α-globin chains. These disorders are most common in South East Asia, but also occur in many other populations. The most common cause of α-thalassemia is gene deletions, of which more than seventy have been reported. In addition, a small but significant proportion of cases involve point mutations of the α-globin genes. Ideally, the diagnostic strategy should include allele-specific assays for commonly occurring deletions, as well as methods for detection of rare or novel deletions and point mutations. Here we provide an overview of the diagnostic methods available and our experience using these assays in a reference laboratory serving a heterogeneous at-risk population.