Key Points KLF1 mutations cause severe congenital hemolytic anemia associated with a deficiency of red cell pyruvate kinase. A severe KLF1 deficiency causes hereditary persistence of embryonic globin synthesis.

Up to now, more than 200 different β-thalassemia (β-thal) mutations have been characterized. The majority are point mutations causing expression defects. Only approximately 10.0% of the defects are caused by large deletions involving the β-globin gene cluster causing β(0)-thal, (δβ)(0)-thal, (G)γ((A)γδβ)(0)-thal and other conditions with or without persistence of fetal hemoglobin (Hb). For the prevention of severe forms of β-thal intermedia and β-thal major, it is important to identify carriers of point mutations as well as carriers of deletions. β-Thalassemia and related disorders are most commonly present among populations from all Mediterranean countries as well as Southeast Asia, India, Africa, Central America and the Middle East. Twelve relatively frequently occurring deletion types have been described involving the β-globin gene cluster. These include the 105 bp β(0)-thal deletion, the 619 bp deletion, the 3.5 kb deletion, the Southeast Asian (SEA) deletion, the Filipino deletion, Hb Lepore, the Thai (δβ)(0)-thal, the Siriraj J (G)γ((A)γδβ)(0)-thal, the Chinese (G)γ((A)γδβ)(0)-thal, the Asian Indian deletion-inversion (G)γ((A)γδβ)(0)-thal as well as the (hereditary persistence of fetal hemoglobin) HPFH-6 and HPFH-7 deletions. To improve the rapid detection of the eight common β-globin cluster deletions in Southeast Asian countries, a simple molecular technique based on a single-tube multiplex gap-polymerase chain reaction (PCR) has been developed in this study. This technique provides a fast, simple and cost effective diagnostic test for deletion types of β-thal that can be applied in every molecular diagnostic laboratory having standard PCR equipment.

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Alpha thalassemia is the most common genetic disease in the world with the prevalence of carriers ranging from 5-50% in several populations. Coinheritance of two defective α-globin genes usually gives rise to a symptomatic condition, hemoglobin (Hb) H disease. Previously, it has been suggested from several studies in different populations that nondeletional Hb H disease (--/α^Tα or --/αα^T) is generally more severe than the deletional type (--/-α). In this report, we describe four rare nondeletional α-thalassemia mutations in Thai individuals, including initiation codon mutation (HBA2:c.1delA), donor splice site mutation (IVSI-1, HBA1:c.95 + 1G>A), Hb Queens Park (HBA1:c.98T>A) [α32(B13)Met>Lys], and Hb Westmead (HBA2:c.369C>G) [α122(H5)His>Gln]. Interactions of the first three mutations with the α⁰-thalassemia resulted in nondeletional Hb H disease; however, their clinical presentations were rather mild and some were detected accidentally. This suggests that a genotype-phenotype correlation of α-thalassemia syndrome might be more heterogeneous and so the type of mutation does not simply imply the prediction of the resulting phenotype. Our data will be of use in future genetic counseling of such conditions that are increasingly identified thanks to the improvement of molecular analysis in routine laboratories.

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