Thalassemia and erythroid transcription factor KLF1 mutations associated with borderline hemoglobin A(2) in the Thai population

INTRODUCTION: Elevated hemoglobin (Hb) A(2) is an important diagnostic marker for β-thalassemia carriers. However, diagnosis of cases with borderline Hb A(2) may be problematic. We described the molecular characteristics found in a large cohort of Thai subjects with borderline Hb A(2). MATERIAL AND METHODS: Examination was done on 21,657 Thai subjects investigated for thalassemia at Khon Kaen University, Thailand. A total of 202 subjects with borderline Hb A(2) (3.5–4.0%) were selectively recruited and hematological parameters were recorded. DNA variants in α-, β-, δ-globin, and Krüppel-like factor 1 (KLF1) genes were examined using PCR. RESULTS: Among 202 subjects, DNA analysis identified carriers of α(+)-thalassemia (n = 48; 23.8%), β-thalassemia (n = 22; 10.9%) and KLF1 mutations (n = 48; 23.8%). No molecular defect was observed in the remaining 84 (41.5%) subjects. Interaction of KLF1 and α-thalassemia was observed in 10 cases. Of the 22 β-thalassemia carriers, five β(+)-thalassemia mutations were identified with lower MCV and higher Hb A(2). Seven KLF1 mutations were detected in 10 genotypes in subjects with higher MCV and Hb F. No β(0)-thalassemia, α-globin gene triplication or δ-globin gene mutation was detected. CONCLUSIONS: A large proportion of subjects with borderline Hb A(2) are not β-thalassemia carriers and for those with β-thalassemia, only mild β(+)-thalassemia mutations were detected. Evaluation of the patients using Hb A(2), Hb F and MCV values will help in selecting cases for further molecular analysis. The results should explain the unusual phenotype of the cases and facilitate a thalassemia screening program in the region.