Molecular Landscape of Cases with Borderline HbA2 Levels in a Malaysian Tertiary Medical Centre

Thalassaemia is a prevalent genetic disease in Malaysia affecting up to 6% of the population. A rise in haemoglobin A2 (HbA2) of more than 4% is among the most important parameters for identification of β-thalassaemia carriers. However, some cases with the HbA2 levels in the borderline range between 3.0% to 3.9% has been shown to harbour α-, β-globin and/or Krüppel-like factor 1 (KLF1) gene abnormalities too. Here, we reported the results of molecular investigations on a group of subjects with borderline HbA2. A total of 45 subjects with borderline HbA2 levels in Hospital Canselor Tuanku Muhriz (HCTM) were identified from the hospital information system. Data of their full blood count using Sysmex XN-1000, and haemoglobin quantitation using Sebia Capillary Variant II were collected. Their DNA were investigated for the presence of locally common pathological mutations in the β-globin gene, deletions of the α-globin gene as well as screened for KLF1 gene mutation. This study found that 44% of the cases with borderline HbA2 in HCTM showed genetic abnormality at the molecular level comprising of β-globin gene mutation (29%), α-gene defect (9%), KLF1 gene abnormalities (4%) and coinheritance of α- and β-gene defect (2%). On the basis of our findings, we strongly suggest molecular methods consisting of β- and α-globin genes study to be considered in the investigation for haemoglobinopathies in the borderline HbA2 group of patients. Further study on KLF1 gene mutation test in our population is recommended to further characterise the common mutations of the gene.