Significance of borderline HbA2 levels in β thalassemia carrier screening

Abstract

Increased HbA₂ levels are the characteristic feature of β-thalassemia carriers. A subset of carriers however do not show HbA₂ levels in the typical carrier range (≥ 4.0%) but show borderline HbA₂ levels. As a result, these carriers escape diagnosis and carry the risk of having β-thalassemia major offspring. Borderline HbA₂ values may occur as a consequence of mild β-thalassemia mutations, co-inherited β-thalassemia and α- or δ- thalassemia or iron deficiency anemia. However, there is insufficient knowledge regarding the cause of borderline HbA₂ levels in specific populations. This study aimed to identify the determinants of borderline HbA₂ levels (which we have considered as HbA₂ 3.0–3.9%) in 205 individuals. Primary screening involved detecting the presence of iron deficiency anemia followed by molecular analysis of α, β and δ globin genes. Remarkably, 168 of 205 individuals were positive for a defect. 87% (149/168) of positive individuals were heterozygous for β thalassemia with (59/149) or without (90/149) the presence of co-existing IDA, α or δ gene defects. Notably, 20 of 149 β thalassemia carriers showed HbA₂ < 3.5% and MCV > 80fL. 7 of these 20 carriers were married to carriers of hemoglobinopathies. Our findings describe the genetic basis of borderline HbA₂ levels and emphasize the necessity of a molecular diagnosis in these individuals in the routine clinical setting.