Borderline HbA2 levels: Dilemma in diagnosis of beta-thalassemia carriers

There is inconsistency in the exact definition of diagnostic levels of HbA(2) for beta thalassemia trait. While many laboratories consider HbA(2) >= 4.0 % diagnostic, still others consider HbA(2) >= 3.3 % or HbA(2) >= 3.5 % as the cut-off for establishing beta thalassemia carrier diagnosis. This is because, over the years, studies have described beta thalassemia carriers showing HbA(2) levels that lie above the normal range of HbA(2) but below the typical carrier range of beta thalassemia. These, borderline HbA(2) levels, though not detrimental to health, are significant in beta thalassemia carrier diagnosis because they can lead to misinterpretation of results. In this review, we have evaluated the prevalence of borderline HbA(2) levels and discussed the causes of borderline HbA(2) values. We have also compiled an extensive catalogue of beta globin gene defects associated with borderline HbA(2) levels and have discussed strategies to avoid misdiagnosing borderline HbA(2) beta thalassemia carriers. Our analysis of studies that have delineated the cause of borderline HbA(2) levels in different populations shows that 35.4 % [626/1766] of all individuals with borderline HbA(2) levels carry a molecular defect. Among the positive samples, 17 % [299/1766] show beta globin gene defects, 7.7 % [137/1766] show alpha thalassemia defects, 2.7 % [49/1766] show KLF1 gene mutations, 2.3 % [41/1766] show the co-inheritance of beta and alpha thalassemia, 2.0 % [37/1766] show the co inheritance of beta and delta thalassemia and 1.8 % [32/1766] show alpha globin gene triplication. It appears that a comprehensive molecular work up of the beta globin gene is the only definite method to detect borderline HbA(2) beta thalassemia carriers, especially in populations with a high prevalence of the disease. The presence of associated genetic or acquired determinants may subsequently be assessed to identify the cause of borderline HbA(2).

Automated summary

There is inconsistency in the exact definition of diagnostic levels of HbA(2) for beta thalassemia trait. Among individuals with borderline HbA(2) levels, 35.4% carry a molecular defect, highlighting the importance of a comprehensive molecular work up for accurate diagnosis of borderline HbA(2) beta thalassemia carriers.