Borderline HbA 2 levels: Dilemma in diagnosis of beta-thalassemia carriers

• Published in: Mutation research. Reviews in mutation research 2021-07, Vol.788, p.108387
• Main Authors: Colaco, Stacy, Nadkarni, Anita
• Format: Article
• Language: English
• Subjects: beta-Thalassemia - blood; beta-Thalassemia - diagnosis; beta-Thalassemia - genetics; Genetic Carrier Screening - methods; Genetic Carrier Screening - standards; Hemoglobins, Abnormal - genetics; Humans
• ISSN: 1388-2139

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