Elevated Hb A₂ is Not Always Indicative of β-Thalassemia

Hb A₂ levels are usually high in carriers of β-thalassemia (β-thal). These levels also provide a sensitive marker for the identification of hemoglobin (Hb) variants. In this study, we aimed to examine two patients from two Chinese families who showed elevated Hb A₂ levels but did not show any signs of β-thal. The HBB variants were analyzed using direct sequencing of HBB and in silico prediction analysis. Moreover, the family's genetic history was investigated. We examined two probands from different Chinese families with elevated Hb A₂ levels who were not afflicted with β-thal, although several nucleotide changes were found at codon 81 (CTC>CTA) (HBB: c.246C>A) in Family 1 and a compound heterozygosity for codon 40 (AGG>AAG) (HBB: c.122G>A) and IVS-II-478 (C>A) (HBB: c.316-373C>A) in Family 2. After investigating the genetic history of both families including the β-thal aspect, we found that these mutations were not responsible for the elevated Hb A₂ levels. It is rarely reported that high Hb A₂ level is not indicative of β-thal. In contrast, low or normal Hb A₂ level is always found with β-thal due to other molecular defects that mask their β-thal genotype. Our results highlight the importance of considering the genetic factors related and unrelated to β-thal to improve the accuracy of future genetic counseling.