Severity ranking of non-deletional alpha thalassemic alleles: Insights from an Omani family study

In an Omani family, four different alpha thalassemic alleles, one single-gene deletional (-α^3.7) and three non-deletional forms (α^TSaudi, α^Δ5nt, and α^ΔG), interact in various combinations and result in two distinct hematological phenotypes, with and without HbH inclusions. After excluding the presence of potential genetic modifiers, viz associated β-thalassemic alleles or functional alpha hemoglobin stabilizing protein (AHSP) polymorphisms, we observed that only the genetic combinations involving α^TSaudi mutation are associated with HbH inclusions (a marker of degree of α/β-chain imbalance) and high reticulocyte count (a marker of ongoing hemolysis). Overall, the α^TSaudi mutation is associated with a more severe α-globin deficiency than the other two (α^Δ5nt and α^ΔG) non-deletional α⁰ thalassemic mutations. The likely molecular explanation is that the compensatory increase in the linked α1 globin gene expression is much more compromised in cases with α^TSaudi mutation.