Modifiers of the β-thalassemia phenotype leading to β-thalassemia intermedia. The primary modifier of phenotype is the severity of the β-globin chain mutation (β⁺⁺, β⁺, or β⁰), with varying α/β-globin chain imbalance. Coinheritance of α-thalassemia and increased expression of α-globin stabilizing protein act as secondary modifiers that mitigate the α/β-globin chain imbalance. In contrast, inheritance of a triplicated or quadruplicated α-globin gene locus may amplify the severity of a heterozygous β-thalassemia state. In some instances, a single dominantly inherited β-globin locus mutation can be responsible for a β-thalassemia intermedia phenotype. HPFH, hereditary persistence of fetal hemoglobin. Figure created with BioRender.