Molecular genetics of alpha thalassemia

Linked duplicate genes in Chromosome 16 condition the production not only of alpha-globin chains in the Hemoglobin A (HbA) molecule, but also of the varied forms of alpha thalassemia in human subjects. Null allelism, not gene deletion, exists at these gene loci. Two codominant alleles occur at each locus; these are characterized as Gb and Ob at one locus, and as Gc and Oc at the second locus. Gb and Gc are genetically active alleles, and either conditions the production of alpha-globin chain. Ob and Oc are null or genetically inert alleles, and neither conditions the production of alpha-globin chain. Gb and Gc are additive in the expression of disease genotype. The number of alpha-globin chains in the HbA molecule, and the absence as well as the varied forms of alpha thalassemia are inherited quantitatively as follows: four alpha-globin chains and the absence of alpha thalassemia result from GbGbGcGc; either GbGbGcOc or GbObGcGc yields three alpha-globin chains and asymptomatic alpha thalassemia minor; any one of three genotypes, GbGbOcOc, GbObGcOc or ObObGcGc, yields two alpha-globin chains and mild alpha thalassemia minor; either GbObOcOc or ObObGcOc yields one alpha-globin chain and severe alpha thalassemia minor; ObObOcOc produces no alpha-globin chain and the fetal alpha thalassemia major. The inheritance of any combination of active and null alleles, and of the associated forms of alpha thalassemia, is deducible from the alpha-globin as well as the disease phenotypes and/or genotypes of parental subjects.