title: Two siblings with unusually mild homozygous beta-thalassemia: a didactic example of the effect of a nonallelic modifier gene of the expressivity of a monogenic disorder.
abstract: Two adult Black sibs with homozygous beta-thalassemia had severe deficiency of beta-chain production but an unusually mild clinical course and almost normal hematocrit values. Their father had the typical hematological findings of beta-thalassemia trait but the mother, in addition to the beta-thalassemia trait, had elevated F cells (42.2%). Elevated F cells were also present in a hematologically normal sister of the affected providing evidence that a gene for heterocellular hereditary persistence of fetal hemoglobulin (HPFH) was also running in this family. The unusually mild clinical course of the two homozygotes is attributed to their inheritance from their mother of the heterocellular HPFH gene. The gene for heterocellular HPFH is nonallelic to the beta-globin locus and apparently acted as a modifier of the homozygous beta-thalassemia phenotype by facilitating F-cell production and thus diminishing the pathophysiological consequences of the beta-thalassemia defect. The effect of heterocellular HPFH on the expression of homozygous beta-thalassemia or Hb S genotypes is an impressive example of the pathophysiological basis of changes in the expressivity of monogenic disorders due to action of nonallelic modifiers.
mesh_terms: D000328:Adult; D004912:Erythrocytes / Q000473:pathology; D005260:Female; D005319:Fetal Hemoglobin / Q000032:analysis / Q000235:genetics; D005786:Gene Expression Regulation; D006400:Hematocrit; D006443:Hemoglobin A2 / Q000032:analysis; D006650:Histocompatibility Testing; D006720:Homozygote; D006801:Humans; D008297:Male; D010375:Pedigree; D013789:Thalassemia / Q000235:genetics*
chemical_list: D006443:Hemoglobin A2; D005319:Fetal Hemoglobin