Relationship between Genotype and Phenotype: Thalassemia Intermedia^a

Abstract

Thalassemia intermedia encompasses a number of clinical conditions ranging in severity from beta-thalassemia carrier state to transfusion-dependent thalassemia major. The molecular bases of thalassemia intermedia, only partially defined, are very heterogeneous, but in general any factor able to reduce the globin-chain imbalance results in a milder form of thalassemia. These factors are the presence of a silent or mild beta-thalassemia allele, associated with a high residual beta-globin production, and the coinheritance of alpha-thalassemia or of genetic determinants that increase the gamma-chain production. Less frequent mechanisms are double heterozygosity for beta-thalassemia and triplicated alpha genes, and the presence of a hyperunstable hemoglobin variant. However, for a consistent number of beta zero-thalassemia homozygotes with a thalassemia intermedia phenotype the modifying factor has not been defined yet. In contrast, there are simple beta-thalassemia carriers who, for unknown reasons, have an unusually severe clinical phenotype.

Phenotypic Heterogeneity of Asian Indian Inversion Deletions Gγ(Aγδβ)0 Breakpoint A and Breakpoint B

“…Molecular studies of these heterogeneous disorders could be classified as deletional and non deletional [8,11]. Co-inheritance of HPFH or db thalassemia with b-thalassemia and other hemoglobinopathies has an ameliorating effect on the severity of the disease and thus usually results in the thalassemia intermedia phenotype [9,21]. In our studied cases, two patients with breakpoint A deletions in which one had heterozygous 3.7 kb deletion was presenting mild anemia and weakness while 2 patients with co-existence of IVS 1-5(G-C) b-thalassemia mutation were transfusion dependent and showed recurrent jaundice with moderate anemia.…”

Association of globin gene quadruplication and heterozygous thalassemia in patients with thalassemia intermedia

“…Part of the clinical heterogeneity of thalassemia intermedia depends on different and only partially defined molecular mechanisms, the most common being homozygosity for mild β-thalassemia mutations, compound heterozygosity for mild/silent and severe β-thalassemia mutations, co-inheritance with homozygous β thalassemia of α thalassemia or of genetic determinants able to increase the production of fetal hemoglobin (HPFH). [1][2][3] Less commonly, the phenotype of thalassemia intermedia has been reported in subjects carrying only one β globin gene defect. Among them 3 groups have been defined: (i) the dominantly inherited β thalassemia mutations (also reported as inclusion body thalassemias); 4,5 (ii) the co-existence of somatic deletions of a region of chromosome 11 p15; 6,7 (iii) co-inheritance of triplicated α globin genes with excessive α globin production.…”

Beta-thalassemia: from genotype to phenotype

“…In this case, the severity of the clinical phenotype correlates with the a globin chain deficiency and with the improved a/nona chain imbalance as a consequence of reduced a chain output. 4 A substantial decrease in a/non-a chain imbalance can also be obtained through the coinheritance of genetic determinants able to sustain a continuous production of gamma chains which, binding the excess a chains, result in a persistent fetal hemoglobin (Hb F) production measurable in adult life. In delta-b0 thalassemia, this ability is due to deletions of variable extent within the b globin cluster, 5 while in other cases it depends on the co-transmission of point mutations at A-gamma or G-gamma promoters (−196 C→T A-gamma; −158 C→T Ggamma).…”

“…T he 46/1 haplotype of chromosome 9p, present in about 45% of the general population, is associated with a predisposition to mutations in the Janus Kinase 2 (JAK2) gene on the same allele and to chronic myeloproliferative neoplasms (MPN): polycythemia vera, essential thrombocythemia and primary myelofibrosis. [1][2][3][4] The 46/1 haplotype is also associated with a predisposition to MPN with no mutation of JAK2, and with MPN with mutation in MPL, a gene located on a different chromosome (1p). 5,6 An increased frequency of the 46/1 haplotype in patients with splanchnic vein thrombosis has also been reported but these findings remain controversial.…”