title: Genetic factors affecting clinical severity in beta-thalassemia syndromes.
abstract: OBJECTIVE
  Heterogeneity in the clinical manifestation of beta-thalassemic diseases may occur from the nature of beta-globin gene mutations, alpha-thalassemia gene interaction, or differences in the amount of hemoglobin (Hb) F production. This study was conducted to determine whether these genetic determinant factors can predict phenotypic severity of patients with beta-thalassemia and to assess the relationship between the genotype and phenotype of the disease.
  
  
  METHODS
  A total of 144 patients with beta-thalassemia were divided into mild (46 patients), intermediate (55 patients), and severe groups (43 patients). DNA analysis based on polymerase chain reaction technique was performed to characterize types of beta-thalassemia mutation, interaction of alpha-thalassemia, and XmnI polymorphism 5' to Ggamma-globin gene.
  
  
  RESULTS
  Two alleles of mild beta-thalassemia mutation (beta+/beta+-thalassemia or beta+-thalassemia/Hb E) resulted in a mild clinical symptom whereas two alleles of severe beta-thalassemia mutation (betao/betao) produced a severe clinical phenotype. Compound heterozygosity for mild and severe alleles of beta-thalassemia (betao/ beta+-thalassemia or betao-thalassemia/Hb E) led to variable severity of anemia. Coinheritance of alpha-thalassemia alleviated the severity of beta-thalassemia disease in those patients with at least one allele of the mild beta-thalassemia genotype. DNA polymorphism at position-158 nt 5' to the Ggamma-globin gene was demonstrated by XmnI restriction enzyme. Homozygote of the XmnI site, +/+, was found to have a strong linkage with high Hb F levels and high hemoglobin production in two patients who had mild clinical symptoms. However, some patients who had XmnI site -/- also had mild clinical symptoms because the XmnI- was found to be associated with beta+-thalassemia mutation.
  
  
  CONCLUSIONS
  Types of beta-thalassemia mutation and coinheritance of alpha-thalassemia in the patient who has at least one allele of the mild beta-thalassemia genotype are predictive for the clinical severity of the disease. However, a mild clinical symptom in some patients with betao/beta+-thalassemia or betao-thalassemia/Hb E who do not have a detectable alpha-thalassemia haplotype and no linkage with XmnI++ suggests that there are other confounding factors responsible for the severity differences of the disease.
authors.affiliation: Thalassemia Research Center, Institute of Science and Technology for Research and Development, Mahidol University, Nakornpathom, Thailand. stpfc@mahidol.ac.th
authors.forename: P
authors.initials: P
authors.lastname: Winichagoon
authors.forename: S
authors.initials: S
authors.lastname: Fucharoen
authors.forename: P
authors.initials: P
authors.lastname: Chen
authors.forename: P
authors.initials: P
authors.lastname: Wasi
mesh_terms: D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D005838:Genotype; D005914:Globins / Q000235:genetics*; D006801:Humans; D009154:Mutation; D011110:Polymorphism, Genetic; D017086:beta-Thalassemia / Q000235:genetics* / Q000503:physiopathology*
chemical_list: D005914:Globins