MOLECULAR BASIS OF THALASSEMIA INTERMEDIA IN PAKISTANI POPULATION

Abstract

The main objectives for this study were to determine the molecular basis of the disease resulting in the particular clinical phenotype of thalassemia intermedia in Pakistan, to identify the factors affecting genotype – phenotype relationship, to determine the possibility for a consistent prediction of phenotype severity from the genotype factors and to asses their relative importance. Thalassemia Intermedia is clinically and genetically heterogeneous and the genotype is retrospective. However, the disease being of milder form is characterized by late commencement of transfusion, lesser degree of anemia and greater survival time. In this study one consistent factor having a fair ground for the classification was the age of the patient at presentation. Age of the patients in this study was between 2.5 – 36 years. These patients in the radiance of presentation were grouped in four categories; Severe, Moderate, Mild and Very Mild depending on the transfusion commencement. Eleven different beta chain mutations were identified, IVSI-5 = 46 %, Fr 8-9 = 11.5 %, Cap+1 = 10%,, Cd30 = 7.0%, IVSI-I 6.5%, HbE = 6%, HbS = 3%, Del 619 = 1.5 %, Cd15 = 1.0%, Fr 41 – 42 = 0.5%, Fr16 = 0.5% and δβ = 5%. However, 1.5 % of the alleles remained unknown. Out of 100 samples tested for Xmn-I polymorphism 79 were found to be positive, 36 % for +/+ genotype and 43% for -/+ genotype and 21% were negative for the genotype. The samples were also tested for δβ mutations and 5 of them were found to be homozygous. Deletions for α- chain were observed in 30% of the samples, all of them had α3.7 deletions out which 8 % had - α/ - α deletions , 21% had -α/αα deletions and 1% had - - / - α deletions (Table 3.46). Frequency of Alpha Thalassemia in different ethnic groups were determined which revealed that alpha thalassemia mutations are more prevalent in Sindhis, Punjabis and Mahajirs. Relating phenotype to genotype is complicated by complex interaction of the environment and other genetic factors such as coinheritance of other hemoglobin mutations. Alpha thalassemia and Xmn-I predominantly contributed the phenotype. Hemoglobinopathies account for only 9% of the patients. Compound heterozygosity was another factor involved particularly with the assistance of Xmn-I polymorphism and coexistence of α- Thalassemia. Xmn-I +/+ and Hemoglobin S mutation accounted for 9% of cases. To establish a comprehensive diagnosis program the problem of detection of an ability to produce fetal hemoglobin, inheritance of β+ Thalassemia genes and inheritance of α Thalassemia and other factors ameliorating the disease should be defined and incorporated. Molecular basis of thalassemia intermedia as defined in this study explains the involvement of different factors that tend to develop the disease phenotype. However, no single factor finds an authority for the discipline of mildness and thus require cooperation of the elements serving in amelioration.