Molecular Pathology of Thalassemia and Triplicated Locus in North Indian Population; Interaction with Heterozygous Thalassemia

The α(+) thalassemias are the most common single gene disorders of humans. They have been documented to be at a high frequency in certain areas of India. To analyze the prevalence of α thalassemia in the north Indian population (Punjab, Haryana, Himachal Pradesh), the α globin genotype of 419 subjects, comprising 208 healthy blood donors and 211 β thalassemia traits, has been studied. The α globin genotype revealed a high frequency of α thalassemia (deletions; 12.4%) and α gene triplications (3.1%). The α(+) thalassemia with-α(3.7)/ααα(anti 3.7) haplotype was found to be prevalent in this population. No case of α(0) thalassemia was detected, indicating its rarity in this population. A single rare case of quadruplicated α genes was also observed. In addition to molecular analysis, hematological phenotype was studied in normal subjects and in β thalassemia traits with and without α gene defect. In the normal group a single α gene deletion (-α/αα) lowered the MCV and MCH as compared to the normal α genotype (p<0.001). In cases with heterozygous triplication (ααα/αα), MCHC was found to be raised as compared to the normal α genotype (p<0.05). However, the values of these red cell indices in the heterozygous deletions and triplications were not in the diagnostic range. In the group of β thalassemia traits, the interaction of heterozygous α gene deletion resulted in higher Hb and MCV when compared to that of the normal α complement, though these values remained in the lower normal range. Our results indicate a high frequency of α gene defects in this population. Though these were observed mostly in heterozygous form, they can and do occur as homozygous. By themselves, these defects of α genes even in homozygous form do not cause significant change in the phenotype, but their interaction with β thalassemia can cause modification of the clinical expression to a variable extent. Thus, the concomitant inheritance of α gene defect with β thalassemia would influence the genetic counseling and prenatal diagnosis in these families.