Impact of β globin gene mutations on the clinical phenotype of β thalassemia in India

The β thalassemias are one of the commonest group of autosomal recessive disorders in India. Although majority of patients are severe and transfusion-dependent, about 10–15% of cases have a milder phenotype. We evaluated the role of β gene mutations in modulating the clinical presentation of 342 β thalassemia patients which included 278 severe thalassemia major (TM) and 64 thalassemia intermedia (TI) cases (severe TI: 27; mild TI: 37) from this region. Thirteen β thalassemia mutations were characterized by reverse dot blot hybridization or amplification refractory mutation system (ARMS); denaturing gradient gel electrophoresis (DGGE) analysis and DNA sequencing helped to characterize the remaining nine mutations. Majority of the patients in the thalassemia major and thalassemia intermedia groups had severe β+ or β0 mutations. IVS 1-5 (G→C) was the commonest mutation in the three groups. The six severe and common Indian mutations [(IVS 1-5 (G→C), 619 bp deletion, IVS 1-1 (G→T), codons 8/9 (+G), codon 15 (G→A), codons 41/42 (-CTTT)] accounted for 92.0% of molecular lesions in the thalassemia major group, 86.8% in the severe TI group, and 72.9% in the mild TI group. IVS 1-1 (G→T) and codon 30 (G→C) were significantly more common in thalassemia intermedia cases. The mild capsite +1 (A→C) mutation was present in both severe and mild cases. Three other mild β+ mutations, poly A (T→C), -28 (A→G), and -88 (C→T), were seen only in the thalassemia intermedia cases. These four mild mutations in combination with other severe β+ or β0 mutations resulted in a very variable clinical presentation. This study reveals that, in majority of Indian patients, the β genotype cannot predict the phenotype.