The
beta 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 beta gene mutations in modulating the clinical presentation of 342
beta 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
beta 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 beta+ or beta0 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 beta+ 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 beta+ or beta0 mutations resulted in a very variable clinical presentation. This study reveals that, in majority of Indian patients, the beta genotype cannot predict the phenotype.