Beta thalassaemia is a major public health problem in India. A comprehensive database of the spectrum of mutations causing beta thalassaemia in the Indian population is necessary. This study in which a large number of patients with beta thalassaemia including those from certain regions that were not explored earlier shows a great heterogeneity of mutations. Several novel and rare alleles that have not been reported earlier in the Indian population have been identified, and mutations differ in frequency in different regions of the country. This information on the spectrum of mutations has implications for the control of beta thalassaemia in a population with complex ethnic background and also on the genotype-phenotype correlation of the disease.

β-thalassaemia is a major public health problem in India. A comprehensive data base of the spectrum of mutations causing β thalassaemia in the Indian population is necessary. Each population group in which the disease is prevalent has a different spectrum of β globin mutations and a few mutations account for most of the alleles. From 1997 to 2006, β-Globin gene mutation analysis was carried out in 1030 individuals. The common mutations in the population were screened by reverse dot blot (RDB). Deletion of 619 bp of the β globin gene was detected by gap-PCR. Rare mutations were screened using temporal temperature gel electrophoresis (TTGE) and DNA sequencing. Haplotyping of rare mutations was done by using established PCR-RFLP methods. Out of the 1030 individuals, 515 were homozygous or compound heterozygotes. Among the others, 178 had heterozygous β thalassaemia, 292 HbE-βthalassaemia, 27 HbS-β thalassaemia, 3 HPFH-β thalassaemia, 5 Lepore-β thalassaemia and 10 (δβ)0-β thalassaemia. Mutation analysis was performed on a total of 1545 β globin alleles from the subjects included in the study. The regional distribution of study subjects were: 533 from the South (Kerala, Tamilnadu, Andhra Pradesh and Karnataka), 529 from the East (Bihar, Orissa, West Bengal and other eastern states), 233 from the West (Gujarat, Maharashtra, Madhyapradesh and Rajasthan) and 92 from the Northern part of the country (Harayana, Punjab, Uttar Pradesh). A total of 41 mutations including 17 mutations that have not been reported earlier in this population were detected. Four, Codon 62/64 (−7bp), Codon 81/87 (−22bp), −25 (A→G) and IVS II- 613 (C→T) are novel mutations causing β thalassaemia. Thirteen mutations, which were detected in other populations but were not reported earlier in the Indian population, were identified. They included −29 (A→G), −87 (C→G), −90 (C→T), Codon 17 (A→T), Codon 22/23/24 (−17 bp), Codon 26 (G→T), Codon 36/37 (−T), Codon 41 (−C), IVS I-129 (A→C), IVS I-130 (G→C), IVS I-130 (G→A), Codon 106/107 (+G) and Codon 110 (T→C). Comparison of the spectrum of β thalassaemia mutations between different regions shows that there are considerable differences in the geographical distribution of mutations in the Indian population (Table). Haplotype analysis revealed that the rare mutations occured denovo and also through population migration. This data will aid in carrier detection, genetic counselling and prenatal diagnosis which play an important role in the prevention of the disease. Regional Distribution of β globin Mutations in India (%) Mutation South East North West IVS I-5(G-C) 57.41 73.51 54.35 49.36 CD 15(G-A) 12.38 6.99 0 3 poly A (T-C) 9 0.73 0 0.86 −28(A-G) 4.5 0 0 0 IVS II-837 (T-G) 2.81 0 0 0 CD 30(G-C) 1.9 7.28 1.09 2.58 CD 41/42(-TCTT) 2.06 3.64 6.52 5.15 619 bp DEL 0 0.44 8.7 20.17 IVS I-1(G-T) 0.9 0.15 11.96 10.73 CD 8/9 (+G) 0.1 1.6 3.26 3 OTHERS 8.94 5.67 14.13 5.15

Key Clinical MessageThe beta thalassemia intermedia phenotype has several genotypes. Hematological and molecular diagnostic approach and logical and sequential conduct of various investigations are necessary for the diagnosis of these disorders. Close observations of the genotype–phenotype correlation will provide a better insight for the development of molecular therapy.

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