The inherited disorders of hemoglobin synthesis are the most common monogenic disorders worldwide. Thalassemia especially β-thalassemia is a common genetic disorder found in the Indian subcontinent. Since thalassemia is difficult to cure and and management involves major financial inputs, the prevention is a priority. The only cure for affected children is bone marrow transplantation which is management involves major financial inputs, the prevention is a priority. The only cure for affected expensive, risky and available only at selected centers. The only treatment to sustain life in thalassemia major is regular blood transfusion with iron chelation but this requires much commitment on part of the family. The treatment is also hampered by less of blood resources available and lack of motivated voluntary donors. Hence, the most effective approach for developing countries like India is preventing thalassemia. This is possible by targeted carrier detection, genetic counseling and prenatal diagnosis. Thalassemia intermedia is a heterogenous group with most patients being homozygous β-thalassemia with milder β-globin mutations, or with concomitant α-globin gene deletions or XmnI polymorphism. Some patients of thalassemia intermedia are heterozygous β-thalassemia with α-globin gene triplication/quadruplication etc, or rarely dominant β-thalassemia. A co-existence of β-thalassemia heterozygous state with structural hemoglobin variants like HbE, HbS, and HbD also leads to thalassemia intermedia phenotype. HPLC and mutation analysis help in classifying and differentiating these conditions.
have reported the presence of five common β-globin mutations covering approximately 88% of mutations in Indian population residing in west. Later the frequencies of these five common mutations in the Indian subcontinent were determined as 93.6% by Varawalla et al,14
91.8% by Verma et al,5
91.2% by Gupta et al,15
74.5% by Edison et al,9
87.5% by Nadkarni et al.16
and 80.0% by Colah et al.7
Specifically in northern part of India the frequency of detection of five common mutations was determined as 76.3%, 90.7% and 91.2% by Agarwal et al.17–18
and Gupta et al.15
respectively in the state of Uttar Pradesh (UP). The frequency of detection was 87.2% and 93.1% reported by Garewal et al.22–23
In our overall analysis in present study, we observed that the five common mutations account for 78.9% of total β-globin gene mutations.
Varawalla et al.19
had defined the spectrum of five common β-thalassemia mutations in Indian subcontinents as IVS1-5(G>C), Cod8-9(+G), IVS1-1(G>T), Cod41-42(−TCTT) and 619bp deletion whereas less common mutations were Cod15 (G>A), Cod16 (−C), Cap+1(A>T), Cod30 (G>C), -88(C>T). Later Agarwal et al.17–18
and Verma et al.5
reported the spectrum of less common mutations in North Indians as only Cod15(G>A), Cod16(−C) and Cap+1(A>C) mutations. The variability may be due to variable representation of different ethnic groups in various studies.
Rare mutations which have been described by Varawalla et al.19
in Asian Indians were namely −25bp del, Cod5 (−CT), IVS1-1(G>A) and IVSII-837 (G>T). Agarwal et al.18
described rare mutation as Cod30 (G>C), Cod5 (−CT), Cod47-48 (+ATCT), IVS1-1 (G>A) present in the population of North Indian origin. Till date 25bp deletion and IVSII-837(G>T) mutation have not been reported from UP state. Gupta et al 2003 reported the less common mutations which included Cod15 (G>A), Cod16 (−C), Cap+1 (A>C) and Cod30 (G>C).
Nadkarni et al.16
and Colah et al.20
reported different spectrum of five common mutations from Central India, and this included IVS1-5 (G>C), 619bp deletion, Cod15 (G>A), IVS1-1(G>T), and Cod8-9(+G). Less common mutation reported by them were Cod41-42(−TCTT), Cod30 (G>C), Cod16 (−C) and Cap+1 (A>C). These differences in the spectrum of mutations in different part of the Indian subcontinent () represent different ethnicities, and different endogamy patterns prevailing in the country.
The beta globin gene mutations reported from different regions of India.
All the previous studies reported Cod16 (−C) as less common or rare mutation but in present study frequency of Cod16 (−C) is very high in population of Uttar Pradesh state. Interestingly the frequency of IVS1-1 (G>T) mutation is found remarkably low in the present study and found position in less common mutation, though it was one of five common mutations especially from Punjab state.
Cod30 (G>C) earlier considered as a rare mutation was found to be a less common mutation in present study. Conversely the promoter mutation -88 (C>T) found to be rare, milder mutation in UP population, though it is frequent in Jat-Sikhs from Punjab.21
It is interesting to note that Cod47-48 (+ATCT) mutation reported earlier were not observed in the present analysis. Thus the spectrum of mutations can vary depending on whether we are studying only thalassemia major patients, or we are including other cases of homozygous beta-thalassemia presenting as thalassemia intermedia.
Though IVS1-5 (G>C) is most common mutation in Indians, its percentage prevalence varies from 25% in Arora & Khatri to 60% in Thakur community. Interestingly Cod41-42(−TCTT) mutation and 619bp del mutation was totally absent in Kayasthas. The Cod15 (G>A) mutation was common in Sunni community where it was found as third most common mutation.
Thus, the present study provides information on the distribution of the β-thalassemia mutations in β-globin gene in the multiethnic population of Uttar Pradesh state. The application of the knowledge of ethnic origin and mutation pattern would help to reduce the screening cost and also facilitate early and better genetic counseling of families and high risk couples.