Reena Das, Additional Professor, Department of Haematology, Postgraduate Institute of Medical Education & Research, Chandigarh 160012, India. Tel.: +91 0172 2755128; Fax: +91 0172 2744401, 2745078; e-mail: [email protected]

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Abstract

Objectives: To assess the molecular basis of phenotypic heterogeneity in north Indian patients with thalassemia major (TM). Methods: To determine the clinical severity, 130 patients of TM were studied for the age of first presentation and frequency of blood transfusion. The type of beta mutations, Xmn–1^Gγ polymorphism and G6PD Mediterranean mutation was characterized. Analysis of the phenotypic presentation and the genotype was performed. Results: Majority (83.8%) presented before 1 year of age (mean 8.8 months). The caste distribution showed 41.6% were Aroras and 32.3% were migrants from Pakistan. IVS1-5(G→C) was commonest (32.7%) and the common five Indian mutations comprised of 88.4% of alleles. The mean age of presentation with IVS1-5(G→C), Fr 8/9, (+G) 619-bp del and IVS1-1(G→T) homozygosity was 4.3, 6, 3.4 and 9.1 months respectively. Xmn–1^Gγ status showed −/− in 66.9%, +/− in 26.1% and +/+ in 6.9% patients. Xmn–1^Gγ−/− presented before 1 year of age. The mean age of presentation with +/+ was 18.3 months. Six hemizygous boys and one heterozygous girl with G6PD Mediterranean were found (prevalence 5.3%). Eight patients could be reclassified as thalassemia intermedia on follow up. Conclusions: This study showed that majority of TM in north India present before 1 year of age and homozygous 619-bp deletion presents the earliest. The presence of Xmn-1^Gγ polymorphism delays the presentation, is associated with the IVS 1-1 (G→T) and shows variable improvement with hydroxyurea therapy. Based on the results of genotyping, reevaluation of patients can improve the outcome in a few patients.

References

1 Weatherall DJ, Clegg JB. Inherited haemoglobin disorders: an increasing global health problem. Bull World Health Organ 2001; 79: 704–12.
CAS PubMed Web of Science® Google Scholar
2 Weatherall DJ. Phenotype-genotype relationships in monogenic disease: lessons from the thalassemias. Nat Rev Genet 2001; 2: 245–55.
10.1038/35066048
CAS PubMed Web of Science® Google Scholar
3 Kattamis C, Ladis V, Metaxatou-Mavromati A. Hemoglobins F and A₂ in Greek patients with homozygous β and β/δβ thalassaemia. In: RM Schmidt, ed. Abnoral haemoglobins and thalassaemia: diagnostic aspects. New York: Academy Press, 1975: 209–28.
Google Scholar
4 Modell CB, Bordoukas VA. The clinical approach to Thalassemia. New York: Grume and Stratton, 1984.
Google Scholar
5 Huisman THJ. The hemoglobinopathies. Edinburgh: Churchill Livingstone, 1986.
Google Scholar
6 Kazazian HH, Orkin SH, Antonarakis SE, Sexton JP, Boehm CD, Goff SC, Waber PG. Molecular Characterization of seven β thalassemia mutations in Asian Indians. EMBO Journals 1984; 3: 593–6.
10.1002/j.1460-2075.1984.tb01853.x
CAS PubMed Web of Science® Google Scholar
7 Gilman G, Huisman THJ. DNA sequence variation associated with elevated fetal G gamma globin production. Blood 1985; 66: 4.
Google Scholar
8 Dedoussis GV, Mandilara GD, Boussiv M, Loutradis A. HbF production in β thalassemia heterozygotes for the IVS1-1 G→A β-globin mutation. Implication of the haplotype and the Gγ-158 C→T mutation on the HbF level. Am J Hemat 2000; 64: 151–5.
10.1002/1096-8652(200007)64:3<151::AID-AJH2>3.0.CO;2-X
CAS PubMed Web of Science® Google Scholar
9 Gonzalez-Redondo JM, Stoming TA, Kutlar A, McKie VC, McKie KM, Huisman TH. A C→T substitution at nt-101 in a conserved DNA sequence of the promoter region of the ß-globin gene is associated with ‘silent’ß thalassemia. Blood 1989; 73: 1705–11.
CAS PubMed Web of Science® Google Scholar
10 Kirkman H, Hendrikson E. Sex linked electrophoretic differences in G6PD A. Am J Hum Genet 1963; 15: 241–58.
CAS PubMed Web of Science® Google Scholar
11 Kultar A, Kultar F, Wilson JB, Headlee MG, Huisman THJ. Quantification of hemoglobin components by High-performance cation exchange liquid chromatography. Am J Hemat 1984; 17: 39–53.
10.1002/ajh.2830170106
PubMed Web of Science® Google Scholar
12 Old JM, Varawalla NY, Weatherall DJ. Rapid detection and prenatal diagnosis of β-thalassemia: studies in Indian and Cypriot populations in the UK. Lancet 1990; 336: 834–7.
10.1016/0140-6736(90)92338-I
PubMed Web of Science® Google Scholar
13 Craig JE, Sheerin SM, Barnetson R, Thein SL. The molecular basis of HPFH in a British family identified by heteroduplex formation. Br J Hemat 1993; 84: 106–10.
10.1111/j.1365-2141.1993.tb03032.x
CAS PubMed Web of Science® Google Scholar
14 Kaeda JS, Chhotray GP, Ranjit MR, et al. A new glucose-6-phosphate dehydrogenase variant, G6PD Orissa is a major polymorphic variant in tribal populations in India. Am J Hum Genet 1995; 47: 1013–9.
PubMed Web of Science® Google Scholar
15 Colah R, Nadkarni A, Gorakshakar A, Phanasgaonkar S, Surve R, Subramaniam PG, Bondge N, Pujari K, Ghosh K, Mohanty D. Impact of β globin gene mutations on the clinical phenotype of β thalassemia in India. Blood Cells Mol Dis 2004; 33: 153–7.
10.1016/j.bcmd.2004.05.002
CAS PubMed Web of Science® Google Scholar
16 Saini A, Chandra J, Goswami U, Singh V, Dutta AK. Case Control Study of Psychosocial Morbidity in β Thalassemia Major. J Pediatr 2007; 150: 516–20.
10.1016/j.jpeds.2007.01.025
PubMed Web of Science® Google Scholar
17 Nadkarni A, Gorakshakar AC, Lu CY, Krishnamoorthy R, Ghosh K, Colah R, Mohanty D. Molecular Pathogenesis and Clinical Variability of β-Thalassemia Syndromes among Indians. Am J Hemat 2001; 68: 75–80.
10.1002/ajh.1156
CAS PubMed Web of Science® Google Scholar
18 Bandyopadhyay A, Bandyopadhyay S, Chowdhury MD, Dasgupta UB. Major β globin gene mutations in Eastern India and their associated haplotypes. Hum Heredity 1999; 49: 232–5.
10.1159/000022880
CAS PubMed Web of Science® Google Scholar
19 Garewal G, Das R. Spectrum of β-thalassemia mutations in Punjabis. Inter J Hum Genet 2003; 3: 217–9.
Google Scholar
20 Verma IC, Saxena R, Thomas E, Jain PK. Regional distribution of β-thalassemia mutations in India. Hum Genet 1997; 100: 109–13.
10.1007/s004390050475
PubMed Web of Science® Google Scholar
21 Garewal G, Das R, Ahluwalia J, Marwaha RK, Varma S. Nucleotide -88 (C-T) promoter mutation is a common β-thalassemia mutation in the Jat Sikhs of Punjab, India. Am J of Haematology 2005; 79: 252–6.
10.1002/ajh.20445
CAS PubMed Web of Science® Google Scholar
22 Edison ES, Shaji RV, Devi SG, Moses A, Viswabandhya A, Mathews V, George B, Srivastava A, Chandy M. Analysis of β globin mutations in the Indian population: presence of rare and novel mutations and region-wise heterogeneity. Clin Genet 2008; 10: 1399–404.
Google Scholar
23 Venkatesan R, Sarkar R, Old JM. β Thalassemia mutations and their linkage to haplotypes in Tamil Nadu in Southern India. Clin Genet 1992; 42: 251–6.
10.1111/j.1399-0004.1992.tb03250.x
CAS PubMed Web of Science® Google Scholar
24 Varawalla NY, Fitches AC, Old JM. Analysis of β globin gene haplotypes in Asian Indians: origin and spread of β on the Indian subcontinent. Hum Genet 1992; 90: 443–9.
10.1007/BF00220475
CAS PubMed Web of Science® Google Scholar
25 Parikh P, Cotton M, Boehm CD, Kazazian HH. Ethnic distribution of β thalassemia in Indian subcontinent. Lancet 1990; 336: 1006.
10.1016/0140-6736(90)92467-V
CAS PubMed Web of Science® Google Scholar
26 Varawalla NY, Old JM, Sarkar R, Venkatesan R, Weatherall DJ. The spectrum of β thalassemia mutations on the Indian subcontinent: the basis for prenatal diagnosis. Br J Hemat 1991; 78: 242–7.
10.1111/j.1365-2141.1991.tb04423.x
CAS PubMed Web of Science® Google Scholar
27 Garewal G, Fearon CW, Warren TC, Marwaha N, Marwaha RK, Mahadik C, Kazazian JJ Jr. The molecular basis of β thalassemia in Punjab and Maharashtrian Indians includes a multilocus etiology involving triplicated α-globin loci. Br J Hemat 1994; 86: 372–6.
10.1111/j.1365-2141.1994.tb04742.x
CAS PubMed Web of Science® Google Scholar
28 Aditya R, Verma IC, Saxena R, Kaul D, Khanna VK. Relation of Xmn-1 polymorphism and five common Indian mutations of Thalassemia with phenotypic presentation in beta -Thalassemia. JK Science 2006; 8: 139–43.
Google Scholar

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Volume84, Issue6

June 2010

Pages 531-537

Evaluation of the genetic basis of phenotypic heterogeneity in north Indian patients with Thalassemia major

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Evaluation of the genetic basis of phenotypic heterogeneity in north Indian patients with Thalassemia major

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