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

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 ^G γ 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.