Genotype-phenotype correlation and report of novel mutations in β-globin gene in thalassemia patients

Heterogeneity in thalassemia is due to various modifying factors viz. coinheritance of alpha-gene defects, abnormal hemoglobin, Xmnl polymorphism, variation in repeat sequences present in LCR, and silencer region of the gene. The present work on populations from eastern regions of India was undertaken to study the genetic profile of heterogeneity in thalassemia patients. Mutation analysis in 126 index families revealed the presence of 3 novel mutations: CD2 (-A) in the 1st exon, -42 (C-G), and -223 (T-C) in the promoter region of beta-globin gene. The modifying effect of coexisting alpha-gene defects, and abnormal Hb (HbS) was clearly observed in our study, however ameliorating effect of T allele of Xmn1 polymorphism was not found. Analysis of the regulatory regions (LCR) exhibited new combinations (CA(15)TA(5) and CA(13)TA(8)) in HS1 region and one (AT)(10)T-3 in (AT)(x)T-y, silencer region. Thus disparate factors, when considered together, were able to explain several of the thalassemic phenotypes, otherwise not explained by the beta globin mutations. However, there were still some cases in this group whose molecular origin could not be ascertained. Our findings confirm not only the extensive genotypic and clinical heterogeneity in beta thalassemia but also the need to look for more modulators and modifiers to better understand the genotype-phenotype correlation in thalassemia. (C) 2015 Elsevier Inc. All rights reserved.