Impact of h globin gene mutations on the clinical phenotype of h thalassemia in India Roshan Colah * , Anita Nadkarni, Ajit Gorakshakar, Supriya Phanasgaonkar, Reema Surve, P.G. Subramaniam, Nagnath Bondge, Kamala Pujari, Kanjaksha Ghosh, Dipika Mohanty Institute of Immunohaematology (ICMR), K.E.M. Hospital Campus, Parel, Mumbai 400012, India Submitted 17 May 2004 (Communicated by E. Beutler, M.D., 20 May 2004) Abstract The h thalassemias are one of the commonest group of autosomal recessive disorders in India. Although majority of patients are severe and transfusion-dependent, about 10–15% of cases have a milder phenotype. We evaluated the role of h gene mutations in modulating the clinical presentation of 342 h thalassemia patients which included 278 severe thalassemia major (TM) and 64 thalassemia intermedia (TI) cases (severe TI: 27; mild TI: 37) from this region. Thirteen h thalassemia mutations were characterized by reverse dot blot hybridization or amplification refractory mutation system (ARMS); denaturing gradient gel electrophoresis (DGGE) analysis and DNA sequencing helped to characterize the remaining nine mutations. Majority of the patients in the thalassemia major and thalassemia intermedia groups had severe h + or h 0 mutations. IVS 1-5 (GYC) was the commonest mutation in the three groups. The six severe and common Indian mutations [(IVS 1-5 (GYC), 619 bp deletion, IVS 1-1 (GYT), codons 8/9 (+G), codon 15 (GYA), codons 41/42 (-CTTT)] accounted for 92.0% of molecular lesions in the thalassemia major group, 86.8% in the severe TI group, and 72.9% in the mild TI group. IVS 1-1 (GYT) and codon 30 (GYC) were significantly more common in thalassemia intermedia cases. The mild capsite +1 (AYC) mutation was present in both severe and mild cases. Three other mild h + mutations, poly A (TYC), -28 (AYG), and -88 (CYT), were seen only in the thalassemia intermedia cases. These four mild mutations in combination with other severe h + or h 0 mutations resulted in a very variable clinical presentation. This study reveals that, in majority of Indian patients, the h genotype cannot predict the phenotype. D 2004 Elsevier Inc. All rights reserved. Keywords: h thalassemia mutations; Phenotypes; India Introduction The h thalassemias are an extremely heterogeneous group of single gene disorders due to an absence or reduction of h globin synthesis. Homozygotes and com- pound heterozygotes exhibit a varied clinical expression ranging from the severe transfusion-dependent disorder from early infancy or thalassemia major to the relatively milder thalassemia intermedia phenotype [1]. This diver- sity is primarily related to the degree of imbalance of globin chain synthesis which could be due to the nature of the h gene mutations or due to interaction with a or g loci [1]. In this study, we have characterized the h thalassemia mutations in severe and mild cases to evaluate their contribution in clinical diversity in Indian patients. 1079-9796/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.bcmd.2004.05.002 * Corresponding author. Institute of Immunohaematology (ICMR), 13th Floor K.E.M. Hospital Campus, Parel, Mumbai 400012, India. Fax: +91 24138521. E-mail address: colah@vsnl.com (R. Colah). Blood Cells, Molecules, and Diseases 33 (2004) 153 – 157 www.elsevier.com/locate/ybcmd