Rare mutations in the beta-globin gene and their clinical phenotypes

Abstract

Objectives: Beta-thalassemia is one of the most common inherited genetic disorders and the repertoire of mutations in the beta-globin gene is ever-expanding. Sequencing for beta-globin gene mutations, is done, where phenotype-high-performance liquid chromatography discrepancies exist or where amplification refractory mutation system – polymerase chain reaction (ARMS-PCR) cannot identify common mutations, and often leads to the discovery of rare and novel mutations. Materials and Methods: This is a retrospective data analysis of 160 patients of beta-thalassemia and other hemoglobinopathies where some patients were found to have unexplained clinical features. Comprehensive genetic diagnosis was done on these patients by ARMS-PCR, gap-polymerase chain reaction, and sequencing. Results: Out of the total, 124 cases were homozygous/compound heterozygous for beta-thalassemia; 26 cases had heterozygous beta mutations with coexistent alpha-triplications and four patients (with unique clinical features) were found to harbor five rare mutations. The mutations detected were hemoglobin (Hb) Monroe (co-occurring with beta nt-42 mutation), beta-globin mutation −90(C>T), Hb Randwick, and Hb-M-Saskatoon (a variant hemoglobin causing methemoglobinemia and cyanosis). The spectrum of common mutations detected, in our study, was similar to that published in the literature. The unique clinical features of the patients were conclusively explained by the sequencing results. Conclusion: This study emphasizes the role of sequencing in the genetic diagnosis of beta-thalassemia. As next-generation sequencing increasingly finds use in routine diagnostics, newer clinically significant mutations will continue to be added to the large palette of mutations in beta-thalassemia.