Effect of Assorted Globin Haplotypes and α-Thalassemia on the Clinical Heterogeneity of Hb S-ß-Thalassemia.

Hemoglobinopathies and thalassemias are the most commonly encountered monogenic disorders of blood in humans, posing a major genetic and public health problem round the globe. Hb S (HBB: c.20A>T)-ß-thalassemia (ß-thal) is a compound aberrant heterozygosity with inconsistent phenotypic expression, which are poorly described and clinically mapped. Comprehensive genetic characterization of such a population is highly warranted for complete understanding of the clinical heterogeneity, disease prognosis and therapeutic management. In this study, Hb S-ß-thal (n = 60) patients, strictly defined by varying degrees of clinical presentations, were selected to evaluate their genotype-phenotype agreement. Furthermore, ß-globin (n = 120) and α-globin gene clusters (n = 60) were genetically characterized and statistically correlated with clinical terminologies to explain the clinical heterogeneity. Our results revealed the association of the Arab-Indian haplotypes with nine different frameworks of ß-thal together with the modulating role of α-thalassemia (α-thal). The study subjects, including carriers of ß-thal haplotype III [- - - - - - -] (8.0%), presented with varying severe patterns of clinical symptoms such as painful crisis, multiple infections and splenomegaly, as an outcome of significantly less Hb F and higher Hb S levels (p < 0.5). The study findings indicated that together with α-thal, ß-thal haplotypes and Hb F levels, may possibly provide a close justification to support the clinical heterogeneity in the study population.

A Novel Frameshift Mutation, Deletion of HBB:c.199_202delAAAG [Codon 66/67 (-AAAG)] in ß-Thalassemia Major Patients from the Western Region of Uttar Pradesh, India.

PURPOSE: Beta thalassemia is one of the most common inherited disorders in India with heterogenous clinical phenotypes from silent carrier to clinically severe ones. Our study aimed to characterize the mutation spectrum in thalassemia patients who are coming to the hospital for follow-up from the western region of Uttar Pradesh India. PATIENTS AND METHODS: For the study, a case series of the retrospective bi-centre study was conducted. The patients from two thalassemia centers in the major hospitals (LLRMC Meerut, and JNMC, Aligarh administered by the Ministry of Health and Family Welfare (MoHFW)) in the Western Uttar Pradesh, India were considered for the study. A total of 77 blood samples were obtained from individuals (both related and unrelated) diagnosed with ß-thalassemia after their consent. After DNA extraction, HBB gene amplification, mutation-specific polymerase chain reaction and gene sequencing were carried out to analyze the mutations. RESULTS: In this study, seven different types of mutations were reported for the first time in Western Uttar Pradesh, India. A novel frameshift mutation, deletion of 4 nucleotides Codon 66/67 (-AAAG) in exon 2 region, is reported for the first time. IVS 1-5 (G>C) and Codon 41/42 (-CTTT) are the most frequently reported mutations. The molecular spectrum for these two cases consists of 44 and 42 alleles out of 108 alleles, respectively. CONCLUSION: A total of 108 ß-thalassemia alleles were studied from 46 homozygous and 31 compound heterozygous patients. All the individuals were from 20 districts of the Western Uttar Pradesh, India.