Identification of a Novel Variant in Gene Resulting in a Beta Null Phenotype in a Proband with Thalassemia Intermedia.

A 21-year-old patient presented with a previous medical history of pallor, mild icterus, increased fatigue, low hemoglobin, and abnormal hemoglobin variant analysis with more than 70 transfusions. He was referred for genetic analysis to identify the pathogenic variations in the β-globin gene. Sanger's sequencing of the proband and his family revealed the presence of a novel frame shift variant in a compound heterozygous state with hemoglobin E (HbE) variant. The father and the sibling of the patient were found to be normal for the gene. Mother was found to be heterozygous for HbE ) variant. analysis by Mutalyzer predicted that variant generated a premature stop codon after seven codons, leading to a truncated protein. FoldX protein stability analysis showed a positive ΔΔG value of 45.27 kcal/mol suggesting a decrease in protein stability. : is a known variant coding for HbE variant, which results in the reduced synthesis of β-globin chain and shows mild thalassemia. Combined effect of and variants in the proband might have led to the reduced synthesis of β-globin chains resulting in a thalassemia intermedia type of clinical manifestation.