Direct sequencing of β-globin gene reveals a rare combination of two exonic and two intronic variants in a β-thalassemia major patient: a case report

BACKGROUND: Due to indels in the β-globin gene, patients with β-thalassemia major exhibit a range of severity, with genotype β(0)β(0) > β(0)β(+) > β(+)β(+), according to the production level of the β-globin chain. More than 300 mutations have been identified in the β-globin gene. CASE PRESENTATION: In this case study, we report a compound heterozygous condition with a rare concoction of four different variants (CD 3(T > C), CD41/42 (-CTTT), IVS II-16 (G > C), and IVS II-666 (C > T) in a single β-globin gene. A regular transfusion-dependent 4-year-old male patient from India was included in the study. Augmented direct sequencing of the β-globin gene helped reveal the presence of an unusual combination of different variants in a single gene. This patient clinically presented as β-thalassemia major and was genotypically considered as β(0)β(+), although CD41/42(-CTTT) was the only causative/pathogenic mutation in the disease severity. CONCLUSION: Although CD41/42-(CTTT) is the only pathogenic variant among the four variants, the clinical complications of such a combination of variants (pathogenic and benign) is not well understood. Intronic mutations may have the ability to modify clinical characteristics. The variants must therefore be reclassified using additional mRNA splicing and expression-based studies. Additionally, these types of combinations may have significance in studying population migration around the world.