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

Abstract

Background Due to indels in the β-globin gene, patients with β-thalassemia major exhibit a range of severity, with genotype β0β0 > β0β+ > 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 β0β+, 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.

Genetic counseling for pre-implantation genetic testing of monogenic disorders (PGT-M)

“…If the variation is confirmed either in the index case or the carrier parents, PGT-M can be offered for the condition (Figure 1). (b) If common genetic variations are absent in a case with clear cystic fibrosis or sickle cell anemia phenotypes, the genetic counselor will order tests with wider scope such as full gene sequencing of CFTR or beta globin gene to identify rare pathogenic variations (28,29). Many times it is seen that the individual with sickle cell anemia may actually have sickle cell thalassemia with a sickle cell heterozygous variation and a thalassemia heterozygous variation (30).…”