The Clinical Significance of the Spectrum of Interactions of the Rare IVS-II-5 G > C (HBB: c.315+5 G > C) Variation with Other beta-Thalassemia Mutations in Southern China

Background: IVS-II-5 G>C (HBB: c.315+5 G>C) is a rare beta-thalassemia mutation. However, there is no clear evidence regarding the effect of this defect or co-inheritance of other beta-thalassemia mutations on phenotypes. Methods: The clinical phenotypes associated with compound heterozygosity for the IVS-II-5 G>C mutation and other beta-thalassemia mutations, together with the genetic modifiers' potential effect of the genetic modifiers alpha-thalassemia, were studied in 13 patients. In addition, analyses of red cell indices, hemoglobin component, iron status, and alpha-globin genes were carried out in 19 heterozygotes. Results: Next-generation sequencing of 24 undiagnosed patients with transfusion-dependent thalassemia (TDT) or non-transfusion-dependent thalassemia (NTDT) identified 13 carriers of the IVS-II-5 G>C mutation. There was a wide spectrum of phenotypic severity in compound heterozygotes and 6 (46.2%) of 13 were transfusion dependent. Analysis of 19 heterozygotes indicated that most were hematologically normal without appreciable microcytosis or hypochromia, and approximately half had normal hemoglobin A2 levels at the same time. Conclusion: Compound heterozygotes for IVS-II-5 G>C and other severe beta-thalassemia mutations are phenotypically severe enough to necessitate appropriate therapy and counselling. Co-inheritance of this nucleotide substitution with other beta-thalassemia mutations may account for a considerable portion of the incidence of undiagnosed patients with NTDT and TDT in Guangxi. Therefore, the IVS-II-5 G>C mutation can pose serious difficulties in screening and counselling.