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β-thalassemia; IVS-II-5 G>C; genotype; phenotype
Background: IVS-II-5 G>C (HBB: c.315+5 G>C) is a rare β-thalassemia mutation. However, there is no clear evidence regarding the effect of this defect or co-inheritance of other β-thalassemia mutations on phenotypes.
Methods: The clinical phenotypes associated with compound heterozygosity for the IVS-II-5 G>C mutation with other β-thalassemia mutations, together with the potential effect of the genetic modifiers α-thalassemia were studied in 13 patients. Analyses of red cell indices, hemoglobin component, iron status, and α-globin genes were carried out in 19 heterozygotes.
Results: Next-generation sequencing of 24 undiagnosed patients with thalassemia major (TM) or thalassemia intermedia (TI) 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 β-thalassemia mutations are phenotypically severe enough to necessitate appropriate therapy and counseling. Co-inheritance of this nucleotide substitution with other β-thalassemia mutations may account for a considerable portion of the incidence of undiagnosed patients with TI and TM in Guangxi. The IVS-II-5 G>C mutation can pose serious difficulties in screening and counseling.
Keywords: β-thalassemia; IVS-II-5 G>C; genotype; phenotype
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