Identification of a Patient with Transfusion-Dependent β-Thalassemia Caused by Compound Heterozygous Mutations of HBB: C.84_85insC and Common Linked Intronic Variants in HBB.

Severe forms of β-thalassemia are typically autosomal recessive disorders characterized by hemolytic anemia, jaundice, and hepatosplenomegaly. More than 300 variants in the β-globin gene cluster have been reported, revealing a complex genotype-phenotype landscape. Here, we report a transfusion-dependent β-thalassemia proband carrying only one allele with the known common frameshift mutation HBB: c.84_85insC (βCD27/28 (+C)), which is expected to lead to premature termination of β-globin synthesis. Whole-genome sequencing (WGS) revealed two additional intronic variants in the proband: HBB:c.315 + 16G > C (IVS-II-16 G > C) and HBB: c.316-185C > T (IVS-II-666 C > T). After excluding the occurrence of other known pathogenic mutations of β-thalassemia, we propose that the compound heterozygous mutation of HBB: c.84_85insC and these intronic mutations contributes to the severe clinical manifestations in this case. Furthermore, WGS identified several variants in the HBS1L-MYB intergenic region, which may be associated with the markedly elevated HbF level (73.6%) observed. In summary, our findings enhance the understanding of phenotypic diversity attributable to HBB intronic variants and expand the mutational spectrum relevant for prenatal diagnosis and genetic counseling of β-thalassemia.