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

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 <i>HBB</i>: c.84_85insC (β^{CD27/28 (+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: <i>HBB</i>:c.315 + 16G &gt; C (IVS-II-16 G &gt; C) and <i>HBB</i>: c.316-185C &gt; T (IVS-II-666 C &gt; T). After excluding the occurrence of other known pathogenic mutations of β-thalassemia, we propose that the compound heterozygous mutation of <i>HBB</i>: 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 <i>HBB</i> intronic variants and expand the mutational spectrum relevant for prenatal diagnosis and genetic counseling of β-thalassemia.