Genotype-Phenotype Correlation of Seven Known and Novel β-Globin Gene Variants.

Variants of uncertain significance (VUS) are often challenging for genetic counseling and require additional data for accurate variant classification. This study aims to describe the genotype-phenotype correlation of the seven β-globin gene variants found in Thailand. Retrospective data in a total of 45,914 subjects encountered at our diagnostic laboratory from January 2012 to December 2024 were reviewed. A total of 33 leftover EDTA blood specimens, suspected of having β-globin gene defects, were included. Eighty-nine normal subjects were also analyzed to confirm phenotypic expression of the variants. The whole β-globin and Krüppel-like factor 1 () genes were examined using PCR-based methods. Seven nucleotide variants were identified among 33 suspected subjects, including a novel (β), four hitherto undescribed in Thailand [β, β, β, and β], and two known variants [β and β]. The β and β variants were also identified in 1.69% of normal subjects, indicating neutral DNA polymorphisms. All subjects of β, β, β, and β with borderline Hb A levels had mutations. Compound heterozygous β and known β-thalassemia trait revealed β-thalassemia trait phenotype. In silico pathogenicity prediction showed that the β, β, β, β, β, and β were associated with benign variants. It was found that heterozygous β had elevated Hb A levels resembling those of β-thalassemia trait. However, the association of the β and Hb E or β-thalassemia revealed a phenotype of Hb E or β-thalassemia trait. Most prediction tools indicate that the β is associated with benign variants; however, PromoterAI revealed that the β is associated with under-expression of the β-globin gene with high sensitivity. Based on these findings, the β is most likely a very mild β-thalassemia allele. This study described the genotype-phenotype correlation of known and novel β-globin gene variants found in Thailand. The data should prove useful for accurate variant classification, genetic counseling, and a prevention and control program of severe thalassemia diseases in Thailand.