Molecular characterization of Hemophilia A in Mongolia: identification of a novel F8 frameshift mutation

Introduction: Identifying pathogenic variants in the F8 gene in patients with hemophilia A (HA) is crucial for improving genetic counseling, understanding genotype–phenotype correlations, assessing inhibitor risk, and establishing family-specific mutation profiles. Methods Long-distance were used to detect intron-22 and intron-1 inversions. While Sanger sequencing identified point mutations. Inhibitors were assessed via an activated partial thromboplastin time (APTT)-based mixing assay. Results Thirty male patients with HA from 25 unrelated families (28 severe, one moderate, and one mild) were analyzed. Pathogenic variants were found in 95.6%(22/23) of patients with severe HA. Large structural rearrangements were detected in 20 patients from 17 families, including intron-22 inversion in 16 cases of 14 families, intron-1 inversion in three cases from two families, and one gross deletion involving exons 1–13 identified in a single family. The one severe case had no pathogenic variant entire F8 . Small scale changes were identified in the remaining patients, including missense in three families and two frameshift variants, all associated with severe phenotype. We found novel c.2240del variant and classified as pathogenic. A known polymorphism (c.3864A > C) was identified in one patient with moderate HA, while a novel intronic deletion (c.1010-106delA) was detected in a patient with mild disease. Inhibitor testing was performed in 13 patients; inhibitor development was observed in only one patient with severe HA. Conclusions Intron-22 (60.8%) and intron-1 (8.6%) inversions in severe patients were observed at higher frequencies than previously reported. A novel pathogenic frameshift variant (c.2240del) was associated with severe HA.