F8 gene mutation spectrum in severe hemophilia A with inhibitors: A large cohort data analysis from a single center in China

Introduction Type of F8 gene mutation is the most important risk factor for inhibitor development in people with severe hemophilia A. However, there are few large cohort studies on the F8 mutation spectrum of people with severe hemophilia A with inhibitors. Objective This was the first large cohort study in children with severe hemophilia A with inhibitors from China that aimed to analyze the association between F8 variant types and inhibitor status. Methods The single-center retrospective cohort study was conducted on children with severe hemophilia A with inhibitors admitted from January 2015 to December 2021. The clinical data were collected, and F8 genetic tests were performed. Results Among the 203 patients investigated, a mutation in F8 was identified in 196 cases. Most patients had deleterious mutations (153; 75.4%), including 82 cases of intron 22 inversions (40.4%); 40 cases of nonsense mutations (19.7%), with 15 cases in the light chain and 25 cases in the heavy chain; and 31 cases of large deletions or insertions (15.3%), with 29 cases involving more than one exon and 2 cases involving one exon. The large deletions or insertions encompassing multiple exons and nonsense mutations residing in the light chain were associated with not only the progression to a high-titer inhibitor (P < .05) but also higher peak inhibitor titer (P < .05). Conclusion The F8 gene deleterious mutations, including intron 22 inversions, nonsense mutations, and large deletions or insertions, constitute the main mutation types in people with severe hemophilia A with inhibitors in China, with the latter mutation types (large deletions or insertions in multiple exons, and nonsense mutations in the light chain) signifying for a higher peak titer of inhibitor.