Abstract
BACKGROUND: Hemophilia A (HA) is an X-linked disorder due to deleterious variants in the factor VIII (FVIII) gene (F8). Few studies from large cohorts have explored F8 genotype in people with HA with origins other than North American and European. OBJECTIVES: We aimed to evaluate the spectrum of F8 variants and haplotypes and affected FVIII domains and chains in the context of inhibitor development in people with severe hemophilia A. METHODS: We performed genotyping of intron 1 and intron 22 inversions (Inv22) and F8 sequencing using a customized gene panel and whole exome sequencing. RESULTS: We included 265 people with severe hemophilia A. We identified deleterious variants in 98.1% of them, totaling 97 unique mutations, of which 32 (33.0%) are novel. Inv22, nonsense, small insertion/deletion, large deletion, and missense variants accounted for 48.3%, 14.7%, 11.3%, 9.8%, and 7.5% of the variants identified. Variants clustered in the FVIII A3 domain were more often associated with people with HA with inhibitors (INH+) than those without inhibitors (INH-) (21.0% vs 0.0%; P < .001); variants clustered in the A1 domain were more often associated with INH- than with INH+ individuals (33.3% vs 7.7%; P < .001). Inv22 was associated with a 4.8-fold increased risk of developing inhibitors in previously untreated patients (odds ratio, 4.81; 95% CI, 2.02-12.01). Conversely, missense variants protected against inhibitor development (odds ratio, 0.09; 95% CI, 0.01-0.50). CONCLUSION: These findings highlight the role of F8 genotype and specific FVIII domains in inhibitor development in an admixed population of people with HA. This could help engineer therapeutic approaches targeting FVIII molecules with reduced immunogenicity.