F8 Gene
The F8 gene encodes coagulation factor VIII, and defects in this gene cause hemophilia A, the most prevalent inherited bleeding disorder, affecting approximately one in 5,000 male live births. The F8 gene spans roughly 180 kb on the X chromosome at band Xq28 and contains 26 exons, with large inverted repeat sequences that make it susceptible to recurrent structural rearrangements, particularly the intron 22 and intron 1 inversions that together account for approximately half of severe hemophilia A cases.
The F8 mutation spectrum is diverse, with null-allele mutations (large deletions, nonsense, and inversions) carrying elevated risk of inhibitor development — the most significant complication of hemophilia A treatment. Treatment has progressed from plasma-derived concentrates through recombinant factor VIII to AAV-based gene therapy. The first AAV gene therapy for hemophilia A, valoctocogene roxaparvovec, achieved durable efficacy with reduced bleeding rates in long-term follow-up. An investigational Chinese AAV8-based therapy, GS001, has demonstrated sustained FVIII activity at lower vector doses. Engineered gain-of-function FVIII variants are in development to further improve gene therapy by enabling lower vector doses and addressing durability challenges. Gene editing approaches using CRISPR, base editing, and prime editing are emerging as the next therapeutic frontier, with the first CRISPR-based in vivo candidate, MGX-001, advancing toward clinical trials. The B-domain of factor VIII, the largest and most heavily glycosylated region of the protein, has been structurally characterized for the first time using an integrative approach combining AlphaFold2, cryo-electron microscopy, and atomic force microscopy, revealing roles in protein stability and immune recognition. Diagnostic testing follows a stepwise cascade from inversion screening through sequencing, and universal genotyping is recommended for all individuals with hemophilia.