F8 – Hemophilia A

Hemophilia A is an X‐linked recessive bleeding disorder caused by loss‐of‐function mutations in F8, which encodes coagulation factor VIII. The gene–disease relationship is Definitive per ClinGen, supported by over 1 000 distinct pathogenic F8 variants identified in thousands of unrelated hemophilia A patients, robust segregation in multigenerational pedigrees, and concordant functional studies demonstrating loss of coagulant activity ([PMID:1979502]).

F8 mutations are inherited in an X‐linked recessive manner, with affected males and rare homozygous or skewed‐X inactivated females. Segregation analyses in pedigrees, including one family with 12 affected males and one female homozygote, confirm co‐segregation of F8 variants with disease ([PMID:39724248]). Case series have screened 793 unrelated hemophilia A patients for point mutations at CpG hotspots, identifying recurrent and novel C→T transitions in arginine codons—particularly intron 22 inversions in 45% of severe cases ([PMID:1979502]).

The F8 variant spectrum includes large inversions (Inv22, Inv1), nonsense and frameshift mutations causing null alleles, splice‐site defects, and missense substitutions across the A, B, and C domains. A prototypical missense change is c.1115C>T (p.Ser372Phe), which disrupts thrombin cleavage at Arg372 and impairs cofactor activation ([PMID:1973901]). Other hotspot substitutions, such as c.6506G>A (p.Arg2169His), affect the C2 domain and reduce binding to von Willebrand factor ([PMID:9184393]).

Functional studies confirm a haploinsufficiency mechanism. The Ser372Phe variant resists essential heavy‐chain cleavage, yielding hypofunctional cofactor activity in vitro ([PMID:2109644]). C2 domain mutations impair FVIII–vWF binding and accelerate clearance. Recombinant B‐domain–deleted FVIII variants engineered for resistance to proteolytic inactivation (e.g., IR8) demonstrate that focused mutations can alter stability and activity, validating key domain interfaces in vivo and in animal models ([PMID:9342326]).

Rare reports describe partial gene duplications or inversions that do not produce a bleeding phenotype. A family with partial F8 duplication and intron 22 inversion exhibited normal FVIII transcript integrity and no clinical hemophilia A, highlighting complexity in structural variant interpretation ([PMID:36845383]).

Overall, extensive genetic and experimental data establish F8 loss‐of‐function as the cause of hemophilia A. The variety of mutation types, recurrent founder alleles, and precise functional assays support reliable molecular diagnosis, variant interpretation, and targeted therapeutic strategies.

Key take‐home: Comprehensive F8 mutational analysis underpins definitive genetic diagnosis and informs personalized management of hemophilia A.

References

• Blood • 1990 • The molecular genetic analysis of hemophilia A: a directed search strategy for the detection of point mutations in the human factor VIII gene. PMID:1979502
• British journal of haematology • 1990 • CRM+ haemophilia A due to a missense mutation (372----Cys) at the internal heavy chain thrombin cleavage site. PMID:1973901
• Blood • 1990 • Purification and characterization of factor VIII 372-Cys: a hypofunctional cofactor from a patient with moderately severe hemophilia A. PMID:2109644
• Thrombosis and haemostasis • 1997 • Factor VIII Ise (R2159C) in a patient with mild hemophilia A, an abnormal factor VIII with retention of function but modification of C2 epitopes. PMID:9184393
• Proceedings of the National Academy of Sciences of the United States of America • 1997 • Characterization of a genetically engineered inactivation-resistant coagulation factor VIIIa. PMID:9342326
• Frontiers in genetics • 2023 • F8 gene inversion and duplication cause no obvious hemophilia A phenotype. PMID:36845383

Evidence Based Scoring (AI generated)