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Severe hemophilia A is an X-linked recessive bleeding disorder caused by pathogenic variants in the F8 gene, leading to factor VIII deficiency (<1% activity) and life-threatening hemorrhage. The association between F8 and Severe Hemophilia A is supported by extensive clinical, genetic, and functional evidence.
F8 variants are inherited in a classic X-linked recessive manner, with rare female cases arising from skewed X-inactivation or compound de novo events. Over 900 unrelated patients with severe hemophilia A have been reported carrying F8 mutations, including intron 22 inversions, large deletions, nonsense and frameshift alleles, and missense changes ([PMID:15810915]; [PMID:26661908]; [PMID:35702590]; [PMID:39276593]). Segregation in multiple families confirms full penetrance in hemizygous males and obligate carrier status in females, with at least 23 additional affected relatives demonstrating co-segregation ([PMID:26661908]).
The F8 variant spectrum encompasses over 250 distinct mutations: large inversions (type I/II), exon deletions, insertions, nonsense and frameshift mutations leading to early termination, and missense substitutions affecting protein folding, stability, or cofactor activity. A representative pathogenic allele is c.1094A>G (p.Tyr365Cys) ([PMID:12139751]), which disrupts the interdomain acidic region and alters thrombin activation kinetics. Other recurrent mutations include intron 22 inversion (~40% of cases), nonsense variants in the light chain, and multi-exon deletions.
Mechanistically, loss-of-function F8 variants result in absent or dysfunctional factor VIII. Functional studies demonstrate accelerated A2 subunit dissociation (e.g., p.Arg531His), impaired von Willebrand factor binding, and reduced factor Xase complex activity in vitro. Recombinant and in vivo models (adenoviral B-domain deletions) corroborate that restoring F8 expression normalizes coagulation parameters and prevents bleeding.
No credible conflicting evidence has emerged disputing the causal link between F8 loss of function and severe hemophilia A. Variants in VWF causing secondary FVIII binding defects represent distinct clinical entities and do not alter the definitive F8–hemophilia A association.
In summary, F8 defects are unequivocally responsible for severe hemophilia A. Genetic testing, including inversion PCR and sequencing, enables precise diagnosis, carrier detection, and informs inhibitor risk stratification. Emerging gene therapy approaches targeting F8 promise durable correction of the bleeding phenotype.
Key take-home: F8 loss-of-function variants cause severe hemophilia A via an X-linked recessive mechanism; comprehensive mutation screening underpins diagnosis, genetic counseling, and tailored therapeutic interventions.
Gene–Disease AssociationDefinitiveOver 900 unrelated severe hemophilia A patients with F8 mutations, consistent X-linked recessive inheritance, multiple segregation and functional concordance across studies. Genetic EvidenceStrongNumerous variant types (inversions, large deletions, frameshift, nonsense, missense) identified in >900 probands, with consistent segregation and recurrence. Functional EvidenceStrongLoss-of-function variants impair factor VIII synthesis or function; in vitro and in vivo models confirm haploinsufficiency mechanism; rescue and characterization studies support pathogenicity. |