F8 was reported in relation to X-linked Hemophilia A as early as 1985 (Gitschier et al., PMID: 2987704). More than 1000 pathogenic variants in this gene are reported in humans, ranging from whole gene deletions, partial deletions and duplications, nonsense, frameshift and splicing variants to a number of functionally-characterized missense variants. Hemophilia A is characterized by severe bleeding diagnosed by an increased bleeding time, reduced Factor VIII activity and antigen levels. Spontaneous bleeding into joints and soft tissues is often reported. Summary of Case Level Data (12 points): Variants in this gene are reported in at least 14 probands in 8 publications (PMIDs: 2987704, 30210749, 3035554, 10886198, 8281136, 2105106, 16805874, 28252515). Variants in this gene segregated with disease in 10 additional family members. More case-level evidence is available in the literature, but the maximum score for genetic evidence has been reached.
The mechanism for disease is hemizygous loss of function in males, with the majority of variants observed resulting in undetectable FVIII activity (PMID: 2987704). Homozygous loss of function is reported in some female patients with severe bleeding diathesis, while most females are heterozygous carriers. A proportion of patients with null variants are reported to develop antibodies to recombinant FVIII. (PMIDs: 24498605, 22102273, 20081061, 19336737).
Summary of Experimental Data (4.5 points): FVIII is involved in the blood coagulation pathway and functions to activate FX by forming the tenase complex with FIX (PMID: 3286010). Hemophilia A has been studied in dogs since 1950 (PMID: 15431070, 24253479, 22137432), while horse (PMID: 6838443) and mouse models (PMID: 7647782, 24705491) also have been used extensively in Hemophilia research. These animal models have been helpful in the development of recombinant FVIII for treatment of Hemophilia A. The F8 gene disruption results in loss of function and absence of detectable FVIII:C in mice with a phenotype of severe bleeding. This is shown to be rescued by RNA trans-splicing to yield a full-length, wild-type protein in FVIII-deficient mice. Gene therapy in humans for Hemophilia A using recombinant adeno-associated virus (rAAV)–mediated gene transfer is at the clinical trials stage.
In summary, the F8-Hemophilia A gene-disease relationship is Definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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