The relationship between F11 and congenital factor XI deficiency inherited in the autosomal recessive and dominant patterns has been evaluated using the ClinGen Clinical Validity Framework as of November, 2018. This association was made using case-level and experimental data. More than a 100 pathogenic variants in this gene are reported in humans, ranging from whole gene deletions, partial deletions and duplications, nonsense, frameshift, missense and splicing variants. Congenital Factor XI deficiency is characterized by a bleeding diathesis, diagnosed by a prolonged aPTT but normal PT and reduced factor XI activity and antigen levels. Mutations in F11 were first associated with this disease in humans as early as 1989 by Asakai et al. (PMID: 2813350).
Summary of Case Level Data (12 points): The association is seen in at least 10 probands in 5 publications (PMID: 15026311, 15953011, 15180874, 21649796, 2813350, 22159456). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached.
The mechanism for disease has been reported to be biallelic loss of function as well as a dominant negative effect (PMID: 15026311, 2813350).
Summary of Experimental Data (4.5 points): FXI activates FIX in the blood coagulation pathway (PMID: 3286010). Mouse and cattle models are reported that recapitulate FXI deficiency (PMID: 15566468, 9518045). In Holstein cows, FXI deficiency is naturally occurring and leads to bleeding symptoms. The deficiency is also reported in dogs (PMID: 5166932).
In summary, the F11-Congenital FXI deficiency gene-disease relationship is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hemostasis/Thrombosis GCEP on October 23, 2019 (SOP Version 6).
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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