Submission Details

The relationship between F12 and congenital factor XII deficiency inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of January, 2020. This association was made using case-level and experimental data. Pathogenic variants in this gene reported in humans range from partial deletions and duplications, nonsense, frameshift, missense and splicing variants. Congenital Factor XII deficiency does not manifest as overt clinical symptoms and is diagnosed as an incidental finding when patients are tested for other reasons. Studies indicate that FXII deficiency neither predisposes to venous thromboembolism nor protects against it (PMID: 25696836, 15306750). Nevertheless, mutations in F12 result in reduced activity with or without reduced antigen levels of FXII. Mutations in F12 were first associated with this disease in humans as early as 1987 by Bernardi et al. (PMID: 2882793); however, the molecular defect was reported by Miyata et al in 1989 (PMID: 2510163).

Summary of Case Level Data (12 points): The association is seen in at least 11 probands in 8 publications (PMID: 29383625, 20022356, 18024408, 20386432, 26709783, 21264442, 28007010, 15205584). 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 is expected to be biallelic loss of function, with heterozygous individuals usually having intermediate levels of factor activity.

Summary of Experimental Data (4 points): FXII is the first component of the intrinsic pathway of the coagulation cascade and activates FXI (PMID: 30700128). The significance of FXII in the coagulation pathway is not clear, however. Mouse models are reported that recapitulate FXII deficiency, without any clinical manifestations, suggesting that FXII deficiency does not affect hemostasis in vivo (PMID: 15351846). This is similar to what is observed in humans. In cats, FXII deficiency is a naturally occurring defect and leads to complete lack of FXII activity and antigen (PMID: 31022435).

In summary, the F12-Congenital FXII 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 January 22, 2020 (SOP Version 7).

Lumping & Splitting information: OMIM assertions - (1) Angioedema, hereditary, type III (MIM: 610618); (2) Factor XII deficiency (MIM: 234000). Orphanet assertions - (1) F12-related hereditary angioedema with normal C1Inh; (2) Congenital factor XII deficiency. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found the phenotype, inheritance pattern and molecular mechanism underlying the two disease entities to be different and hence the association of F12 with each entity was evaluated separately.