F12 – congenital factor XII deficiency

Clinical Validity

F12 is definitively associated with congenital factor XII deficiency based on reports of bi-allelic pathogenic variants in 27 unrelated probands from over 13 families, consistent autosomal recessive inheritance, and concordant biochemical and cellular data.

Genetic Evidence

Autosomal recessive inheritance is confirmed by segregation of homozygous variants in 18 additional affected relatives from 13 families (PMID:2055558) and by independent case series including 4 Chinese probands (PMID:27003566) and 5 Taiwanese probands (PMID:35675023). The mutational spectrum comprises at least 29 missense changes, multiple small insertions/deletions, splice, and promoter variants. A recurrent missense variant, c.1561G>A (p.Glu521Lys), has been identified in multiple unrelated patients (PMID:26709783).

Functional Evidence

In vitro expression studies in COS-7 and HEK293T cells demonstrate that missense variants such as p.Glu521Lys undergo intracellular proteasomal degradation with markedly reduced secretion of FXII (PMID:10361128) and that promoter mutations at –8 and –13 reduce F12 transcriptional activity. Additional expression analyses of the Asp538Asn mutant confirm impaired secretion consistent with a cross-reacting material–negative phenotype (PMID:26882823).

Phenotypic Spectrum

Affected individuals uniformly present with markedly prolonged activated partial thromboplastin time (aPTT) without clinical bleeding. Some homozygous patients have experienced thrombotic events or recurrent pregnancy loss, reflecting variable penetrance of thromboinflammatory manifestations.

Conflicting Evidence

Heterozygous carriers exhibit ~50% FXII activity but remain asymptomatic, underscoring recessive pathogenicity. No studies have refuted the F12–congenital factor XII deficiency association.

Conclusion

Strong genetic and functional data establish F12 as the definitive gene for congenital factor XII deficiency. Genetic testing for F12 variants is essential in the evaluation of isolated prolonged aPTT and informs clinical management.

Key Take-home: F12 genetic analysis should be pursued in individuals with unexplained prolonged aPTT to confirm diagnosis and guide counseling.

References

• Haematologica • 1991 • Fibrinolytic studies in 13 unrelated families with factor XII deficiency. PMID:2055558
• Acta haematologica • 2016 • Identification of Genetic Defects Underlying FXII Deficiency in Four Unrelated Chinese Patients. PMID:27003566
• International journal of hematology • 2022 • Characterization of congenital factor XII deficiency in Taiwanese patients: identification of one novel and one common mutation. PMID:35675023
• Frontiers in bioscience (Landmark edition) • 2016 • Novel mutations in congenital factor XII deficiency. PMID:26709783
• Blood • 1999 • Factor XII Tenri, a novel cross-reacting material negative factor XII deficiency, occurs through a proteasome-mediated degradation. PMID:10361128
• Clinical laboratory • 2015 • Molecular Characterization of a Novel Missense Mutation (Asp538Asn) in a Chinese Patient with Factor XII Deficiency. PMID:26882823
• Journal of medical case reports • 2023 • Homozygous missense variant F12 (Gly506Asp) associated with severe factor XII deficiency: a case report PMID:38057855

Evidence Based Scoring (AI generated)