Clinical heterogeneity in congenital factor XII deficiency: Coexisting risk factors in thrombotic and bleeding events

Summary

Congenital factor XII (FXII) deficiency is a rare disorder resulting from F12 gene mutations and its precise contribution to thrombotic or haemorrhagic risk has yet to be established. We identified the same mutation of the F12 gene across five pedigrees, yet the clinical manifestations varied markedly, ranging from asymptomatic to thrombotic and haemorrhagic phenotypes. Haematological assessments and deoxyribonucleic acid sequencing were conducted in five pedigrees. All five probands displayed prolonged activated partial thromboplastin time, markedly reduced FXII activity and an identical frameshift mutation in F12 (c.303_304delCA, p.H101Qfs*36), leading to the loss of functional domains. In Pedigree A, characterized by thrombotic clustering, thrombotic events were documented in 4 of 6 mutation carriers and 4 of 13 non‐carriers. In Pedigree B, the proband experienced bleeding events, and her father died of intracerebral haemorrhage. Probands C and D remained asymptomatic. Proband E was diagnosed with essential thrombocythaemia and thrombosis. Across all pedigrees, haemorrhagic or thrombotic events could be attributed to additional contributing factors. The identified apolipoprotein E and butyrophilin subfamily 2 member A1 variants were consistently associated with thrombotic events in Pedigree A. This F12 variant does not appear to independently drive pathological coagulation phenotypes but may potentiate susceptibility to thrombosis in the presence of additional genetic or acquired risk factors.