Clinical and molecular characteristics of hereditary factor XII deficiency in Chinese Han patients: Novel mutations, a high-frequency frameshift variant, and plasma metabolomic profiling.

BACKGROUND: Hereditary factor XII (FXII) deficiency is a rare autosomal recessive disorder rarely causing spontaneous bleeding, though its link to thrombosis remains debated. This study characterized clinical and genetic features of FXII deficiency in Chinese Han patients and performed preliminary in vitro functional assays. METHODS: Clinical and coagulation data from 14 patients diagnosed 2018-2025 were retrospectively collected. Whole-exome sequencing identified F12 variants, followed by ACMG-based pathogenicity assessment. In vitro secretion and chromogenic activity assays were conducted on five novel mutants. Untargeted metabolomics was performed on 10 case-control pairs for hypothesis generation. Semi-quantitative plasma FXII antigen ELISA was completed for eight patients. RESULTS: All patients exhibited prolonged APTT (mean 155.9 ± 89.7 s) and severely reduced FXII activity (mean 3.8 ± 4.0%). Fifteen distinct F12 variants were identified, including eight novel ones. The frameshift variant c.1092dup was homozygous in 28.6% of this single-center cohort. In vitro, p.Q254P, p.S528Y, p.G376W, and p.V211Wfs*40 showed severely impaired secretion, whereas p.A255S secreted normally. In a silica-induced chromogenic assay using crude cell supernatants, p.A255S retained approximately 95% of wild-type activity; however, functional consequences remain incompletely characterized. Untargeted metabolomics revealed differential metabolites enriched in lipid and amino acid pathways. ELISA showed reduced plasma FXII antigen (23.9%-30.5% of normal), though these data are semi-quantitative due to dilution requirements and differences in sample storage duration. CONCLUSION: This study delineates clinical and genetic profiles of Chinese Han FXII-deficient patients, expands the F12 variant spectrum with eight novel mutations, and provides preliminary in vitro secretory evidence. The high c.1092dup homozygous rate requires validation in larger multi-center cohorts. All findings are constrained by the small single-center design.