A Novel F12 Gene Pathogenic Mutation Identified in a Consanguineous Pedigree with Clustered Thrombotic and Pulmonary Disease

Background: Factor XII (FXII, Hageman factor) is important in the activation of intrinsic coagulation system measured by activated partial thromboplastin time (APTT). Congenital FXII deficiency is a rare disease caused by mutations in the F12 gene. The epidemiological data about the clinical manifestations of patients with congenital FXII deficiency are equivocal. While some individuals exhibit an elevated thrombotic risk, others remain asymptomatic. We elucidated a novel F12 mutation in a consanguineous pedigree with clustered thrombotic and pulmonary disease and provided molecular analysis.

Methods: We report a 44-year-old male patient who presented to our hospital because of significantly prolonged APTT without bleeding symptoms. He has a notable family history of both thrombosis and cancer. And he had encountered 2 episodes of myocardial infarction (MI) at ages 30 and 44 and received percutaneous coronary intervention (PCI) /stenting therapy 8 months ago. We detailed clinical manifestations, pedigree survey, biochemical examinations and gene diagnosis in the patient's pedigree. Genomic DNA was extracted from the proband's peripheral blood and investigated using Whole-exome sequencing (WES). The conformational changes of FXII protein were predicted using SWISS-MODEL. PCR targeted amplification and Sanger sequencing were performed to confirm the mutation and familial pedigree in the candidate gene.

Results: In the proband, APTT was significantly prolonged to > 200 s (reference: 22.6-32.1 s), and FXII activity (FXII:C) was decreased to 1.8% (reference: 50%-150%), while other hemostatic laboratory parameters remained within normal limits.

In terms of pedigree investigations, the proband's parents are first cousins, indicating that the 20 individuals across 5 generations included in the study share varying degrees of consanguinity. His mother, father, grandfather, one uncle and two aunts all have suffered MI, and another aunt has suffered deep vein thrombosis (DVT). Furthermore, his mother, another uncle and grandfather also have suffered cerebral infarction (CI). In this pedigree, a familial aggregation of pulmonary diseases also has been observed. His grandmother, grandmother's brother, father and one aunt have been diagnosed with lung cancer, while his mother and another aunt have been found to have pulmonary nodules.

A novel genetic aberration was identified in this pedigree: a previously unreported truncating-type mutation in F12 (c.303_304delGA, p.H101Qfs*36). This deletion involves the removal of guanine and adenine at positions 303_304 within the coding region, which caused the substitution of glutamine for histidine at amino acid position 101, accompanied by sequential amino acid alterations and the presence of a stop codon at amino acid position 36. This mutation induced a frameshift and premature stop codon, resulting in the formation of a truncated protein characterized by the complete absence of the crucial catalytic domain. In this pedigree, the proband was homozygous for the F12 mutation, whereas his heterozygous parents, son, and an uncle all exhibited reduced FXII:C levels; notably, the son and uncle did not experience any thrombotic events. This observation highlights an intriguing phenomenon of variable thrombotic presentations among individuals carrying the mutation within this pedigree. Additionally, among family members with a history of thrombosis, some do not carry this mutation. Considering the family's cancer history, we hypothesize that there may be additional mutations contributing to an increased risk of thrombosis and cancer in conjunction with this mutation. Therefore, we will subsequently perform WES and coagulation-related laboratory assessments to investigate this hypothesis.

Conclusions: This report provides a comprehensive overview of a consanguineous pedigree with a novel F12 pathogenic mutation, illustrating the diversity of clinical manifestations that may be associated with this mutation. Although there is a clear clustering of thrombotic events and pulmonary diseases within this pedigree, the relationship between these observations and the F12 mutation requires further validation. This report broadens our understanding of the genetic horizons of congenital FXII deficiency and provides evidence for the diversity of clinical presentations.

No relevant conflicts of interest to declare.