关键词: F12基因, Kringle结构, 基因突变, 凝血因子Ⅻ缺陷

Abstract: Objective To analyze the clinical phenotype and genetic variation of a consanguineously married family with deficiency resulting from a homozygous missense mutation c.826T>C (p.Cys247Arg) in exon 8 of the coagulation factor Ⅻ (FⅫ) gene, and investigate the molecular mechanism. Methods A male proband with hereditary FⅫ deficiency, who was found to have abnormal coagulation function during a physical examination for hematopoietic stem cell donation on October 13, 2023, and his family members (five individuals across three generations) were selected as the research subjects. Using direct DNA sequencing technology, we conducted a comprehensive analysis of the F12 gene in the proband, which included the determination of all exons and their flanking sequences, as well as the analysis of corresponding variant regions in family members. The potential pathogenicity of the variant sites was assessed using bioinformatics software. Results The proband activated partial thromboplastin time (APTT) was significantly prolonged to 158.4 seconds, while the APTT mixing test showed correction. The proband's Factor Ⅻ activity (FⅫ:C ) and Factor Ⅻ antigen (FⅫ:Ag ) were 0% and 2% respectively. A homozygous missense mutation c.826T>C (p.Cys247Arg) was identified in exon 8 of the F12 gene, with both the father and mother being heterozygous carriers of this variant. Bioinformatics software analysis revealed that Cys247 is highly evolutionarily conserved, and this variant was determined to be pathogenic. Conclusion The c.826T>C variation in exon 8 of F12 gene might be associated with the decreased level of FⅫ in this family, and this variation was first reported in the world.

Key words: F12 gene, Kringle structure, Gene variation, Coagulation factor Ⅻ deficiency