[Clinical and genetic analysis of two families with combined defect in antithrombin and protein C genes].

Objective: To analyze the clinical characteristics and genetic mutations in two families with combined antithrombin (AT) and protein C (PC) deficiency, and to explore the relationship between combined SERPINC1 and PROC gene mutations and disease development. Methods: The AT activity (AT∶A) , AT antigen (AT∶Ag) , PC activity (PC∶A) , PC antigen (PC∶Ag) , and protein S activity (PS∶A) of the probands and their family members were measured. Next-generation sequencing (NGS) and CNVplex technology were used to detect point mutations, small deletions or insertions, and CNVs in the coding and regulatory regions of the selected genes, with mutation sites verified by Sanger sequencing. The conservation of mutation sites was analyzed using ClustalX-2.1-win software; the pathogenicity of these mutations was predicted using online bioinformatics tools; thrombin generation was assessed using the CAT method. Results: In proband 1, a c.400+5G>A splice site mutation was found in exon 5 of the PROC gene, along with a c.883G>A (p.Val295Met) heterozygous missense mutation in exon 5 of the SERPINC1 gene; in proband 2, a c.811C>T (p.Arg271Trp) heterozygous missense mutation in exon 9 of the PROC gene and a c.880C>T (p.Arg294Cys) heterozygous missense mutation in exon 5 of the SERPINC1 gene were identified. The mutation sites were inherited from the patient's father and mother, respectively. Bioinformatics analysis revealed that most of the mutation sites were conserved, and the majority of these gene mutations were predicted to be "disease-causing and harmful." These mutations may lead to abnormal levels or functions of AT and PC by altering protein structure and destabilizing protein stability. Thrombin generation tests showed that all four mutation carriers exhibited varying degrees of increased endogenous thrombin potential, indicating a hypercoagulable state. In the presence of soluble thrombomodulin (sTM) , the anticoagulant function of the PC pathway was significantly impaired. Conclusion: Two families were found to harbor mutations in AT and PC genes, respectively, which may contribute to recurrent venous thromboembolism in the affected patients. Notably, individuals carrying combined mutations in the SERPINC1 and PROC genes have a significantly higher risk of venous thrombosis.