Wu Conglian, Zhang Zhishan, Chen Yiyin, Tian Mengcha, Liu Meina, Cheng Shuibing
Department of Clinical Laboratory, Quanzhou First Hospital Affiliated to Fujian Medical University, Fujian, People's Republic of China.
Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Zhejiang, People's Republic of China.
Hematology. 2025 Dec;30(1):2524235. doi: 10.1080/16078454.2025.2524235. Epub 2025 Jul 2.
This study aimed to analyze the phenotype and genotype of a consanguineous marriage pedigree with inherited coagulation factor Ⅻ (FⅫ) deficiency and to elucidate the potential molecular pathogenesis.
The proband was a 51-year-old male with persistent symptoms of tinnitus. He was found to have a significantly prolonged activated partial thromboplastin time (APTT) at 117.7s (reference range, 29.1∼43.3s) during routine coagulation screening.
Direct DNA sequencing was performed in the coding regions and flanking sequences of gene to screen for variants. Thromboelastography and thrombin generation assays were conducted to simulate the dynamic changes in the blood coagulation process in vitro and in vivo. The conservatism and pathogenicity of variants were estimated using multiple bioinformatics tools and PyMOL software.
The proband exhibited significantly prolonged APTT, and severely decreased FⅫ activity and antigen levels, who harbored a c.811_813delAAC (p.Asn271del) homozygous deletion variant in exon 9 and a homozygous 46 T/T variant. The thromboelastography assay demonstrated reduced activity of the intrinsic coagulation cascade, whereas the thrombin generation assay showed a normal ability for thrombin formation in the proband. Conservative analysis revealed that Asn271 was completely conserved among homologous species. Moreover, inframe deletion variant p.Asn271del was declared to be pathogenic and could impair structure and function of FⅫ protein, which was assessed by the bioinformatics and protein modeling analysis.
The c.811_813delAAC deletion variant in exon 9 together with C46 T variant of gene may synergistically contribute to the FⅫ deficiency in this pedigree.
本研究旨在分析一个患有遗传性凝血因子Ⅻ（FⅫ）缺乏症的近亲结婚家系的表型和基因型，并阐明潜在的分子发病机制。
先证者为一名51岁男性，有持续性耳鸣症状。在常规凝血筛查中，发现他的活化部分凝血活酶时间（APTT）显著延长，为117.7秒（参考范围为29.1～43.3秒）。
对该基因的编码区和侧翼序列进行直接DNA测序以筛选变异。进行血栓弹力图和凝血酶生成试验，以模拟体内外凝血过程的动态变化。使用多种生物信息学工具和PyMOL软件评估变异的保守性和致病性。
先证者表现出APTT显著延长，FⅫ活性和抗原水平严重降低，其在外显子9中存在一个c.811_813delAAC（p.Asn271del）纯合缺失变异和一个纯合的46 T/T变异。血栓弹力图试验显示内源性凝血级联反应活性降低，而凝血酶生成试验显示先证者的凝血酶形成能力正常。保守性分析显示，Asn271在同源物种中完全保守。此外，通过生物信息学和蛋白质建模分析评估，框内缺失变异p.Asn271del被判定为致病性变异，可损害FⅫ蛋白的结构和功能。
外显子9中的c.811_813delAAC缺失变异与该基因的C46 T变异可能协同导致了这个家系中的FⅫ缺乏。
