摘要目的:探讨1个 F11基因新变异导致复合杂合性遗传性凝血因子Ⅺ(FⅪ)缺陷症家系的分子致病机制。 方法:选取2020年11月30日因"尿路结石"就诊于温州医科大学附属第一医院的1例遗传性凝血因子Ⅺ缺陷症男性先证者及其家系成员(3代7人)作为研究对象，收集先证者的临床资料，检测先证者及其家系成员的相关凝血指标。提取外周血基因组DNA进行PCR扩增，用DNA直接测序法分析先证者 F11基因的全部外显子、侧翼序列、5′和3′端非翻译区序列及家系成员相应的变异位点区域。用生物信息学软件分析氨基酸变异位点的保守性，分析变异对蛋白质功能的影响。根据美国医学遗传学与基因组学学会(ACMG)相关变异评级指南对变异位点进行评级。 结果:先证者为36岁男性，其活化部分凝血活酶时间(APTT)为89.2 s，明显延长，FⅪ活性(FⅪ：C)和FⅪ抗原(FⅪ：Ag)分别为2.0%和3.5%，均极度降低。基因测序发现先证者和其姐姐的 F11基因第7外显子存在父源c.689G>T(p.Cys230Phe)杂合错义变异，第13外显子存在母源c.1556G>A(p.Trp519*)杂合无义变异。保守性分析结果表明Cys230呈高度保守。c.1556G>A(p.Trp519*)为已报道的致病性变异。依据ACMG变异评级指南，c.689G>T评级为可能致病变异(PM2_Supporting+PM5+PP1+PP3+PP4)。 结论:F11基因第7外显子c.689G>T杂合错义变异及第13外显子c.1556G>A杂合无义变异考虑是该FⅪ缺陷症家系的致病原因。

abstractsObjective:To explore the molecular pathogenesis of a Chinese pedigree affected with Hereditary coagulation factor Ⅺ (FⅪ) deficiency due to variants of the F11 gene. Methods:A male proband with Hereditary coagulation factor Ⅺ deficiency who was admitted to the First Affiliated Hospital of Wenzhou Medical University due to urinary calculi on November 30, 2020 and his family members (7 individuals from 3 generations in total) were selected as the study subjects. Clinical data of the proband were collected, and relevant coagulation indices of the proband and his family members were determined. Genomic DNA of peripheral blood samples was extracted for PCR amplification. All exons, flanking sequences, and 5′ and 3′ untranslated regions of the F11 gene of the proband were analyzed by direct sequencing. And the corresponding sites were subjected to sequencing in other family members. The conservation of amino acid variation sites was analyzed by bioinformatic software, and the effect of the variant on the protein function was analyzed. Variants were graded based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Results:The proband was a 36-year-old male. His activated partial thromboplastin time (APTT) was 89.2s, which was significantly prolonged. The FⅪ activity (FⅪ: C) and FⅪ antigen (FⅪ: Ag) were 2.0% and 3.5%, respectively, which were extremely reduced. Both the proband and his sister were found to harbor compound heterozygous variants of the F11 gene, including a c. 689G>T (p.Cys230Phe) missense variant in exon 7 from their father and a c. 1556G>A (p.Trp519*) nonsense variant in exon 13 from their mother. Conservation analysis indicated the Cys230 site to be highly conserved. The c. 1556G>A (p.Trp519*) variant was known to be pathogenic, whilst the c. 689G>T variant was classified as likely pathogenic (PM2+ PM5+ PP1+ PP3+ PP4) based on the ACMG guidelines. Conclusion:The c. 689G>T and c. 1556G>A compound heterozygous variants of the F11 gene probably underlay the pathogenesis of FⅪ deficiency in this pedigree.