| 乔莹利,李冰洁,吴凡,等.遗传性凝血因子 Ⅺ缺陷症家系表型诊断及基因分析[J].安徽医药,2025,29(12):2379-2383. |
| 遗传性凝血因子 Ⅺ缺陷症家系表型诊断及基因分析 |
| Phenotype diagnosis and genotype analysis of a family with congenital factor Ⅺ deficiency |
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| DOI：10.3969/j.issn.1009-6469.2025.12.010 |
| 中文关键词: 因子 Ⅺ缺乏 因子 Ⅺa 基因测序 F11基因 常染色体隐性遗传 基因突变 生物信息学分析 |
| 英文关键词: Factor Ⅺ deficiency Factor Ⅺa Gene sequencing F11 gene Autosomal recessive hereditary Gene mutation Bioinformatics analysis |
| 基金项目:河南省卫生健康中青年学科带头人培养项目( HNSWJW-2022010)；河南省自然科学基金面上科学基金项目(242300421291)；阜外华中心血管病医院青年专项( FWQN240005)；阜外华中心血管病医院优秀人才项目( FWYX240004) |
| 作者 | 单位 | E-mail | | 乔莹利 | 阜外华中心血管病医院,检验科,河南郑州 450003 | | | 李冰洁 | 阜外华中心血管病医院,检验科,河南郑州 450003 | | | 吴凡 | 阜外华中心血管病医院,检验科,河南郑州 450003 | | | 王倩 | 阜外华中心血管病医院,检验科,河南郑州 450003 | | | 李涛 | 阜外华中心血管病医院,检验科,河南郑州 450003
阜外华中心血管病医院,健康管理中心,河南郑州 450003 | litao0510@163.com |
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| 中文摘要: |
| 目的对 1个遗传性凝血因子 Ⅺ(FⅪ)缺陷症家系进行表型诊断及基因分析，初步探讨其分子致病机制。方法对 2020年 12月 18日至 2024年 1月 18日阜外华中心血管病医院收治的先证者及家系成员进行凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、凝血因子 Ⅺ活性(FⅪ:C)、凝血因子 Ⅺ抗原(FⅪ:Ag)等检测，用 Sanger测序检测 F11基因的相关变异并进行家系成员验证，用 ClustalX 2.0软件研究该突变的保守性，用 PyMOL 2.6.0软件对突变氨基酸进行构象分析，结合多个在线生物信息学软件及罕见外显子组变异集成学习器(REVEL)分析结果，用美国医学遗传学与基因组学会(ACMG)指南评级评估突变位点的致病性。结果先证者 APTT明显延长， FⅪ:C和 FⅪ:Ag显著下降，家系成员(Ⅰ-1、Ⅰ-2和Ⅲ-1)FⅪ:C和 FⅪ:Ag均有不同程度下降。先证者存在 F11 c.569T>C:p.Leu190Pro和 c.1627G>A:p.Glu543Lys复合杂合突变，分别来自母亲(Ⅰ-1)和父亲(Ⅰ-2)，并将 F11 c.569T>C:p.Leu190Pro杂合突变遗传给了儿子(Ⅲ-1)。 F11基因 c.569位点和 c.1627位点在多个同源物种间高度保守， F11 c.569T>C:p.Leu190Pro和 c.1627G>A:p.Glu543Lys 2个突变位点对应蛋白结构均发生了变化， 2个突变位点的 ACMG指南评级均为致病。结合先证者临床表型、家系遗传特点、基因测序及生物信息学结果，诊断为常染色体隐性遗传性 F Ⅺ缺陷症。结论 F11 c.569T>C:p.Leu190Pro和 c.1627G>A:p.Glu543Lys复合杂合突变可能影响 FⅪ蛋白分子结构而影响其功能，导致血浆 FⅪ:C和 FⅪ:Ag降低，是该家系常染色体隐性遗传性 FⅪ缺陷症的致病原因。该杂合突变组合为国内外首次报告。 |
| 英文摘要: |
| Objective To make a phenotypic diagnosis and genetic analysis of a pedigree with inherited factor Ⅺ (FⅪ) deficiency,and to preliminarily explore its molecular pathogenesis. Methods Prothrombin Time (PT), activated partial thromboplastin time(APTT), factor Ⅺ activity (FⅪ:C) and factor Ⅺ antigen (FⅪ:Ag) were detected in the proband and her family members to Fuwai Cen-tral China Cardiovascular Disease Hospital from December 18, 2020 to January 18, 2024. Sanger sequencing was used to detect F11gene variants and the mutation sites of all family members were verified. ClustalX2.0 software was used to study the conservatism of themutation. The mutant amino acids were analyzed by PyMOL2.6.0 software. Combined with multiple online bioinformatics software andRare Exome Variant Ensemble Learner (REVEL) analysis results, American College of Medical Genetics and Genomics (ACMG) guide-line rating was used to evaluate the pathogenicity of mutation sites.Results APTT of the proband was prolonged, FⅪ:C and FⅪ:Agwere decreased significantly, and FⅪ:C and FⅪ:Ag of the family members (Ⅰ-1, Ⅰ-2 and Ⅲ-1) were decreased to different degrees.The proband had compound heterozygous mutations of F11 c.569T>C:p.Leu190Pro and c.1627G>A:p.Glu543Lys, which were inheritedfrom her mother (Ⅰ-1) and her father (Ⅰ-2) respectively, and she passed the heterozygous mutation of F11 c.569T>C:p.Leu190Pro to her son (Ⅲ-1). The c.569 site of F11 gene and the c.1627 site of F11 gene were highly conserved among homologous species. The pro-tein structures of F11 c.569T>C:p.Leu190Pro and c.1627G>A:p.Glu543Lys mutations were changed. According to ACMG guidelines,both mutation sites were pathogenic. Combined with the clinical phenotype of the proband, genetic characteristics of the family, gene se-quencing and bioinformatics results, the proband was diagnosed with autosomal recessive F Ⅺ deficiency. Conclusions The com-pound heterozygous mutations of c.569T>C:p.Leu190Pro and c.1627G>A:p.Glu543Lys in F11 gene may affect the molecular structureof FⅪ protein and its function, resulting in the decrease of plasma FⅪ:C and FⅪ:Ag. It is the pathogenic cause of autosomal recessiveFⅪ deficiency in this family. This heterozygous mutation combination is first reported at home and abroad. |
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