F12基因起始密码子c.1A>G变异所致遗传性凝血因子Ⅻ缺陷症一家系的遗传学分析  

Genetic analysis of a Chinese pedigree affected with Congenital coagulation factor Ⅻ deficiency due to a c. 1A>G start codon variant of F12 gene

作　　者：季伟丹 林森[1] 陈杰[1] 金超俊 林小悦 叶智远 邱丽君 钱定良[1] Ji Weidan;Lin Sen;Chen Jie;Jin Chaojun;Lin Xiaoyue;Ye Zhiyuan;Qiu Lijun;Qian Dingliang(Department of Clinical Laboratory,Ruian People′s Hospital,Ruian,Zhejiang 325200,China)

机构地区：[1]瑞安市人民医院检验科,瑞安325200

出　　处：《中华医学遗传学杂志》2023年第5期547-551,共5页Chinese Journal of Medical Genetics

摘　　要：目的探讨1个姨表近亲婚配的遗传性凝血因子Ⅻ(FⅫ)缺陷症家系的临床特征与遗传学病因。方法选取2021年7月12日于瑞安市人民医院泌尿外科就诊的1个遗传性FⅫ缺陷症家系为研究对象。收集家系临床资料,抽取受试者外周静脉血样,分别进行凝血指标检测与基因检测,采用Sanger测序进行家系验证,并对候选变异进行生物信息学分析。结果遗传性FⅫ缺陷症家系成员共3代6人,包括先证者及其父亲、母亲、妻子、妹妹和儿子。先证者为男性,51岁,临床表现为肾结石。凝血指标检测结果显示,先证者活化部分凝血活酶时间(APTT)显著延长,FⅫ活性(FⅫ:C)与FⅫ抗原(FⅫ:Ag)均极度降低;先证者父亲、母亲、妹妹和儿子FⅫ:C和FⅫ:Ag均降低至正常参考值下限的一半左右。基因检测结果提示,先证者F12基因第1外显子起始密码子存在c.1A>G(p.Arg2Tyr)纯合错义变异。经Sanger测序验证,先证者父亲、母亲、妹妹和儿子均携带F12基因c.1A>G杂合变异,先证者妻子未见该变异。该变异在HGMD数据库未见报道。经SIFT在线软件分析,预测该变异为有害性变异;经Swiss-Pbd Viewerv4.0.1软件模拟,该变异对FⅫ蛋白的结构影响较大。根据美国医学遗传学与基因组学学会(ACMG)制订的《序列变异解释的标准和指南》,对该变异评级为可能致病性变异。结论F12基因c.1A>G(p.Arg2Tyr)变异可能为该姨表近亲婚配的遗传性FⅫ缺陷症家系的遗传学病因,进一步丰富了F12基因变异谱,为该病家系临床诊断与遗传咨询提供参考依据。Objective To explore the clinical characteristics and genetic etiology of a consanguineous Chinese pedigree affected with Congenital coagulation factorⅫ(FⅫ)deficiency.Methods Members of the pedigree who had visited Ruian People′s Hospital on July 12,2021 were selected as the study subjects.Clinical data of the pedigree were reviewed.Peripheral venous blood samples were taken from the subjects.Blood coagulation index and genetic testing were carried out.Candidate variant was verified by Sanger sequencing and bioinformatic analysis.Results This pedigree has comprised 6 individuals from 3 generations,including the proband,his father,mother,wife,sister and son.The proband was a 51-year-old male with kidney stones.Blood coagulation test showed that his activated partial thromboplastin time(APTT)was significantly prolonged,whilst the FⅫactivity(FⅫ:C)and FⅫantigen(FⅫ:Ag)were extremely reduced.The FⅫ:C and FⅫ:Ag of proband′s father,mother,sister and son have all reduced to about half of the lower limit of reference range.Genetic testing revealed that the proband has harbored homozygous missense variant of c.1A>G(p.Arg2Tyr)of the start codon in exon 1 of the F12 gene.Sanger sequencing confirmed that his father,mother,sister and son were all heterozygous for the variant,whilst his wife was of the wild type.By bioinformatic analysis,the variant has not been included in the HGMD database.Prediction with SIFT online software suggested the variant is harmful.Simulation with Swiss-Pbd Viewer v4.0.1 software suggested that the variant has a great impact on the structure of FⅫprotein.Based on the Standards and Guidelines for the Interpretation of Sequence Variants:A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics(ACMG),the variant was rated as likely pathogenic.Conclusion The c.1A>G(p.Arg2Tyr)variant of the F12 gene probably underlay the congenital FⅫdeficiency in this pedigree.Above finding has further expanded the spectrum of F12 gene variants and provided a refere

关 键 词：凝血因子Ⅻ F12基因 近亲婚配 

分 类 号：R596[医药卫生—内科学]