SERPINC1基因变异所致遗传性抗凝血酶缺陷症家系的临床表型和遗传学分析  

Phenotypic and genetic analysis of a Chinese pedigree affected with Hereditary antithrombin deficiency due to a novel variant of SERPINC1 gene

作　　者：陈迎迎[1] 姚雅婷 李婷[2] 舒旷怡[2] 杨啸 李姗姗[2] 王晓欧[2] 王锦院 张婷[2] 江明华[2] Chen Yingying;Yao Yating;Li Ting;Shu Kuangyi;Yang Xiao;Li Shanshan;Wang Xiaoou;Wang Jinyuan;Zhang Ting;Jiang Minghua(Department of Otolaryngology,the Second Affiliated Hospital of Wenzhou Medical University,Yuying Children’s Hospital,Wenzhou,Zhejiang 325027,China)

机构地区：[1]温州医科大学附属第二医院·育英儿童医院耳鼻咽喉科,温州325027 [2]温州医科大学附属第二医院·育英儿童医院医学检验中心,温州325027

出　　处：《中华医学遗传学杂志》2024年第3期312-316,共5页Chinese Journal of Medical Genetics

基　　金：浙江省自然科学基金(LY20H200002);浙江省医药卫生科技项目(2016RCA023)。

摘　　要：目的分析1个遗传性抗凝血酶(AT)缺陷症家系的临床表型及遗传学特征。方法回顾性分析2020年6月"因反复多部位形成静脉血栓"就诊于温州医科大学附属第二医院的1对AT先证者及其家系成员的临床资料。用STA-R全自动血凝分析仪检测先证者及家系成员血浆凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、纤维蛋白原(FIB)、凝血酶时间(TT);用发色底物法和免疫散色比浊法检测先证者及其家系成员血浆AT活性(AT:A)和AT抗原(AT:Ag)。用PCR扩增先证者及家系成员抗凝血酶基因SERPINC1的所有外显子及侧翼序列,测序并寻找变异位点;采用生物信息学预测软件对蛋白质功能的影响和蛋白质构象的改变进行分析。结果先证者(Ⅱ2、Ⅱ10)及其兄弟(Ⅱ5)和儿子(Ⅲ1、Ⅲ8)的PT、APTT、FIB及TT均在正常范围,而AT:A和AT:Ag明显下降,分别为34%、57%、56%、48%、53%和13.51、13.44、18.39、17.36、17.71 mg/dL,其余家系成员均在正常范围。先证者及家系成员测序结果显示均携带SERPINC1基因第5外显子c.851T>C(p.Met284Thr)杂合错义变异;生物信息学软件预测提示该变异可导致c.851位点编码氨基酸的氢键改变,影响蛋白质的结构。根据美国医学遗传学与基因组学学会变异评级标准指南,该变异评级为致病性变异(PS1+PM1+PM5+PP1+PP4)。结论先证者及其他患者家系成员被确诊为Ⅰ型遗传性AT缺陷症患者,SERPINC1基因c.851T>C(p.Met284Thr)变异是其遗传学病因。Objective To analyze the clinical phenotype and genetic characteristics of a Chinese pedigree affected with Hereditary antithrombin deficiency.Methods A pedigree diagnosed at the the Second Affiliated Hospital of Wenzhou Medical University,Yuying Children’s Hospital in June,2020 was selected as the study subject.Plasma prothrombin time(PT),activated partial thromboplastin time(APTT),fibrinogen(FIB),and thrombin time(TT)of the probands and their pedigree members were determined using a STA-R automatic coagulation analyzer.Antithrombin activity(AT:A)and antithrombin antigen(AT:Ag)in plasma were determined with chromogenic substrate and immunonephelometry assays.All exons and flanking sequences of the anticoagulant protein gene SERPINC1 were amplified by PCR and subjected to Sanger sequencing.Candidate variants were verified with bioinformatic tools(PolyPhen-2,SIFT,Mutation Taster and PYMOL)to explore their effect on the function and structural conformation of the protein.Results The probands(Ⅱ2,Ⅱ10),their brother(Ⅱ5)and sons(Ⅲ1,Ⅲ8)had shown normal PT,APTT,FIB,and TT,but significantly decreased AT:A and AT:Ag,with their levels being 34%,57%,56%,48%,53%and 13.51 mg/dL,13.44 mg/dL,18.39 mg/dL,17.36 mg/dL,17.71 mg/dL,respectively.The remaining pedigree members had normal values.Sanger sequencing revealed that the probands and all affected pedigree members had harbored a heterozygous c.851T>C(p.Met284Thr)missense variant in exon 5 of the SERPINC1 gene.Bioinformatic analysis and simulation suggested that the variant has resulted in alteration of hydrogen bonds at the c.851 position,which may affect the structure of the protein.Based on the guidelines from the American College of Medical Genetics and Genomics(ACMG),the variant was classified as pathogenic(PS1+PM1+PM5+PP1+PP4).Conclusion The probands and other affected members were all diagnosed with type I hereditary AT deficiency,for which the c.851 T>C(p.Met284Thr)variant of the SERPINC1 gene may be accountable.

关 键 词：血液凝集障碍 遗传性 遗传性抗凝血酶缺陷症 SERPINC1基因 基因变异 

分 类 号：R596[医药卫生—内科学]