1例c.1117C>T/c.7288-9T>G复合杂合突变所致血管性血友病家系的发病机制分析  

Study on pathogenesis and laboratory diagnosis of a family with von Willebrand disease caused by c.1117C>T/c.7288-9T>G compound heterozygous mutation

作　　者：谭忠州 陆遥[1] 苗林子[1] 李园园 朱梓静 宋一楠[1] 龚岩[1] 屈晨雪[1] TAN Zhongzhou;LU Yao;MIAO Linzi;LI Yuanyuan;ZHU Zijing;SONG Yinan;GONG Yan;QU Chenxue(Department of Clinical Laboratory,Peking University First Hospital,Beijing 100034,China)

机构地区：[1]北京大学第一医院检验科,北京100034

出　　处：《临床检验杂志》2024年第2期121-125,共5页Chinese Journal of Clinical Laboratory Science

摘　　要：目的探讨1例血管性血友病(vWD)家系的诊断及发病机制。方法家系收集。收集北京大学第一医院就诊的先证者及其家系成员(共4人),检测活化部分凝血活酶时间(APTT)、血管性血友病因子抗原(vWF:Ag)和活性(vWF:Ac)、凝血因子Ⅷ活性(FⅧ:C)、vWF瑞斯托霉素辅因子(vWF:RCo),进行瑞斯托霉素诱导血小板聚集试验(RIPA)、vWF胶原结合(vWF:CB)试验,对先证者及其家系成员进行诊断。提取先证者及其家系成员外周血基因组DNA,进行全外显子测序,分析vWF基因突变,采用生物信息分析工具进行基因突变位点致病性分析,探讨先证者发病机制。结果先证者(Ⅲ_(1))的APTT轻度延长、FⅧ:C正常、vWF:Ag、vWF:Ac、vWF:RCo和vWF:CB明显减低,1.0 mg/mL和1.25 mg/mL的RIPA无明显聚集;父亲(Ⅱ_(3))的APTT、FⅧ:C、vWF:Ag、vWF:Ac和vWF:CB均正常,vWF:RCo轻度减低;母亲(Ⅱ_(4))的APTT、FⅧ:C、vWF:Ag、vWF:RCo和vWF:CB均正常,vWF:Ac明显减低;哥哥(Ⅲ_(2))的APTT、FⅧ:C均正常,vWF:Ag、vWF:Ac、vWF:RCo及vWF:CB均不同程度减低;父亲(Ⅱ_(3))、母亲(Ⅱ_(4))和哥哥(Ⅲ_(2))的1.0 mg/mL RIPA均无明显聚集。基因分析显示先证者(Ⅲ_(1))存在vWF基因c.7288-9T>G和c.1117C>T复合杂合突变,其父亲(Ⅱ_(3))存在vWF基因c.7288-9T>G杂合突变;母亲(Ⅱ_(4))和哥哥(Ⅲ_(2))存在vWF基因c.1117C>T杂合突变。结论先证者为2A型vWD,其vWF基因c.1117C>T和c.7288-9T>G杂合突变可能是导致该先证者发病的原因。Objective To explore the diagnosis of clinically suspicious von Willebrand disease(vWD)in a family and its pathogenesis.Methods The pedigree information and the biological specimen were collected from the clinically suspected VWD patient and her family members(4 persons in total)in Peking University First Hospital.The levels of platelet count(PLT),activated partial thromboplastin time(APTT),vWF antigen(vWF:Ag),vWF activity(vWF:Ac)and FVII activity(FⅧ:C)were detected,and vWF ristocetin cofactor(vWF:RCo)assay,ristocetin-induced platelet aggregation assay(RIPA)and vWF collagen binding(vWF:CB)assay were performed for phenotype diagnosis.The peripheral blood genomic DNAs were extracted from the proband and her family members to perform whole-exome sequencing for identifying the mutation of vWF gene,The mutation site was analyzed by using bioinformation tools to explore the pathogenesis of the proband.Results The APTT of proband(Ⅲ_(1))was slightly prolonged and her vWF:Ag,vWF:Ac,vWF:RCo and vWF:CB were significantly decreased.There was no obvious aggregation in RIPA assay(1.0 mg/mL and 1.25 mg/mL).In her father(Ⅱ_(3)),APTT,FⅧ:C,vWF:Ag,vWF:Ac and vWF:CB were normal,but vWF:RCo was slightly decreased.In her mother(Ⅱ_(4)),APTT,FⅧ:C,vWF:Ag,vWF:RCo and vWF:CB were all normal,but vWF:Ac significantly decreased.In her brother(Ⅲ_(2)),APTT and FⅧ:C were normal,but vWF:Ag,vWF:Ac,vWF:RCo and vWF:CB were reduced to varying degrees.In all the family members(father,mother and brpther),no apparent aggregation in RIPA(1.0 mg/mL)was shown.Genetic analysis showed that the proband(Ⅲ_(1))carried a compound heterozygous mutation of vWF gene c.7288-9T>G and c.1117C>T,her father(Ⅱ_(3))carried vWF gene c.7288-9T>G heterozygous mutation,and vWF gene c.1117C>T heterozygous mutation was presented in both mother(Ⅱ_(4))and brother(Ⅲ_(2)).Conclusion According to the results of laboratory tests,the proband was diagnosed as type 2A vWD.The heterozygous mutation in vWF gene c.1117C>T and c.7288-9T>G may be the molecular mechani

关 键 词：血管性血友病 血管性血友病因子 诊断 发病机制 

分 类 号：R446[医药卫生—诊断学]