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J Zhejiang Univ (Med Sci)  2018, Vol. 47 Issue (6): 606-611    DOI: 10.3785/j.issn.1008-9292.2018.12.07
Screening for inherited thrombophilia and genome sequencing
YIN Li1(),LI Ge2,SHEN Jian3,LIU Zhenjie1,*()
1. Department of Vascular Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
2. Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
3. Institute of Cardiovascular Diseases, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
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Objective: To screening coagulation and anticoagulation genes and mutations in Chinese patients with venous thromboembolism suspected of inhered thrombophilia. Methods: Patients with venous thromboembolism caused by inherited thrombophilia were collected from the second Affiliated Hospital, Zhejiang University School of Medicine during June 2015 and December 2017. Gene sequencing was conducted to screen the anticoagulant-related genes PROC, PROS1, SERPINC1 and coagulation-related genes F5, F2, F8, CBS, MTHFR. The thousands of human genome database, ESP6500 database, Genoma database, HGMD mutation database were used to compare the mutation sites, and the pathogenic mutation sites were predicted according to SIFT, Polyphen, MutationTaster and CADD databases. Results: Among 25 patients screened, eight patients with PROC mutations, two patients with PROS1 mutations, three patients with SERPINC1 mutations; one patient with F5 mutation, one patient with F2 mutation, one patient with F8 mutation, two patient with CBS mutations, and one patient with MTHFR mutation. Conclusion: The second generation gene sequencing helps to diagnose inherited thrombophilia and guide the decision of anticoagulation duration.

Key wordsVenous thrombosis/genetics      Thrombophilia/genetics      Blood coagulation      Antithrombins      Genes      Mutation     
Received: 14 August 2018      Published: 15 March 2019
CLC:  R446  
Corresponding Authors: LIU Zhenjie     E-mail:;
Cite this article:

YIN Li,LI Ge,SHEN Jian,LIU Zhenjie. Screening for inherited thrombophilia and genome sequencing. J Zhejiang Univ (Med Sci), 2018, 47(6): 606-611.

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目的: 检测和分析遗传性易栓症的相关基因及其突变位点,为中国人群遗传性易栓症患者的基因突变特点积累资料。方法: 对2015年6月至2017年12月在浙江大学医学院附属第二医院就诊的遗传性易栓症疑似患者25例进行血清蛋白C、蛋白S,抗凝因子相关基因蛋白C(基因名PROC)、蛋白S(基因名PROS1)和抗凝血酶Ⅲ(基因名SERPINC1),凝血因子相关基因凝血因子Ⅴ(基因名F5)、凝血因子Ⅱ(基因名F2)、凝血因子Ⅷ(基因名F8)、高型半胱氨酸血症相关因子(CBSMTHFR)第二代测序分析。利用千人基因组数据库、ESP6500数据库、Genoma数据库、HGMD突变数据库比对突变位点,根据SIFT、Polyphen、MutationTaster、CADD数据库预测突变位点的致病性。结果: 25例患者中,发现抗凝因子相关基因PROC突变患者8例,PROS1突变患者2例,SERPINC1突变患者3例;凝血相关基因F5突变1例,F2突变1例,F8突变1例,CBS突变2例,MTHFR突变1例。结论: 应用第二代基因测序分析有助于诊断遗传性易栓症相关静脉血栓,指导精准治疗。

关键词: 静脉血栓形成/遗传学,  血栓形成倾向/遗传学,  血液凝固,  抗凝血酶类,  基因,  突变 
Fig 1 Screening patients with inherited thrombophilia
患者序号 性别 年龄 突变基因 突变位点 氨基酸改变 静脉血栓栓塞症类型
1 24 PROS1 g.78261A>G p.Y266C 深静脉血栓形成
2 24 PROS1 Ch1:93643083, C>T 剪切区域突变 深静脉血栓形成
PROC c.975C>G p.V325V
3 42 PROC c.631C>T p.R211W 深静脉血栓形成+肺栓塞
4 23 PROC c.962C>T p.P321L 深静脉血栓形成
5 21 PROC c.944C>T p.T340M 深静脉血栓形成
6 29 PROC c.267G>A p.G423S 深静脉血栓形成+肺栓塞
7 22 PROC c.889G>C p.D297H 深静脉血栓形成
8 45 PROC c.1152C>G p.N384K 深静脉血栓形成+肺栓塞
c.1207G>T p.G403W
9 25 PROC c.1273 G>A p.R393C 深静脉血栓形成
10 35 SERPINC1 c.1274G>A p.R425H 深静脉血栓形成
11 44 SERPINC1 c.967T>C p.S323P 深静脉血栓形成
12 26 SERPINC1 c.667T>C p.S223P 深静脉血栓形成+肺栓塞
Tab 1 Characteristics of patients with antithrombin factors mutations
Fig 2 Pedigree drawing and mutations for a patient with protein C deficiency
患者序号 性别 年龄 突变基因 突变位点 氨基酸改变 静脉血栓栓塞症类型
2 24 F5 c.1154A>G p.N385S 深静脉血栓形成
CBS Ch21:44480542 G>A 剪切区域突变
9 25 F8 c.3169G>C p.E1057K 深静脉血栓形成
13 32 F2 c.1621C>T p.R541W 深静脉血栓形成
14 29 CBS c.400G>A p.G134R 深静脉血栓形成+肺栓塞
15 24 MTHFR chr1:11862935 T>C 剪切区域突变 深静脉血栓形成
Tab 2 Characteristics of patients with clotting factors mutations
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