Journal of Diagnostics Concepts & Practice ›› 2019, Vol. 18 ›› Issue (04): 394-401.doi: 10.16150/j.1671-2870.2019.04.004
• Original articles • Previous Articles Next Articles
LI Lei1,2, WU Xi2, XU Guanqun2, LIANG Qian2, DAI Jing2, WU Wenman2, DING Qiulan2, WANG Hongli1, WANG Xuefeng2,3()
Received:
2019-05-01
Online:
2019-08-25
Published:
2019-08-25
Contact:
WANG Xuefeng
E-mail:wangxuefeng6336@hotmail.com
CLC Number:
LI Lei, WU Xi, XU Guanqun, LIANG Qian, DAI Jing, WU Wenman, DING Qiulan, WANG Hongli, WANG Xuefeng. Establishment and application of thrombophilia gene detection panel based on next generation sequencing in identification of genetic background of Chinese patients with venous thromboembolism[J]. Journal of Diagnostics Concepts & Practice, 2019, 18(04): 394-401.
基因(蛋白) | OMIM# | 基因(蛋白) | OMIM# |
---|---|---|---|
F2(凝血因子Ⅱ) | 188050 | SERPINC1(抗凝血酶) | 613118 |
F5(凝血因子Ⅴ) | 188055 | PROC(PC) | 176860/612304 |
F7(凝血因子Ⅶ) | 608446 | PROS1(PS) | 612336/614514 |
F8(凝血因子Ⅷ) | 300841 | PROCR(内皮细胞PC受体) | 600646 |
F9(凝血因子Ⅸ) | 300807 | THBD(血栓调节蛋白) | 614486 |
F10(凝血因子Ⅹ) | 613872 | SERPIND1(肝素辅因子Ⅱ) | 612356 |
F11(凝血因子Ⅺ) | 264900 | TFPI(组织因子途径抑制物) | 152310 |
F12(凝血因子Ⅻ) | 610609 | PLG(纤溶酶原) | 217090 |
ADAMTS13(ADAMTS13) | 274105 | HRG(富组氨酸糖蛋白) | 613116 |
基因名称(蛋白名称) | 受累患者数 | 携带已报道突变的患者数 | 携带新突变的患者数 | 合并获得性血栓危险因素的患者数 | |
---|---|---|---|---|---|
与表型结果一致 | 无表型结果 | ||||
PROC(PC) | 36 | 31 | 3 | 2 | 9 |
PROS1(PS) | 43 | 26 | 16 | 1 | 7 |
SERPINC1(AT) | 17 | 8 | 9 | 0 | 7 |
F2 (凝血因子Ⅱ) | 1 | 1 | 0 | 0 | 0 |
F5 (凝血因子Ⅴ) | 2 | 0 | 2 | 0 | 0 |
F9 (凝血因子Ⅸ) | 1 | 0 | 0 | 1 | 0 |
F12 (凝血因子Ⅻ) | 1 | 0 | 0 | 1 | 0 |
PROCR (EPCR) | 4 | 1 | 0 | 3 | 2 |
THBD (TM) | 2 | 0 | 0 | 2 | 2 |
SERPIND1(HCⅡ) | 2 | 0 | 0 | 2 | 2 |
PLG(纤溶酶原) | 1 | 0 | 1 | 0 | 1 |
编号 | 年龄(岁)/ 性别 | VTE次数 (发病年龄) | 获得性血栓 危险因素 | 基因名称 | 突变位点 | 表型结果 |
---|---|---|---|---|---|---|
1 | 50/男 | 1 (49) | 无 | PROC | c.565C>T, p.R189WMI;c.247T>C, p.W83RFI | PC活性 42% |
2 | 47/男 | 1 (47) | 无 | PROC | c.565C>T, p.R189WFI;c.325G>C, p.G109RMI | PC活性 38% |
3 | 51/男 | 2 (35) | 无 | PROC | c.565C>T, p.R189WMI;c.658C>T, p.R220WFI | PC活性 43% |
4 | 22/男 | 2 (21) | 无 | PROC | c.565C>T, p.R189WMI;c.659G>A, p.R220QFI | PC活性 41% |
5 | 31/女 | 1 (31) | 避孕药 | PROC | c.565C>T, p.R189WFI;c.1081A>G, p.N361DMI,* | PC活性 36% |
6 | 30/男 | 1 (30) | 无 | PROC | c.565C>T, p.R189WFI;c.1130T>C, p.M377TMI | PC活性 35% |
7 | 56/男 | 2 (42) | 无 | PROC | c.565C>T, p.R189WMI;c.1157T>C, p.L386PFI | PC活性 32% |
8 | 67/男 | 3 (51) | 手术2nd | PROC | c.565C>T, p.R189WFI;c.1140delG, p.V381CfsX39MI,* | PC活性 31% |
9 | 14/男 | 1 (14) | 无 | PROC | c.574_576delAAG, p.K192delMI;c.303C>G, p.C101WFI,* | PC活性 48% |
10 | 28/男 | 1 (21) | 无 | PROC | c.574_576delAAG, p.K192delMI;c.896_899delACAT, p.D299AfsX15FI,* | PC活性 54% |
11 | 32/男 | 1 (32) | 无 | PROC | c.574_576delAAG, p.K192delFI;c.1353delC, p.D451EfsX54MI,* | PC活性 56% |
12 | 23/男 | 2 (21) | 无 | PROC | c.574_576delAAG, p.K192delFI;c.1099G>A, p.V367MMI | PC活性 56% |
13 | 45/男 | 2 (39) | 无 | PROC | c.574_576delAAG, p.K192delFI;c.678+9C>TMI | PC活性 67% |
14 | 35/男 | 1 (34) | 手术 | PROC | c.565C>T, p.R189WFI;c.574_576delAAG, p.K192delMI | PC活性 89% |
15 | 25/男 | 2 (18) | 无 | PROC | c.76G>A, p.V26MFI;c.191G>A, p.C64YMI,* | PC活性 15% |
16 | 54/男 | 2 (22) | 无 | PROC | c.749C>T, p.T250IFI, *;c.889G>C, p.D297HMI | PC活性 19% |
17 | 34/男 | 1 (34) | 无 | PROC | c.889G>C, p.D297HFI;c.1161T>G, p.C387WMI,* | PC活性 21% |
18 | 49/女 | 2 (46) | 无 | PROS1 | c.1334G>A, p.R445HFI;c.1155+5G>CMI,* | PS活性 38% |
19 | 38/男 | 2 (37) | 无 | PROS1 | c.200A>C, p.E67AFI;c.802G>T, p.D268YMI,* | PS活性 25% |
20 | 20/男 | 2 (15) | 无 | PROS1 | c.200A>C, p.E67AFI;c.1681C>T, p.R561WMI | PS活性 23% |
21 | 28/男 | 2 (21) | 手术2nd | PROS1 | c.1681C>T, p.R561WFI;c.1551_52delCAinsG, p.T518RfsX41MI,* | PS活性 18% |
编号 | 年龄(岁)/ 性别 | VTE次数 (发病年龄) | 获得性血栓 危险因素 | 基因名称 | 突变位点(生物学意义) | 表型结果 |
---|---|---|---|---|---|---|
1 | 29/男 | 2 (27) | 无 | PROC | c.262+2T>C*(T) | PC活性45% |
PROS1 | c.1680T>A, p.Y560X(T) | PS活性40% | ||||
2 | 14/男 | 1 (14) | 无 | PROC | c.889G>C, p.D297H(T) | PC活性52% |
PROS1 | c.1680T>A, p.Y560X(T) | PS活性53% | ||||
3 | 35/男 | 1 (35) | 无 | PROC | c.170G>A, p.R57Q(T) | PC活性104% |
PROS1 | c.200A>C, p.E67A(T) | PS活性37% | ||||
4 | 18/男 | 1 (16) | 无 | PROC | c.574_576delAAG, p.K192del(T) | PC活性103% |
PROS1 | c.200A>C, p.E67A(T) | PS活性45% | ||||
5 | 31/男 | 1 (31) | 无 | PROC | c.574_576delAAG, p.K192del(T) | PC活性101% |
PROS1 | c.134T>A, p.L45X*(T) | PS活性51% | ||||
6 | 48/女 | 2 (47) | 手术2nd | PROC | c.574_576delAAG, p.K192del(T) | PC活性96% |
PROS1 | exon1-4 deletion*(T) | PS活性62% | ||||
7 | 36/男 | 1 (36) | 无 | PROC | c.565C>T, p.R189W(T) | PC活性75% |
PROS1 | c.1681C>T, p.R561W(T) | PS活性38% | ||||
8 | 17/男 | 3 (11) | 无 | PROC | c.574_576delAAG, p.K192del(T) | PC活性93% |
SERPINC1 | c.1033_1035del, p.E345del(T) | AT活性55% | ||||
9 | 38/男 | 2 (25) | 无 | PROC | c.1207dupG, p. P405AfsX19*(T) | PC活性43% |
SERPINC1 | c.1274G>A, p.R425H(T) | AT活性65% | ||||
10 | 40/男 | 1 (39) | 无 | PROC | c.574_576delAAG, p.K192del(T) | PC活性99% |
SERPINC1 | c.938T>C, p.M313T*(UN) | AT活性96% | ||||
11 | 54/男 | 3 (26) | 无 | PROS1 | c.200A>C, p.E67A(T) | PS活性35% |
SERPINC1 | c.1033_1035del, p.E345del(T) | AT活性57% | ||||
12 | 54/男 | 3 (51) | 手术1st, | PROC | c.574_576delAAG, p.K192delH(T) | PC活性113% |
卧床3rd | PROCR | c.434C>T, p.P145L(UN) | 未检测 | |||
13 | 56/男 | 2 (54) | 无 | PROC | c.703A>C, p.K235Q(T) | PC活性56% |
PROCR | exon1-3 duplication*(UN) | 未检测 | ||||
14 | 31/男 | 2 (29) | 无 | PROC | c.262+2T>C*(T) | PC活性63% |
PROCR | c.434C>T, p.P145L(UN) | 未检测 | ||||
15 | 14/男 | 1 (14) | 无 | PROC | c.574_576delAAG, p.K192del(T) | PC活性 105% |
PROCR | exon1-3 duplication*(UN) | 未检测 | ||||
16 | 22/男 | 1 (19) | 无 | PROS1 | c.1680T>A, p.Y560X(T) | PS活性 52% |
PROCR | exon1-3 duplication*(UN) | 未检测 | ||||
17 | 38/男 | 1 (38) | 手术 | PROS1 | c.1553delC,p.T518RfsX40*(T) | PS活性 37% |
PROCR | exon1-3 duplication*(UN) | 未检测 | ||||
18 | 48/男 | 1 (48) | 无 | PROS1 | c.268C>T, p.R90C(T) | PS活性 47% |
PROCR | exon1-3 duplication*(UN) | 未检测 | ||||
19 | 28/男 | 2 (23) | 无 | SERPINC1 | c.486_487delCT, p.Y163SfsX24(T) | AT活性 57% |
PROCR | c.434C>T, p.P145L(UN) | 未检测 | ||||
20 | 39/男 | 2 (37) | 无 | SERPINC1 | c.1315C>A, p.P439T(T) | AT活性 70% |
PROCR | c.434C>T, p.P145L(UN) | 未检测 | ||||
21 | 41/男 | 2 (39) | 无 | PROC | c.565C>, p.R189W(T) | PC活性 85% |
PLG | exon1-2 deletion*(UN) | PLG活性 52% | ||||
22 | 38/男 | 2 (32) | 无 | PROC | c.574_576delAAG, p.K192del(T) | PC活性 101% |
THBD | c.840C>A, p.C280X*(UN) | 未检测 | ||||
23 | 60/男 | 2 (59) | 无 | PROC | c.574_576delAAG, p.K192del(T) | PC活性 111% |
F5 | c.1114G>C, p.D372H*(UN) | FⅤ活性 94% | ||||
24 | 34/男 | 2 (24) | 外伤1st, 2nd | PROS1 | c.200A>C, p.E67A(T) | PS活性 40% |
TFPI | c.757A>G, p.N253D*(UN) | 未检测 | ||||
25 | 33/男 | 1 (33) | 无 | PROS1 | exon7-15 deletion*(T) | PS 活性 37% |
ADAMTS13 | c.923C>G, p.T308R*(UN) | VWF:Ag 166% | ||||
26 | 53/女 | 1 (52) | 手术 | F5 | c.1663A>C, p.K555Q*(UN) | FⅤ活性 107% |
PROCR | exon1-3 duplication*(UN) | 未检测 | ||||
27 | 32/男 | 3 (16) | 抗磷脂综合征 | PROC | c.574_576delAAG, p.K192del(T) | PC活性 111% |
PROS1 | c.751_752delAT,p.M251VfsX16*(T) | PS活性 39% | ||||
PROCR | exon1-3 duplication*(UN) | 未检测 | ||||
28 | 23/男 | 2 (21) | 无 | PROC | c.-148T>C H*(T) | PC活性 14% |
F2 | c.1436A>G, p.H479R*(UN) | FⅡ活性 75% | ||||
F12 | c.1417G>C, p.G473RH*(UN) | FⅫ活性 15% |
[1] | 丁秋兰, 王学锋. 遗传性易栓症的表型和基因诊断流程[J]. 诊断学理论与实践, 2019, 18(2):127-132. |
[2] |
Ding Q, Wang M, Xu G, et al. Molecular basis and thrombotic manifestations of antithrombin deficiency in 15 unrelated Chinese patients[J]. Thromb Res, 2013, 132(3):367-373.
doi: 10.1016/j.thromres.2013.07.013 URL |
[3] |
Ding Q, Shen W, Ye X, et al. Clinical and genetic features of protein C deficiency in 23 unrelated Chinese patients[J]. Blood Cells Mol Dis, 2013, 50(1):53-58.
doi: 10.1016/j.bcmd.2012.08.004 URL |
[4] |
Li L, Wu X, Wu W, et al. Clinical Manifestation and Mutation Spectrum of 53 Unrelated Pedigrees with Protein S Deficiency in China[J]. Thromb Haemost, 2019, 119(3):449-460.
doi: 10.1055/s-0038-1677031 URL |
[5] |
Simioni P, Tormene D, Tognin G, et al. X-linked thrombophilia with a mutant factor IX (factor IX Padua)[J]. N Engl J Med, 2009, 361(17):1671-1675.
doi: 10.1056/NEJMoa0904377 URL |
[6] |
Ichinose A, Espling ES, Takamatsu J, et al. Two types of abnormal genes for plasminogen in families with a predisposition for thrombosis[J]. Proc Natl Acad Sci U S A, 1991, 88(1):115-119.
pmid: 1986355 |
[7] |
Shigekiyo T, Yoshida H, Matsumoto K, et al. HRG Tokushima: molecular and cellular characterization of histidine-rich glycoprotein (HRG) deficiency[J]. Blood, 1998, 91(1):128-133.
pmid: 9414276 |
[8] |
Moatti D, Haidar B, Fumeron F, et al. A new T-287C polymorphism in the 5' regulatory region of the tissue factor pathway inhibitor gene. Association study of the T-287C and C-399T polymorphisms with coronary artery disease and plasma TFPI levels[J]. Thromb Haemost, 2000, 84(2):244-249.
doi: 10.1055/s-0037-1614003 URL |
[9] |
Hu B, Wang QY, Tang L, et al. Association of thrombomodulin c.1418C>T polymorphism and venous thromboembolism[J]. Gene, 2017, 628:56-62.
doi: 10.1016/j.gene.2017.07.024 URL |
[10] |
Wu C, Dwivedi DJ, Pepler L, et al. Targeted gene sequencing identifies variants in the protein C and endothelial protein C receptor genes in patients with unprovoked venous thromboembolism[J]. Arterioscler Thromb Vasc Biol, 2013, 33(11):2674-2681.
doi: 10.1161/ATVBAHA.113.302137 URL |
[11] |
Villa P, Aznar J, Vaya A, et al. Hereditary homozygous heparin cofactor II deficiency and the risk of developing venous thrombosis[J]. Thromb Haemost, 1999, 82(3):1011-1014.
doi: 10.1055/s-0037-1614320 URL |
[12] |
Lee EJ, Dykas DJ, Leavitt AD, et al. Whole-exome sequencing in evaluation of patients with venous thromboembolism[J]. Blood Adv, 2017, 1(16):1224-1237.
doi: 10.1182/bloodadvances.2017005249 URL |
[13] |
Yin T, Takeshita S, Sato Y, et al. Alarge deletion of the PROS1 gene in a deep vein thrombosis patient with protein S deficiency[J]. Thromb Haemost, 2007, 98(4):783-789.
doi: 10.1160/TH07-03-0211 URL |
[14] |
Choung HS, Kim HJ, Gwak GY, et al. Inherited protein S deficiency as a result of a large duplication mutation of the PROS1 gene detected by multiplex ligation-dependent probe amplification[J]. J Thromb Haemost, 2008, 6(8):1430-1432.
doi: 10.1111/j.1538-7836.2008.03026.x pmid: 18489710 |
[15] |
Reitsma PH. Genetics in thrombophilia. An update[J]. Hamostaseologie, 2015, 35(1):47-51.
doi: 10.5482/HAMO-14-11-0062 pmid: 25465384 |
[16] |
Zhang Z, Li C, Wu F, et al. Genomic variations of the mevalonate pathway in porokeratosis[J]. ELife, 2015, 4:e06322.
doi: 10.7554/eLife.06322 URL |
[17] |
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5):405-424.
doi: 10.1038/gim.2015.30 pmid: 25741868 |
[18] |
Sivasundar S, Oommen AT, Prakash O, et al. Molecular defect of 'Prothrombin Amrita': substitution of arginine by glutamine (Arg553 to Gln) near the Na(+) binding loop of prothrombin[J]. Blood Cells Mol Dis, 2013, 50(3):182-183.
doi: 10.1016/j.bcmd.2012.11.008 URL |
[19] |
Djordjevic V, Kovac M, Miljic P, et al. A novel prothrombin mutation in two families with prominent thrombophi-lia--the first cases of antithrombin resistance in a Caucasian population[J]. J Thromb Haemost, 2013, 11(10):1936-1939.
doi: 10.1111/jth.12367 pmid: 23927452 |
[20] |
Baglin T, Gray E, Greaves M, et al. Clinical guidelines for testing for heritable thrombophilia[J]. Br J Haematol, 2010, 149(2):209-220.
doi: 10.1111/j.1365-2141.2009.08022.x URL |
[21] |
Connors JM. Thrombophilia Testing and Venous Thrombosis[J]. N Engl J Med, 2017, 377(12):1177-1187.
doi: 10.1056/NEJMra1700365 URL |
[1] | ZHOU Lu, LEI Hang, HONG Ye, JIN Shuang, DONG Yongqin, WANG Xuefeng, CAI Xiaohong. AwB subtype caused by a novel ABO *A allele and its molecular mechanisms [J]. Journal of Diagnostics Concepts & Practice, 2021, 20(06): 547-551. |
[2] | LEI Hang, FAN Liangfeng, CAI Xiaohong, WANG Yuqing, LIU Xi, JIN Sha, SHEN Wei, LU Qiong, XIANG Dong, WANG Xuefeng, ZOU Wei. The study on molecular basis of ABO blood subgroups in the Chinese population [J]. Journal of Diagnostics Concepts & Practice, 2020, 19(04): 364-369. |
[3] | GONG Ruhan, LI Jia, HUANG Kaifeng. Establishment of fluorescence PCR method using blood specimens for a rapid genetyping and its application in ADRB1 genotyping [J]. Journal of Diagnostics Concepts & Practice, 2020, 19(04): 402-406. |
[4] | ZHU Chao, GUAN Jialiang, LI Zhe, LIU Yu, WANG Xuefeng, WU Wenman. Research on correlation between results of diluted Russell viper venom time (dRVVT) test and mixing test in detection of lupus anticoagulant [J]. Journal of Diagnostics Concepts & Practice, 2020, 19(1): 28-31. |
[5] | . [J]. Journal of Diagnostics Concepts & Practice, 2019, 18(2): 127-132. |
[6] | WANG Dengfeng, CUI Wenyan, ZOU Wei, LI Fang, WANG Xuefeng, CAI Xiaohong. Molecular mechanism of Ax subtype caused by p.M142I mutation in alpha 1-3-N-acetylgalactosaminyltransferase [J]. Journal of Diagnostics Concepts & Practice, 2018, 17(03): 260-265. |
[7] | . [J]. Journal of Diagnostics Concepts & Practice, 2017, 16(04): 358-362. |
Viewed | ||||||
Full text |
|
|||||
Abstract |
|
|||||