Clinical Manifestation and Mutation Spectrum of 53 Unrelated Pedigrees with Protein S Deficiency in China
Clinical Manifestation and Mutation Spectrum of 53 Unrelated Pedigrees with Protein S Deficiency in China
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中国53个无亲缘关系的蛋白S缺乏家系的临床表现和突变谱
DOI：
10.1055/s-0038-1677031
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发表时间：
2019
影响因子：
6.7
通讯作者：
Xuefeng Wang
中科院分区：
文献类型：
--
作者：
Lei Li;Xi Wu;Wenman Wu;Qiulan Ding;Xiaohong Cai;Xuefeng Wang
蛋白S（PS）缺乏与静脉血栓栓塞（VTE）风险增加10倍相关，但其诊断相当困难和复杂。在这项研究中，我们确定了53个无关的家系PS缺乏症在中国。收集患者的临床特征和实验室检查资料。对先证者及相关家族成员进行PROS 1基因分析，包括直接测序、拷贝数变异检测和信使核糖核酸分析。52.8%（28/53）的先证者有多部位和/或反复血栓形成，主要表现为深静脉血栓形成和/或肺栓塞（82.7%）。39.6%（21/53）的先证者存在VTE的其他危险因素，其中7例合并抗磷脂综合征。大多数先证者和家族成员表现出定量PS缺乏，同时伴有活化蛋白C和组织因子途径抑制剂辅因子活性受损。值得注意的是，通过综合表型和遗传分析获得了87.2%（34/39）的PROS 1可检测突变率。在48例先证者中共检测到36个PROS 1致病突变，其中包括16个新突变，而在其他5例先证者中未检测到PROS 1突变。在中国人群中首次发现Glu 67 Ala、Arg 561 Trp和Tyr 560三个热点突变。本文提供了一个框架，相关的临床发病机制PS缺乏症的遗传背景，在中国的人口
Protein S (PS) deficiency is associated with a 10-fold increased risk of venous thromboembolism (VTE), but its diagnosis is quite difficult and complicated. In this study, we identified 53 unrelated pedigrees with PS deficiency in China. Data of their clinical characteristics and laboratory examinations were collected. Genetic analysis of PROS1 including direct sequencing, copy number variant detection and messenger ribonucleic acid analysis was performed in probands and related family members. Of these 53 probands, 52.8% (28/53) experienced multi-site and/or recurrent thrombotic episodes, mainly manifested as deep venous thrombosis and/or pulmonary embolism (82.7%). Additional risk factors of VTE were observed in 39.6% (21/53) probands who exhibited a significantly higher rate of recurrent VTE compared with those not, in which 7 probands were complicated by anti-phospholipid syndrome. Most probands and family members exhibited quantitative PS deficiency with impairment of both activated protein C and tissue factor pathway inhibitor cofactor activities. Note that 87.2% (34/39) PROS1 detectable mutation rate was obtained through comprehensive phenotypic and genetic analysis. A total of 36 PROS1 causative mutations including 16 novel mutations were identified in 48 probands, whereas no PROS1 mutations were detected in the other 5 probands. Three hotspot mutations (Glu67Ala, Arg561Trp and Tyr560 ) were identified in the Chinese population for the first time. This article provides a framework for correlating the clinical pathogenesis of PS deficiency to genetic backgrounds in the Chinese population