# Clinical and genetic analysis of two families with combined defect in antithrombin and protein C genes

## TL;DR

This study investigates two families with combined genetic defects in antithrombin and protein C, linking these mutations to increased risk of venous thrombosis.

## Contribution

The paper identifies novel gene mutations in SERPINC1 and PROC and their association with thrombotic events in affected families.

## Key findings

- Two families were found to have combined mutations in SERPINC1 and PROC genes.
- Mutations were predicted to be pathogenic and associated with abnormal anticoagulant function.
- Carriers of these mutations showed increased thrombin generation and a procoagulant state.

## Abstract

对2个抗凝血酶（AT）和蛋白C（PC）联合缺陷家系进行临床特征和基因突变分析，探讨SERPINC1基因和PROC基因联合缺陷与疾病发生的关系。

采用常规方法检测先证者及其家系成员AT活性（ＡT∶A）、AT抗原（AT∶Ag）、PC活性（PC∶A）、PC抗原（PC∶Ag）、蛋白S活性（PS∶A）指标。采用二代测序（NGS）和CNVplex技术对筛选基因的编码区和调控区进行点突变、小缺失或插入及基因拷贝数变异的检测，并对突变位点进行Sanger法测序验证。运用ClustalX-2.1-win软件分析突变位点的保守性；使用在线生物信息学软件预测突变位点的致病性；通过CAT法检测凝血酶生成情况。

先证者1的PROC基因第5外显子存在c.400+5G>A剪切位点突变，SERPINC1基因第5外显子存在c.883G>A（p.Val295Met）杂合错义突变；先证者2的PROC基因第9外显子存在c.811C>T（p.Arg271Trp）杂合错义突变，SERPINC1基因第5外显子存在c.880C>T（p.Arg294Cys）杂合错义突变，突变位点分别来源于患者的父亲和母亲。生物信息学分析发现以上突变位点大多数为保守位点，这些基因突变大多数被预测为“致病的、有害的”，可通过改变蛋白空间结构、破坏蛋白稳定性，引起AT和PC水平或功能异常。凝血酶生成试验结果显示，4例突变携带者均出现不同程度的内源性凝血酶生成增多呈高凝倾向，在血栓调节蛋白（sTM）的存在下，PC途径的抗凝功能明显减弱。

在2个家系中发现AT和PC两个突变位点，可能与2例患者的反复静脉血栓发生有关；SERPINC1和PROC基因联合突变携带者具有更高的静脉血栓发生风险。