研究背景： Gordon综合征，又名家族性高血钾性高血压(FHHt)或假性醛固酮减少症二型(PHAⅡ)，是一种罕见的单基因高血压疾病，主要临床表现是高血压和与肾功能不匹配的高钾血症。Gordon综合征有4个致病基因已被证实，分别是WNK1、WNK4、 CUL3和KLHL3。这些特定的基因变异通过复杂的级联信号通路和泛素化通路，引起肾脏远曲小管的Na-Cl协同转运蛋白过度激活，导致NaCl重吸收增多和下游钾离子分泌减少，进而造成盐敏感的高血压和高钾血症。噻嗪类利尿剂和限盐疗法对控制该类高血压效果显著。Gordon综合征临床表现异质性大，发病率低，临床医生对该病认识不足，许多患者被误诊误治，年轻时即出现严重的靶器官损害，甚至猝死。 研究目的： 本文对1例疑诊Gordon综合征患者进行家系调查和基因检测，以明确患者的临床诊断和致病基因是否为家族遗传性，并探讨该突变类型与表现型的关系。 研究方法： 对一名33岁的早发高血压、早发脑卒中男性患者进行二代测序，发现了一种未报道的WNK1基因突变。严格遵照知情同意原则，调查和收集先证者及其家系的临床资料，包括病史、血压、血清电解质、超声心动图、血浆肾素浓度(或血浆肾素活性)和血浆醛固酮浓度等。应用Sanger测序验证和检测患者及家系成员的WNK1突变。对携带突变的患者给予口服氢氯噻嗪治疗，1月和3月后分别进行随访。此外，通过检索Scopus和万方数据库，入选2001年至2019年5月在中英文文献中公开报道过的经基因检测确诊的Gordon综合征病例，提取散发病例或家系成员的实验室资料、临床数据和基因突变，应用SPSS22.0进行统计分析。 研究结果： 本研究纳入包括先证者在内的8名家系成员。Sanger测序显示家系中先证者(Ⅲ-7)，先证者的儿子(Ⅳ-1)和先证者的妹妹(Ⅲ-8)共3人携带有WNK1基因9号外显子的C.3154G＞A错义突变。该突变为首次报道。先证者(Ⅲ-7)有明确的早发高血压和早发脑卒中病史，病程中联合使用多种降压药物效果差。给予Gordon综合征的针对性治疗1个月、3个月后分别随访，先证者血压控制好，血钾水平无明显异常，因此可确诊Gordon综合征。先证者的儿子(Ⅳ-1岁，8岁)和妹妹(Ⅲ8岁，26岁)未达到高血压病的诊断标准，但其血压接近正常高值。先证者父亲(Ⅱ-6)和先证者大姑(Ⅱ-2)均有早发高血压病史，分别于55岁、56岁时死于高血压脑卒中。家系中所有成员的血电解质未见明显异常。 通过检索Scopus和万方数据库，共有35个Gordon家系或散发病例纳入分析。在突变携带者中，高血压的发生率是64.3%，高钾血症的发生率是71.4%，低醛固酮血症的发生率是50.0%。 结论： 本研究通过对疑诊Gordon综合征病例进行家系研究和突变基因检测，发现了一个新的致病突变，指导了患者的临床诊疗和携带者的长期随访，也拓展了Gordon综合征的突变谱。通过对家系临床资料的总结，提示C.3154G＞A突变对血压影响较大，对肾脏泌钾功能影响较大，且可能与脑卒中事件相关。Gordon综合征等罕见的单基因高血压疾病临床诊断难度较大。对早发高血压患者，在排除继发因素外，可考虑筛查单基因高血压相关的基因突变，一旦发现致病突变，应对先证者的家系成员进行基因筛查，以实现单基因高血压病的早发现、早诊断、早治疗。 关键词：Gordon综合征；WNK1基因；基因检测

 Background: Gordon syndrome, also known as Familial hyperkalemia and Hypertension (FHHt) or Pseudohypoaldosteronism Type 2 (PHAⅡ), is a monogenic hypertension syndrome with a characteristic hyperkalemia despite normal glomerular filtration rate. Mutations in 4 genes, including WNK1, WNK2, CUL3 and KLHL3, have been proven to cause Gordon syndrome. These gene mutations overactivates thiazide-sensitive Na/Cl cotransporter (NCC) in the distal nephron by a complex signal transduction cascade and a ubiquitination pathway. Increased NCC activity causes an increase in NaCl reabsorption and a decrease in renal potassium secretion, leading to salt-sensitive arterial hypertension with hyperkalemia. Patients with Gordon Syndrome respond well to aggressive salt-restriction or relatively small doses of thiazide diuretics. Gordon syndrome is an extremely rare heterogeneous disorder, and most clinicians have a poor knowledge of it. As a consequence, Gordon's patients can be misdiagnosed with mistreatment, suffering early-onset severe target organ damage and even sudden death. Objectives: A family of suspicious Gordon syndrome was investigated, aiming to distinguish whether the gene mutation is familiar or sporadic, to clarify the diagnosis, and to explore their genotype-phenotype relationship. Methods: A new WNK1 mutation was found in a 33-yr-old man with early-onset hypertension and stroke. This study included the man and his family members. Clinical investigation was conducted, including medical history, blood pressure, serum electrolyte, echocardiogram, plasma renin activity/concentrations, and plasma aldosterone concentrations. Molecular analysis of WNK1 used polymerase chain reaction (PCR), then the products of PCR were purified and sequenced directly to examine the genetic structure. Patients with disease-causing mutations were treated with salt-restriction diet and thiazide diuretics. Additionally, the reported Gordon's cases confirmed by genetic testing from 2001 to May 2019 were collected by searching for Scopus and Wanfang database. A database was made with the abstracted information about gene mutations, laboratory data and clinical features of the sporadic cases or Gordon's families. Statistical analysis was performed using SPSS version 22.0. Results: This study included 8 members of the family. Sanger sequencing indicated that a missense WNK1 mutation in exon 9,C.3154G>A, was detected in three family members, that is,the proband (Ⅲ-7), the proband's son (Ⅳ-1) and the proband's younger sister (Ⅲ-8). The mutation had never been reported before. The proband (Ⅲ-7) had a clear history of early-onset hypertension and early-onset stroke,and did not respond to the combination of multiple antihypertensive agents. One-month and three-month follow-up revealed great response to thiazide diuretics and salt-restriction diet, and therefore the diagnosis of Gordon syndrome was made. The proband's son (Ⅳ-1,8 years old) and the younger sister (Ⅲ-8,26 years old) were not diagnosed as hypertension, while their blood pressure were both close to the normal high value. The proband's father (Ⅱ-6) and the proband's aunt (Ⅱ-2) had a history of early-onset hypertension, and died of hypertensive stroke respectively at 55 and 56. No significant abnormalities in blood electrolytes was detected in the whole family. Through Scopus database and Wanfang database search, a total of 35 families with Gordon syndrome were included in analysis. Hypertension was present in 64.3%, hyperkalemia was present in 71.4%, hypoaldosteronism was present in 60.7% of the carriers. Conclusions: A novel pathogenic mutation of Gordon syndrome was identified in WNK1 gene by pedigree research and DNA Screening. The study clarified a Gordon's cases and two highrisk family members, which helped to guide the management. At the same time, the new mutation extended the mutation spectrum of Gordon syndrome. The clinical features of the family suggested that the C.3154G>A mutation had a significant influence on blood pressure but little influence on the renal potassium secretion. Moreover, the mutation was probably related to the stroke events. The clinical diagnosis of several familial hypertensive diseases, such as Gordon syndrome, was difficult to be made. Genetic screening for monogenic hypertension should be considered in hypertensive patients with early penetrance, after exclusion of common secondary causes of hypertension. Keywords: Gordon syndrome; WNK1; genetic testing