Research On Clinical Pedigree And Pathogenic Genes Of Gordon Syndrome

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 NaC1 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(?-7),the proband's son(?-1)and the proband's younger sister(?-8).The mutation had never been reported before.The proband(?-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(?-1,8 years old)and the younger sister(?-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(?-6)and the proband's aunt(?-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 high-risk 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.