Liddle Syndrome:Genetic Diagnosis And Genotype-Phenotype Analysis

BACKGROUNDLiddle syndrome(LS)is autosomal dominant mendelian hypertension caused by mutations in genes encoding epithelial sodium channel(ENaC).Conventional diagnosis base on a typical set of symptoms,including severe early-onset hypertension,hypokalemia,suppression of the renin-angiotensin-aldosterone system(RAAS),and responsive to ENaC blockers.Liddle Syndrome was considered a rare disease,accounting for 1%of hypertension of undetermined cause in Chinese population.Underdiagnosis of Liddle syndrome and long-term poor blood control often result in end organ damage.AIM1.Screened the C-terminus of SCNN1B and SCNN1G in a pedigree with family history of early onset hypertension and suppressed RAAS.2.Thorough reviewof the reported mutations in genes encoding ENaC,causing Liddle syndrome.METHODS1.DNA samples were collected from the 17-year-old proband and 8 other kindreds.The 13th exons of SCNN1B,SCNN1Gwasamplified and sequenced.The candidate disease-causing variants were verified by Sanger sequencing.Clinical examinations were used to comprehensively evaluate the phenotypes of two patients.2.Systematicsearchofgenetically comfirmed Liddle syndrome cases and phenotype-genotype analysis was conducted.RESULTSGenetic analysis of the proband revealed a novel frameshift mutation c.1756delC(p.R586Vfs*13)in exon 13 of SCNN1G.This heterozygous mutation resulted in deletion of the crucial PY motif.Identical mutation was also found in one affected family member and one asymptomatic member.Amiloride was effective in both hypertensive patients.There were no SCNN1G mutation in this family.Sytematic literature review found that,to date,34 different causative mutations have been reported in 98 families(including the family in this study).Hypertension was present in 91.5%,hypokalemia was present in 66.7%,suppressed RAAS was present in 60.7%of the heterzygotic carriers.CONCLUSION1.A novel causative frameshift mutation c.1756de1C(p.R586Vfs*13)in exon 13 of SCNN1G was identified.2.A spectrum of phenotype of the Liddle syndrome was found-Genetic diagnosis is crucial for early diagnose of atypical Liddle syndrome.3.The panetrance of mutations involving PY motif,or not involving PY motif varies.