The Associations Between Location Of Mutation In The KCNQ1 And Phenotypic Presentation Of Congenital Long QT Syndrome Type 1: Meta-Analysis

Objective:Congenital long QT syndrome(LQTS)is a hereditary ion channel disease characterized by prolonged QT interval that can progress to a fatal polymorphic ventricular tachycardia/torsades-de-pointes.It often manifests as palpitation,syncope,sudden cardiac arrest or sudden death.KCNQ1 is the most prevalent genetic form of long QT syndrome.Studies have shown that location of mutation in KCNQ1 gene was identified as a factor in affecting penetrance and expressivity of long QT syndrome type1(LQTS1).We performed a meta-analysis to explore the associations between mutation location(transmembrane domain vs non-transmembrane domain)in the KCNQ1 and phenotypic presentation of LQTS1.Methods:We searched the databases of Pub Med,EMBASE,Web of Science and Cochrane Library from inception to June 2020.Included studies were cohorts that compared the phenotypic features in patients with transmembrane mutation and non-transmembrane mutation.After the critical evaluation on the quality of literature,the extracted data was analyzed by Rev Men 5.3 software.Data from each study were combined using the random effects model to calculate overall odds ratios(OR)or mean difference(MD)and the 95%confidence interval(CI).Results:A total of 8 cohorts including 2061 patients with mutations in transmembrane domain(n=1087)and non-transmembrane domain(n=984)of KCNQ1 were included.Patients with transmembrane mutations are more likely to develop symptoms(OR 4.51,95%CI 3.27–6.22,P<0.00001,I~2=27%),show a longer QTc value(MD 14.37,95%CI 7.96–20.8,P<0.0001,I~2=38%)and have a higher risk of sudden death(OR 4.89,95%CI 1.62–14.77,P 0.003,I~2=70%)when compared with patients with non-transmembrane mutations.No significant difference for age of onset is observed between two groups(MD 1.38,95%CI-6.41-9.17,P 0.73,I~2=68%).Conclusion:Present meta-analysis demonstrated the mutations of KCNQ1 located in the transmembrane domain are important risk factors influencing the penetrance and expressivity of long QT syndrome type 1.