Monday 29 August 2016

Background: Long QT syndrome (LQTS) is characterized by QT prolongation in 12-lead ECG and peculiar ventricular tachycardia called as torsade de pointe (TdP).The disease frequency is estimated around 1 per 2000.The main cause of LQTS is mutations in genes encoding cardiac ion channels and more than 60% of patients carried mutations in KCNQ1, KCNH2 and SCN5A.These gene mutations cause LQT1, LQT2 and LQT3.The frequency of compound or double mutations has been reported as 4 to 10%, however, patients with triple mutations have been rarely reported.Objective: The aim of this study is to search for the frequency of triple mutation carriers in LQTS and clarify the detailed clinical severity of them. Methods and results:The cohort of this study consisted of 1015 LQTS probands and their family members.We performed genetic screening for genes related with LQTS including KCNQ1, KCNH2, and SCN5A by Sanger methods or targeted resequencing using next generation sequencer.We identified two unrelated probands with three mutations in three genes (0.2%).The first proband was a 9 year-old boy who experienced syncope while playing, and KCNQ1-R174C, KCNH2-E1039X, and SCN5A-E428K were identified.Another proband was an 11 year-old boy who suffered cardiac arrest while playing ball game.He carried KCNQ1-T587M, KCNH2-R148W, and SCN5A-K1244N.The minor allele frequencies of all mutations were less than 0.001 in ethnic matched healthy controls.We further performed clinical and genetic analysis of family members for three generations in both families (figure).Only probands were the three mutation carriers except for 2 years-old sister.Several members with one or two mutations showed QT prolongation, however, their symptoms were mild or none.These data suggest that the accumulation of the pathogenic mutations caused severe phenotype. Family treesConclusion: Although the frequency of triple mutation carriers was very rare (0.2%) among patients who diagnosed with LQTS, screening for three genes and identification of mutations would be indispensable for the clinical treatment and familial analysis.