Characterization of a KCNQ1/KVLQT1 polymorphism in Asian families with LQT2: implications for genetic testing

Abstract

Congenital long QT syndrome (LQTS) is a genetic disease that predisposes affected individuals to arrhythmias, syncope, and sudden death. Mutations in several ion channel genes have been discovered in different families with LQTS: KCNQ1 (KVLQT1, LQT1), KCNH2 (HERG, LQT2), SCN5A (LQT3), KCNE1 (minK, LQT5), and KCNE2 (MiRP1, LQT6). Previously, the P448R-KVLQT1 missense mutation has been reported as an LQT1-causing mutation. In this report, we demonstrate the presence of the P448R polymorphism in two, unrelated Chinese LQTS families. Although absent from 500 reference alleles derived from 150 white and 100 African-American subjects, P448R was present in 14% of healthy Chinese volunteers. Given the inconsistencies between the genotype (LQT1) and clinical phenotype (LQT2) in our two LQTS families, together with the finding that the P448R appears to be a common, ethnic-specific polymorphism, mutational analysis was extended to the other LQTS-causing genes resulting in the identification of distinct HERG missense mutations in each of these two families. Heterologous expression of P448R-KVLQT1 yielded normal, wild-type (WT) currents. In contrast, the two unique HERG mutations resulted in dominant-negative suppression of the WT HERG channel. Our study has profound implications for those engaged in genetic research. Importantly, one child of the original proband was initially diagnosed with LQT1 based upon the presence of P448R-KVLQT1 and was treated with beta-blockers. However, he did not possess the subsequently determined LQT2-causing mutation. On the other hand, his untreated P448R-negative brother harbored the true, disease-causing HERG mutation. These findings underscore the importance of distinguishing channel polymorphisms from mutations pathogenic for LQTS and emphasize the importance of using appropriate ethnically matched controls in the genotypic analysis of LQTS.

Postmortem molecular analysis of KCNQ1, KCNH2, KCNE1 and KCNE2 genes in sudden unexplained nocturnal death syndrome in the Chinese Han population

“…While in the AFR, AMR and EUR populations, this locus was a high conservational locus, with a C allele frequency 1. Sharma et al confirmed that KCNQ1-P448R most likely represents a benign polymorphism with no detectable changes in the current kinetics or expression level compared to the WT channel, and further that the identified polymorphism was ethnic specific [39]. We also identified G643S, as a MAF of 0.02 in SUNDS cohort, while Tester et al found 1 case among 173 Sudden Unexplained Death decedents in America [40].…”

Phenotypic Variability in Caucasian and Japanese Patients with Matched LQT1 Mutations

“…Thus, the identification of risk factors among LQTS populations with similar mutations may be important for risk-stratification in this genetic disorder. Ethnic-specific polymorphisms on the LQTS-related genes have been described in previous reports 8-15,25-27. Notably, Ackerman et al8 studied 744 healthy black, white, Asian and Hispanic subjects and reported 49 distinct amino acid-altering variants of four LQTS-related potassium channel genes.…”

“…In addition, ethnic-specific SNPs have been recognized as important in the correct diagnosis and clinical management of LQTS suspected patients. In one report, a previously established KCNQ1 mutation, P488R, was found to be a common polymorphism in 14% of healthy Chinese volunteers after a healthy child of a proband was mistakenly diagnosed with LQTS while his undiagnosed brother was later found to have a novel HERG mutation 27. Therefore, diagnosis based on genotyping requires correct discrimination of genetic polymorphisms from pathologic mutations, which may be confounded by ethnic genetic variability.…”

Cardiac ion channel mutations in the sudden infant death syndrome

“…No mutations were found in KCNE1 or KCNJ2. However, one rare KCNQ1 variant (p.P448R, three cases) appeared a common, ethnic-specific polymorphism [44], whereas the mutations p.V279M, p.R885C and p.S1040G in KCNH2 (three cases in total) exhibited biophysical properties indistinguishable from wildtype [45] and are probably benign variants. For the remaining five cases clear functional effects have been found [43,45].…”