Origin of the Swedish long QT syndrome Y111C/KCNQ1 founder mutation

A Common Mutation of Long QT Syndrome Type 1 in Japan

“…The Y111C mutation in the N-terminus is frequent in Sweden, and the dominant-negative effect leads to insufficient trafficking of the normal KCNQ1 protein; however, despite marked QT prolongation, the incidence of cardiac events is lower than for A341V (symptomatic carriers, 30% in Y111C vs. 75% in A341V). 9 In contrast, in Finland, the founder mutation G589D causes a benign phenotype and occurs in 30% of LQTS cases. G589D carriers have mild prolongation of the QT interval (460 ms) under heterozygous conditions, and 26% of patients are symptomatic.…”

Third Trimester Fetal Heart Rate Predicts Phenotype and Mutation Burden in the Type 1 Long QT Syndrome

“…In this study, we take advantage of our large and relatively homogeneous Swedish LQT1 founder populations segregating the p.Y111C 16 and p.R518X 11 mutations to investigate whether fetal heart rate differs between LQT1 genotype groups (including noncarriers, carriers of single LQT1 mutations, and carriers of double LQT1 mutations). Furthermore, we aim to investigate whether fetal heart recordings, obtained as part of standard medical care, have a predictive value for postnatal phenotype in these LQT1 populations.…”

“…The study population was recruited from 2 large Swedish founder populations, segregating either p.Y111C 16 (22 index families) or p.R518X 11 (13 index families), where cascade-screening for KCNQ1 gene (LQT1) mutations had been previously performed in the clinical setting. The term family here indicates the first ascertained index case/proband in a family without known relations to any other LQTS family, plus all tested family members identified through the process of cascade-screening of first-degree relatives.…”

“…The term family here indicates the first ascertained index case/proband in a family without known relations to any other LQTS family, plus all tested family members identified through the process of cascade-screening of first-degree relatives. 11,16 Using pedigrees of the cascade-screened families, mothers with children of ascertained genotype born from 1980 and onwards were invited to participate in the study (irrespective of maternal genotype). Among the mothers who wished to participate in the study, all pregnancies, including carrier and noncarrier fetuses, were included in the analysis.…”

“…As previously described, 11,16 ascertainment of carriership status had been performed according to the clinical praxis, using genomic DNA extracted by a standard salting-out procedure, and genotypes in index cases had been ascertained by denaturing high-performance liquid chromatography (Wave 3500 HT, Transgenomic Inc, Omaha, Neb) and sequencing all coding exons of the KCNQ1 gene (CEQ 8000, Beckman Coulter, Fullerton, CA). In some probands, >1 KCNQ1 mutation were identified.…”