Phenotype, origin and estimated prevalence of a common long QT syndrome mutation: a clinical, genealogical and molecular genetics study including Swedish R518X/KCNQ1families

Abstract

BackgroundThe R518X/KCNQ1 mutation is a common cause of autosomal recessive (Jervell and Lange Nielsen Syndrome- JLNS) and autosomal dominant long QT syndrome (LQTS) worldwide. In Sweden p.R518X accounts for the majority of JLNS cases and is the second most common cause of LQTS. Here we investigate the clinical phenotype and origin of Swedish carriers of the p.R518X mutation.MethodsThe study included 19 Swedish p.R518X index families, ascertained by molecular genetics methods (101 mutation-carriers, whereof 15 JLNS cases and 86 LQTS cases). In all families analyses included assessment of clinical data (symptoms, medications and manually measured electrocardiograms), genealogy (census records), haplotype (microsatellite markers) as well as assessment of mutation age and associated prevalence (ESTIAGE and DMLE computer software).ResultsClinical phenotype ranged from expectedly severe in JLNS to surprisingly benign in LQTS (QTc 576 ± 61 ms vs. 462 ± 34 ms, cumulative incidence of (aborted) cardiac arrest 47% vs. 1%, annual non-medicated incidence rate (aborted) cardiac arrest 4% vs. 0.04%).A common northern origin was found for 1701/1929 ancestors born 1650-1950. Historical geographical clustering in the coastal area of the Pite River valley was shown. A shared haplotype spanning the KCNQ1 gene was seen in 17/19 families. Mutation age was estimated to 28 generations (95% CI 19;41). A high prevalence of Swedish p.R518X heterozygotes was suggested (~1:2000-4000).ConclusionsR518X/KCNQ1 occurs as a common founder mutation in Sweden and is associated with an unexpectedly benign phenotype in heterozygous carriers.

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

“…There was a mean of 9±3 intrauterine heart rate recordings per fetus (range, 1-18) including a mean of 6±3 recordings during the third trimester and onwards (range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. When considering all heart rates from week 29 onwards, including heart rates recorded at admission to the delivery ward, pedigree-based association analysis including all founder population cases (n=184) revealed that mean heart rates were lower per added mutation (no mutation, 142±6 beats per minute (n=74); single mutation, 133±8 beats per minute (n=97); double mutations, 111±6 beats per minute (n=13); P<0.0001).…”

“…To provide relatedness data for the SOLAR and SAGE software, pedigrees were constructed for each founder population, linking the nuclear families and family branches, via a best estimate approach based on available family pedigrees and previously published genealogical and microsatellite data for all included families. 11,16,20 The measured genotype approach 21,22 estimates genotype-specific trait means in large pedigrees by a fixed-effects model. To control for effects of multiple covariates, an initial maximum likelihood model was constructed in SOLAR (and validated using SAGE) for the primary trait mean third trimester heart rate, screening the covariates fetal genotype (no mutation=0, single mutation=1, double mutations=2), fetal sex (female=1, male=2), fetal phenotype (no arrhythmia symptoms=0, syncope and intrauterine arrhythmia=1), mothers' genotype (noncarrier=0, mutation carrier=1), and intrauterine β-blocker exposure (no exposure=0, exposure to β-blockers=1) for significant association with the primary trait.…”

“…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.…”

“…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.…”

“…Probands with a clinical JLNS diagnosis were also screened for additional mutations in the KCNE1 gene. 8,11 In family members, mutation carriage was ascertained by sequencing or targeted mutation analysis of the identified mutations (MGB-probes by ABI 7000, Applied Biosystems, Foster City, CA).…”