The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD.
Over half of SADS deaths were likely to be due to inherited heart disease; accurate identification is vital for appropriate prophylaxis amongst relatives who should undergo comprehensive cardiological evaluation, guided and confirmed by mutation analysis.
BackgroundClinical interpretation of the large number of rare variants identified by high throughput sequencing (HTS) technologies is challenging. The aim of this study was to explore the clinical implications of a HTS strategy for patients with hypertrophic cardiomyopathy (HCM) using a targeted HTS methodology and workflow developed for patients with a range of inherited cardiovascular diseases. By comparing the sequencing results with published findings and with sequence data from a large-scale exome sequencing screen of UK individuals, we sought to quantify the strength of the evidence supporting causality for detected candidate variants.Methods and results223 unrelated patients with HCM (46±15 years at diagnosis, 74% males) were studied. In order to analyse coding, intronic and regulatory regions of 41 cardiovascular genes, we used solution-based sequence capture followed by massive parallel resequencing on Illumina GAIIx. Average read-depth in the 2.1 Mb target region was 120. Rare (frequency<0.5%) non-synonymous, loss-of-function and splice-site variants were defined as candidates. Excluding titin, we identified 152 distinct candidate variants in sarcomeric or associated genes (89 novel) in 143 patients (64%). Four sarcomeric genes (MYH7, MYBPC3, TNNI3, TNNT2) showed an excess of rare single non-synonymous single-nucleotide polymorphisms (nsSNPs) in cases compared to controls. The estimated probability that a nsSNP in these genes is pathogenic varied between 57% and near certainty depending on the location. We detected an additional 94 candidate variants (73 novel) in desmosomal, and ion-channel genes in 96 patients (43%).ConclusionsThis study provides the first large-scale quantitative analysis of the prevalence of sarcomere protein gene variants in patients with HCM using HTS technology. Inclusion of other genes implicated in inherited cardiac disease identifies a large number of non-synonymous rare variants of unknown clinical significance.
ObjectiveA predictable relation between genotype and disease expression is needed in order to use genetic testing for clinical decision-making in hypertrophic cardiomyopathy (HCM). The primary aims of this study were to examine the phenotypes associated with sarcomere protein (SP) gene mutations and test the hypothesis that variation in non-sarcomere genes modifies the phenotype.MethodsUnrelated and consecutive patients were clinically evaluated and prospectively followed in a specialist clinic. High-throughput sequencing was used to analyse 41 genes implicated in inherited cardiac conditions. Variants in SP and non-SP genes were tested for associations with phenotype and survival.Results874 patients (49.6±15.4 years, 67.8% men) were studied; likely disease-causing SP gene variants were detected in 383 (43.8%). Patients with SP variants were characterised by younger age and higher prevalence of family history of HCM, family history of sudden cardiac death, asymmetric septal hypertrophy, greater maximum LV wall thickness (all p values<0.0005) and an increased incidence of cardiovascular death (p=0.012). Similar associations were observed for individual SP genes. Patients with ANK2 variants had greater maximum wall thickness (p=0.0005). Associations at a lower level of significance were demonstrated with variation in other non-SP genes.ConclusionsPatients with HCM caused by rare SP variants differ with respect to age at presentation, family history of the disease, morphology and survival from patients without SP variants. Novel associations for SP genes are reported and, for the first time, we demonstrate possible influence of variation in non-SP genes associated with other forms of cardiomyopathy and arrhythmia syndromes on the clinical phenotype of HCM.
Background Drug-induced long QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. Here, we tested the hypothesis that common variants in key genes controlling cardiac electrical properties modify the risk of diLQTS. Methods and Results In a case-control setting, we included 176 patients of European descent from North America and Europe with diLQTS, defined as documented torsades de pointes during treatment with a QT prolonging drug. Control samples were obtained from 207 patients of European ancestry who displayed <50 msec QT lengthening during initiation of therapy with a QT-prolonging drug, and 837 controls from the population based KORA study. Subjects were successfully genotyped at 1,424 single nucleotide polymorphisms (SNPs) in 18 candidate genes including 1,386 SNPs tagging common haplotype blocks, and 38 non-synonymous ion channel gene SNPs. For validation we used a set of cases (n=57) and population-based controls of European descent. The SNP KCNE1 D85N (rs1805128), known to modulate an important potassium current in the heart, predicted diLQTS with an odds ratio of 9.0 (95% confidence interval: 3.5–22.9). The variant allele was present in 8.6% of cases, 2.9% of drug-exposed controls, and 1.8% of population controls. In the validation cohort the variant allele was present in 3.5% of cases, and in 1.4% of controls. Conclusions This high-density candidate SNP approach identified a key potassium channel susceptibility allele that may be associated with the rare adverse drug reaction torsades de pointes.
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