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Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare inherited heart-muscle disorder, which is the most common cause of life-threatening arrhythmias and sudden cardiac death (SCD) in young adults and athletes. Early and accurate diagnosis can be crucial in effective ARVC management and prevention of SCD. The genome Aggregation Database (gnomAD) population of 138,632 unrelated individuals was searched for previously identified ARVC variants, classified as pathogenic or unknown on the disease genetic variant database (http://www.arvcdatabase.info/), in five most-commonly mutated genes: PKP2, DSP, DSG2, DSC2and JUP, where variants account for 40–50% of all the ARVC cases. Minor allele frequency (MAF) of 0.001 was used to define variants as rare or common. The gnomAD data contained 117/364 (32%) of the previously reported pathogenic and 152/266 (57%) of the unknown ARVC variants. The cross-ethnic analysis of MAF revealed that 11 previously classified pathogenic and 57 unknown variants were common (MAF ≥ 0.001) in at least one ethnic gnomAD population and therefore unlikely to be ARVC causing. After applying our MAF analysis the overall frequency of pathogenic ARVC variants in gnomAD was one in 257 individuals, but a more stringent cut-off (MAF ≥ 0.0001) gave a frequency of one in 845, closer to the estimated phenotypic frequency of the disease. Our study demonstrates that the analysis of large cross-ethnic population sequencing data can significantly improve disease variant interpretation. Higher than expected frequency of ARVC variants suggests that a proportion of ARVC-causing variants may be inaccurately classified, implying reduced penetrance of some variants, and/or a polygenic aetiology of ARVC.

Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS.

The 825C>T polymorphism of the G-protein β3-subunit gene (GNB3) has been associated with hypertension, although results are not entirely consistent. In a sample of 282 female Caucasian dizygotic twins aged 21–80 years, we aimed to investigate the associations between blood pressure and five single nucleotide polymorphisms (SNPs) including the 825C>T and haplotypes of the GNB3 gene. The polymorphisms (−350A>G, 657A>T, 814G>A, 825C>T and 1429C>T) were genotyped by polymerase chain reaction-restriction enzyme assays. Regular association tests did not show a significant effect on blood pressure for any of the five SNPs. However, strongly significant interactions between the −350A>G, 825C>T and 1429C>T loci and adiposity (both body mass index and waist circumference) were observed for systolic blood pressure (Ps<0.01) as well as diastolic blood pressure (Ps<0.05), suggesting increases in adiposity amplify the effects of the SNPs on blood pressure. Haplotype analyses confirmed the effects of the GNB3gene–obesity interaction on hypertension risk. Additionally, sib-transmission disequilibrium tests (sib-TDTs) showed significant associations with blood pressure for the 825C>T and 1429C>T loci. In summary, the presence of obesity reveals an association between blood pressure and the GNB3gene in White females. Our data suggest that adiposity is a final pathway through which gene–lifestyle interactions may exert their effects on the development of hypertension. Our results from the combined SNP, haplotype and sib-TDT analyses also support the hypothesis that the 825C>T is a susceptibility locus for hypertension, whereas effects of other loci on blood pressure may result from their strong linkage disequilibrium with the 825C>T locus.