Re‐evaluating pathogenicity of variants associated with the long QT syndrome

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The congenital long QT syndrome (LQTS) is a genetic arrhythmia syndrome characterized by delayed repolarization, manifest as a prolonged QTc on electrocardiogram, torsades de pointes, and sudden cardiac arrest. The prevalence of LQTS is estimated at 1 per 2,500 persons of European and other ancestries.1 There are 15 defined subtypes of the LQTS, but the vast majority of genetically confirmed LQTS is explained by mutations in three genes, KCNQ1, KCNH2, and SCN5A.3 Beta‐blockers are the primary therapy for LQTS with sodium channel blockers sometimes used in patients with SCN5A mutations. Implantable cardioverter‐defibrillators are reserved for patients who have experienced a prior cardiac arrest or who are at highest risk.
Approximately 72% of those with high probability of LQTS carry a mutation in a known LQTS gene,4 including pathogenic variants identified in genes associated with cardiac potassium and sodium channels. Recent studies have expanded the type of genes associated with LQTS to nonchannel proteins,5 increasing the catalog of potential susceptibility genes to over 30.7
Clinical genetic testing for the LQTS has become common with the goal of confirming disease, refining treatment strategies, and facilitating cascade screening to identify at‐risk relatives. Several commercial companies currently offer gene panel testing that evaluates pathogenic variants in 12 to 17 LQTS‐associated genes.8
Pathogenic variants of genetic diseases have historically been determined by their presence in one or more clinical cases and their absence in healthy populations. However, assessing the rarity of a variant in a control population has been constrained by the relatively limited number of available sequenced genomes. The recent release of data from the Exome Aggregation Consortium (ExAC) and Genome Aggregation Database (gnomAD), including 60,706 and 123,136 exome sequences from unrelated individuals, respectively, has allowed for a deeper understanding of genetic diversity within the general population.10 With the much improved catalog of exome‐wide variation, ExAC has demonstrated that rare genetic variation is, collectively, not so rare in the general population. Thus, this type of collective database can serve as a powerful filter to rule out candidate pathogenic variants in Mendelian disease.10 The recent American College of Medical Genetics and Genomics guidelines for interpretation of sequence variants state that an allele frequency (AF) for a candidate variant in a control population, such as ExAC and gnomAD, that is greater than expected for the disorder is strong evidence for a benign interpretation.12 Studies in cardiomyopathy13 and catecholaminergic polymorphic ventricular tachycardia14 have shown that some variants labelled as pathogenic might be misclassified due, in part, to relatively common AF in the ExAC population.
Re‐evaluating the pathogenicity of LQTS variants is critical since genetic testing results increasingly guide treatment options and screening decisions, and false positive results might have adverse clinical implications. Therefore, the purpose of this study is to examine the presence of LQTS‐associated genetic variants in the gnomAD population, and assess the impact of these variants in different functional domains in the most commonly mutated genes, KCNQ1, KCNH2, and SCN5A.
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