Genetics of Cardiac Electrical Disease

doi:10.1016/j.cjca.2012.07.847

Canadian Journal of Cardiology

Volume 29, Issue 1, January 2013, Pages 89-99

https://doi.org/10.1016/j.cjca.2012.07.847 Get rights and content

Abstract

Few tragedies compare to the sudden death of a family member. Sadly, this may represent the first sign of a familial vulnerability to such events. One common cause is an inherited cardiac arrhythmia syndrome. Sufferers are prone to premature sudden cardiac death due to altered ion channel function in the heart. Typical causes include Brugada syndrome, long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and the newly recognized early repolarization syndrome. Our knowledge of the genetic underpinnings of each of these disorders has increased markedly in recent years. Genetic screening is now a routine part of clinical care and promises more accurate diagnosis and efficient family screening. This review summarizes the diagnosis and management of each of the listed syndromes in the context of currently available genetic testing.

Résumé

Peu de tragédies se comparent à la mort subite d'un membre de la famille. Malheureusement, cela peut être le premier signe d'une vulnérabilité familiale à de tels événements. L'une des causes les plus fréquentes est le syndrome d'une arythmie cardiaque héréditaire. Les malades sont prédisposés à la mort cardiaque subite prématurée en raison de la perturbation du fonctionnement des canaux ioniques du cœur. Les causes typiques incluent le syndrome des Brugada, le syndrome du QT long, le syndrome du QT court, la tachycardie ventriculaire polymorphe catécholaminergique et le syndrome, nouvellement reconnu, de repolarisation précoce. Notre connaissance des fondements génétiques de chacun de ces troubles s'est nettement accrue au cours dernières années. Le dépistage génétique fait maintenant partie des soins cliniques habituels, et promet d'offrir un diagnostic plus précis et un dépistage familial plus efficace. Cette revue résume le diagnostic et la prise en charge de chacun des syndromes énumérés ci-dessus selon le contexte de dépistage génétique actuellement disponible.

Section snippets

Long QT Syndrome

LQTS is characterized by a prolonged QT interval and a peculiar form of polymorphic ventricular tachycardia called torsades de pointes—“twisting of the points.” The population prevalence is 1 in 2000.²

In 1957, Jervell and Lange-Nielsen described a clinical phenotype of deafness, QT prolongation, and high mortality. This syndrome was autosomal recessive.³ Later, Romano et al. and Ward reported prolonged QT intervals accompanying syncope and sudden cardiac death (SCD) but without hearing

Short QT Syndrome

The short QT syndrome (SQTS) is marked by an abbreviated QT interval and a risk of atrial and/or ventricular arrhythmias. As SQTS is rare, data on its prevalence and demographics are limited. A recent review of 61 reported cases found 75% to be in males. The median age of clinical presentation (symptomatic subjects) was 21 years. SCD was reported in 33% and atrial fibrillation in 18%.⁴⁴

Predisposition to arrhythmia in SQTS arises from an increased dispersion of repolarization. Analogous to LQTS,

Early Repolarization Syndrome (J-Wave Syndrome)

Current guidelines consider “early repolarization” (ER) a variant of normal.⁵² This form is defined by J-point (junction of QRS and ST segment) elevation with a normal or rapidly upsloping ST segment. However, multiple case reports and 2 seminal papers have now demonstrated an association between J-point elevation and idiopathic ventricular fibrillation (VF).53, 54 In these reports J-point elevation was described as a terminal “slurred” or “notched” appearance of the QRS complex (Fig. 1).

Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by sympathetically mediated ventricular arrhythmia in the absence of structural heart disease. Symptoms present early in life—usually before age 10 years.72, 73 A family history of exercise-related syncope or SCD is present in 30%.72, 73

CPVT is a disorder of abnormal calcium release from the sarcoplasmic reticulum. This most commonly results from a mutation in the cardiac ryanodine receptor protein (RYR2).⁷⁴ The

Brugada Syndrome

The key characteristics of BrS include ST elevation in the right precordial leads of the ECG, a structurally normal heart, and a risk of SCD. BrS shows marked male predominance (male-to-female, 8:1) and an overall population prevalence of 1 in 2000.⁸⁷ Cardiac events usually occur at rest or during the night.

The characteristic ECG pattern of BrS (“Type 1”) consists of ≥ 0.2 mV of ST elevation (“coved”) followed by a negative T wave in > 1 right precordial ECG lead (V₁ through V₃; Fig. 1).⁸⁷ When

Conclusions

Genetic screening in familial cardiac arrhythmia syndromes has moved from the lab bench to the clinical setting. It promises more accurate diagnosis and an efficiency of family screening not possible with clinical testing alone. It is now common to identify a genotype of disease without any overt expression of the disorder. This knowledge may be used to guide therapy and monitoring and thus avoid the tragedy of an SCD. It is hoped that future research will allow more sharply targeted therapy

Funding Sources

M.J.P. is supported by a postgraduate scholarship from the University of Ottawa. M.H.G. is supported by the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Ontario.

Disclosures

The authors have no conflicts of interest to disclose.

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Citation Excerpt :
Our attention has been particularly drawn to the channel encoded by human eag-related gene 1 (hERG1/KCNH2/Kv11.1) because of its relevance to human disease, especially cardiac arrhythmias (Vandenberg et al., 2012). Disruption of hERG1 activity caused by either genetic mutations or drugs is a major cause of long QT syndrome that increases the risk of potentially fatal arrhythmias (Perrin and Gollob, 2013; Perry et al., 2015). Interestingly, the prevalence of long QT syndrome is also elevated in PD patients (Deguchi et al., 2002) and emerging evidence indicates an interaction between arrhythmias and AD (Ihara and Washida, 2018), but the potential relevance of hERG to PD or AD has not been explored.
Environmental toxicants have the potential to contribute to the pathophysiology of multiple complex diseases, but the underlying mechanisms remain obscure. One such toxicant is the widely used fungicide ziram, a dithiocarbamate known to have neurotoxic effects and to increase the risk of Parkinson's disease. We have used Drosophila melanogaster as an unbiased discovery tool to identify novel molecular pathways by which ziram may disrupt neuronal function. Consistent with previous results in mammalian cells, we find that ziram increases the probability of synaptic vesicle release by dysregulation of the ubiquitin signaling system. In addition, we find that ziram increases neuronal excitability. Using a combination of live imaging and electrophysiology, we find that ziram increases excitability in both aminergic and glutamatergic neurons. This increased excitability is phenocopied and occluded by null mutant animals of the ether a-go-go (eag) potassium channel. A pharmacological inhibitor of the temperature sensitive hERG (human ether-a-go-go related gene) phenocopies the excitability effects of ziram but only at elevated temperatures. seizure (sei), a fly ortholog of hERG, is thus another candidate target of ziram. Taken together, the eag family of potassium channels emerges as a candidate for mediating some of the toxic effects of ziram. We propose that ziram may contribute to the risk of complex human diseases by blockade of human eag and sei orthologs, such as hERG.
Using high-resolution variant frequencies to empower clinical genome interpretation
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Whole-exome and whole-genome sequencing have transformed the discovery of genetic variants that cause human Mendelian disease, but discriminating pathogenic from benign variants remains a daunting challenge. Rarity is recognized as a necessary, although not sufficient, criterion for pathogenicity, but frequency cutoffs used in Mendelian analysis are often arbitrary and overly lenient. Recent very large reference datasets, such as the Exome Aggregation Consortium (ExAC), provide an unprecedented opportunity to obtain robust frequency estimates even for very rare variants.
We present a statistical framework for the frequency-based filtering of candidate disease-causing variants, accounting for disease prevalence, genetic and allelic heterogeneity, inheritance mode, penetrance, and sampling variance in reference datasets.
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We outline a statistically robust framework for assessing whether a variant is “too common” to be causative for a Mendelian disorder of interest. We present precomputed allele frequency cutoffs for all variants in the ExAC dataset.
Proprietary Considerations in the Use of Cardiovascular Genetic Data
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Cardiovascular researchers and clinicians who analyze next-generation sequencing data often search databases of previously reported mutations to determine if an observed mutation is pathogenic. In 2012 we created a database of all reported mutations causing human dyslipidemia syndromes. In 2015, we were advised that some information in our database was now proprietary, after the acquisition of a human disease genetic database by a private biotechnology company. To make our dyslipidemia database and tables of mutations compliant with this new reality, we wrote custom computer scripts to remove certain data fields from the previously reported tables. Data columns in the revised tables now include: accession number, gene name and symbol, mutation type, exon number, inheritance pattern, minor allele frequencies, predictive functional scores, reported functional effects, and additional patient information. The revised mutation tables provide a comprehensive qualitative and quantitative description of genetic variants causing monogenic dyslipidemias, but do not have complete information on all mutations. This experience indicates that free and unlimited access to human disease mutation data should not be taken for granted. Investigators or clinicians who require additional data that is not within the revised tables can still access the data through academic institutions that hold subscriptions to proprietary human mutation databases.
Les chercheurs et les cliniciens spécialisés en santé cardiovasculaire qui analysent les données de séquençage de nouvelle génération interrogent souvent les bases de données à la recherche de mutations déjà rapportées afin de déterminer si l’une d’elles serait pathogène. En 2012, nous avons constitué une base de données regroupant toutes les mutations rapportées à ce jour à l’origine de syndromes de dyslipidémie chez l’humain. En 2015, on nous a informés que certaines de ces données relevaient maintenant du domaine privé, à la suite de l’acquisition, par une entreprise de biotechnologie privée, d’une base de données sur les maladies génétiques humaines. Pour ajuster notre base de données sur la dyslipidémie et nos tableaux de mutations en conséquence, nous avons dû ajouter des scripts informatiques sur mesure afin d’éliminer certains champs de données. Les colonnes de données des tableaux révisés sont maintenant les suivantes : numéro de référence, nom et symbole du gène, type de mutation, numéro d’exon, modalités de transmission héréditaire, fréquence des allèles minoritaires, scores fonctionnels prédictifs, effets fonctionnels observés et renseignements additionnels sur les patients. La version révisée des tableaux offre désormais une description qualitative et quantitative détaillée des variantes génétiques à l’origine des dyslipidémies monogéniques sans toutefois afficher toute l’information relative à toutes les mutations. Cette expérience nous apprend que l’accès gratuit et illimité aux données sur les mutations génétiques pathogènes ne doit pas être tenu pour acquis. Les chercheurs et les cliniciens qui ont besoin de données supplémentaires qui n’apparaissent pas dans nos nouveaux tableaux peuvent encore y avoir accès par l’intermédiaire des établissements universitaires abonnés aux bases de données privées.
Iron Overload Leading to Torsades de Pointes in β-Thalassemia and Long QT Syndrome
2016, Cardiac Electrophysiology Clinics
Citation Excerpt :
LQTS is a heterogeneous disease, and more than 600 mutations in 15 genes have been reported (Table 1). These mutations comprise loss-of-function mutations in potassium channel genes (KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2) or gain-of-function mutations in sodium or calcium channel genes (SCN5A, CACNA1C).9,10 Based on the affected genes and gene product, LQTS is subtyped with LQT1 (KCNQ1, KV7.1), LQT2 (KCNH2, KV11.1), and LQT3 (SCN5A, NaV1.5), accounting for most cases.
Ablation of the epicardial substrate in the right ventricular outflow tract in a patient with brugada syndrome refusing implantable cardioverter defibrillator therapy
2014, Canadian Journal of Cardiology
Brugada syndrome is associated with a high risk of sudden cardiac death. Currently, the cornerstone of therapy is implantation of an implantable cardioverter defibrillator (ICD). Recently, a novel approach to preventively ablate the substrate located in the anterior epicardial region of the right ventricular outflow tract showed promising results by reducing the number of ventricular fibrillation episodes in patients with ICD. Here we report on a patient with Brugada syndrome who refused ICD therapy in whom a successful epicardial right ventricular outflow tract substrate ablation was performed. In some special cases, ablation therapy might be considered as the sole therapeutic option for these patients.
Le syndrome de Brugada est associé à un risque élevé de mort cardiaque subite. Actuellement, la pierre angulaire du traitement est l’implantation d’un défibrillateur cardioverteur implantable (DCI). Récemment, une nouvelle approche pour procéder de manière préventive à l’ablation du substrat localisé dans la région épicardique antérieure de la chambre de chasse du ventricule droit a montré des résultats prometteurs en réduisant le nombre d’épisodes de fibrillation auriculaire chez les patients portant un DCI. Nous rapportons ici le cas d’un patient souffrant du syndrome de Brugada qui a refusé le traitement par DCI chez qui une ablation du substrat épicardique de la chambre de chasse du ventricule droit a été réussie. Dans certains cas particuliers, le traitement par ablation pourrait être considéré comme la seule option thérapeutique chez ces patients.
New molecular genetic tests in the diagnosis of heart disease
2014, Clinics in Laboratory Medicine
Citation Excerpt :
Two of the genes implicated in AD ARVC (DSP, JUP) have also been associated with rare AR disorders (Naxos disease and Carvajal syndrome) characterized by ARVC with cutaneous phenotypes, notably wooly hair and palmoplantar keratoderma. Although less than with the cardiomyopathies, there still is substantial genetic heterogeneity within the channelopathies and cardiac arrhythmia syndromes.26 Furthermore, there is an appreciable overlap between the genes associated with each subphenotype.

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ReviewGenetics of Cardiac Electrical Disease

Abstract

Résumé

Section snippets

Long QT Syndrome

Short QT Syndrome

Early Repolarization Syndrome (J-Wave Syndrome)

Catecholaminergic Polymorphic Ventricular Tachycardia

Brugada Syndrome

Conclusions

Funding Sources

Disclosures

Am Heart J

Cell

Cell

Heart Rhythm

Cell

Cell

Heart Rhythm

Cell

Am J Hum Genet

J Am Coll Cardiol

J Electrocardiol

Can J Cardiol

Heart Rhythm

Heart Rhythm

Heart Rhythm

Heart Rhythm

Heart Rhythm

J Am Coll Cardiol

Heart Rhythm

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Heart Rhythm

Heart Rhythm

Heart Rhythm

J Am Coll Cardiol

Heart Rhythm

Heart Rhythm

Heart Rhythm

Heart Rhythm

J Am Coll Cardiol

Heart Rhythm

J Am Coll Cardiol

Am J Hum Genet

J Mol Cell Cardiol

J Am Coll Cardiol

J Mol Cell Cardiol

Heart Rhythm

Heart Rhythm

J Am Coll Cardiol

Can J Cardiol

Heart Rhythm

Sudden death from cardiac causes in children and young adults

N Engl J Med

Prevalence of the congenital long-QT syndrome

Circulation

Rare cardiac arrhythmias of the pediatric age, II: syncopal attacks due to paroxysmal ventricular fibrillation

La Clinica pediatrica

A new familial cardiac syndrome in children

J Ir Med Assoc

Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias

Nat Genet

A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome

Nat Genet

Review
Genetics of Cardiac Electrical Disease