Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death
Connie R. BezzinaJulien BarcYuka MizusawaCarol Ann RemmeJean‐Baptiste GourraudFloriane SimonetArie O. VerkerkPeter J. SchwartzLia CrottiFederica DagradiPascale GuicheneyVéronique FressartAntoine LeenhardtCharles AntzelevitchS. BartkowiakMartin BorggrefeRainer SchimpfEric Schulze‐BahrSven ZumhagenElijah R. BehrRachel BastiaenenJacob Tfelt‐HansenMorten S. OlesenStefan KääbBritt Maria BeckmannPeter E. WeekeHiroshi WatanabeNaoto EndoTohru MinaminoMinoru HorieSeiko OhnoKanae HasegawaNaomasa MakitaAkihiko NogamiWataru ShimizuTakeshi AibaPhilippe FroguelBeverley BalkauOlivier LantieriMargherita TorchioCornelia WieseDavid WeberRianne WolswinkelRuben CoronelBastiaan J. BoukensStéphane BezieauÉric CharpentierStéphanie ChatelAurore DesprésF GrosFlorence KyndtSimon LecointePierre LindenbaumVincent PorteroJade ViolleauManfred GesslerHanno L. TanDan M. RodenVincent M. ChristoffelsHervé Le MarecArthur A.M. WildeVincent ProbstJean‐Jacques SchottChristian DinaRichard Redon
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Inherited arrhythmia (IA) is one of the main causes of sudden cardiac death (SCD) in young people, and is reported to be a more prevalent cause of SCD in Asia than in Western countries. IAs are a group of genetic disorders caused by mutations in genes encoding cardiac ion channels, leading to electrophysiological characteristics that often occur in the absence of structural abnormalities. Channelopathies, such as long QT syndrome and Brugada syndrome, carry a potential risk of life-threatening ventricular tachyarrhythmias that predispose to SCD, although early prediction and prevention of the risk remain challenging. Recent advances in genetic testing have facilitated risk stratification as well as a precise diagnosis for IA, despite ongoing debates about the implications. Herein, we provide epidemiological data, a pathophysiological overview, and the current clinical approach to IAs related to SCD. In addition, we review the general issues arising from genetic testing for IAs.
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The Brugada syndrome is an inherited channelopathy that alters the main transmembrane ion currents that constitute the cardiac action potential. These changes not only modify the resting electrocardiogram but also predispose patients to develop malignant ventricular tachyarrhythmias that can lead to syncope, cardiac arrest, and sudden cardiac death. This syndrome is responsible for nearly 20% of all sudden cardiac deaths in patients with structurally normal hearts and up to 12% of all sudden cardiac deaths. Brugada syndrome is diagnosed by its characteristic electrocardiogram consisting of a coved-type ST-segment elevation of at least 2 mm followed by a negative T wave in either one of the right precordial leads. These changes can be observed spontaneously or after administration of a sodium channel blocker. While our understanding of this disease has increased tremendously since its first description in 1992, the primary therapeutic option remains implantation of an implantable cardioverter-defibrillator to avoid sudden cardiac death. Therefore, tremendous effort is being made to effectively risk stratify patients to determine who would benefit from implantable cardioverter-defibrillator implantation.
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Brugada syndrome is a rare but serious inherited heart disease that causes sudden cardiac death by polymorphic ventricular tachycardia or ventricular fibrillation. It is an autosomal dominant genetic disease that usually occurs in patients in their forties with a structurally normal heart. Electrically, it manifests by ST elevation segment ≥ 2 mm of at least one right precordial lead (V1 and/or V2). Stratification of sudden cardiac death in Brugada syndrome is not always easy and constitutes a real challenge for the practitioner. In this review, we will present the current state of knowledge for arrhythmic risk stratification and the prevention of sudden cardiac death that can result from this syndrome.
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Genome-wide association study (GWAS)-based pathway association analysis is a powerful approach for the genetic studies of human complex diseases. However, the genetic confounding effects of environment exposure-related genes can decrease the accuracy of GWAS-based pathway association analysis of target diseases. In this study, we developed a pathway association analysis approach, named Mendelian randomization-based pathway enrichment analysis (MRPEA), which was capable of correcting the genetic confounding effects of environmental exposures, using the GWAS summary data of environmental exposures. After analyzing the real GWAS summary data of cardiovascular disease and cigarette smoking, we observed significantly improved performance of MRPEA compared with traditional pathway association analysis (TPAA) without adjusting for environmental exposures. Further, simulation studies found that MRPEA generally outperformed TPAA under various scenarios. We hope that MRPEA could help to fill the gap of TPAA and identify novel causal pathways for complex diseases.
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This chapter discusses the history, signs and symptoms, assessment, investigations, and treatment of Brugada syndrome. Brugada syndrome is an autosomal dominant ion-channelopathy, which occurs in structurally normal hearts. The condition may only manifest when the patient presents with an aborted sudden cardiac death, but pre-morbid symptoms may include syncope, palpitations and seizures. The most common cardiac arrhythmia is polymorphic ventricular tachycardia (VT), which may deteriorate to ventricular fibrillation. It is a leading cause of sudden cardiac death in healthy individuals. There is a wide phenotype variation and some patients may be asymptomatic and only diagnosed on routine 12-lead electrocardiogram (ECG) examination. The diagnosis is aided by patient and family history, ECG and genetic testing. Anti-arrhythmic drug therapy is not useful in Brugada syndrome and the only effective treatment is implantation of an internal implantable cardioverter defibrillator (ICD). Genetic testing and counselling is essential for any family members affected.
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Abstract Brugada syndrome (BrS) may cause a spectrum of symptoms from asymptomatic patients to those who experience cardiac arrest and sudden cardiac death. The diagnosis is confirmed after observation of type I Brugada pattern on the electrocardiogram. Following the diagnosis, risk stratification can help select therapeutic options. Cascade screening should be started to find other family members with BrS. We present a 41-year-old woman diagnosed with BrS, and cascade screening of her relatives unveiled a pedigree of BrS among their family.
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