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    Topic review

    Inherited Arrhythmogenic Syndromes

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    Submitted by: Oscar Campuzano


    Inherited arrhythmogenic syndromes are the primary cause of unexpected lethal cardiac episodes in young people. It is possible that the first sign of the condition may be sudden death. Inherited arrhythmogenic syndromes are caused by genetic defects that may be analyzed using different technical approaches. A genetic alteration may be used as a marker of risk for families who carry the genetic alterations. Therefore, the early identification of the responsible genetic defect may help the adoption of preventive therapeutic measures focused on reducing the risk of lethal arrhythmias.

    1. Introduction

    Cardiovascular diseases are the leading global cause of death, accounting for 30% of documented mortality ( Sudden cardiac death (SCD) is responsible for most cardiovascular deaths, and coronary artery disease accounts for more than 80% of all SCD cases[1]. SCD accounts for 20% of deaths among young individuals, and results from familial genetic cardiomyopathies. Further, 5% to 10% of SCDs result from inherited arrhythmogenic syndromes (IASs) caused by channelopathies with alterations in ion channels or associated proteins[2]. IASs are usually autosomal-dominant, but autosomal-recessive, X-linked, and even mitochondrial-inheritance cases have been reported, and are usually associated with highly lethal episodes or syndromic phenotypes. Near Mendelian inheritance has been proposed, demonstrating a strong genetic factor modulated by additional genetic variants[3].The four predominant IASs are long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and short QT syndrome (SQTS)[4]. These inherited disorders are characterized by incomplete penetrance and variable expressivity, usually impeding definite diagnosis. Phenotypic overlap may be observed due to a combination of genetic variants and the additive effect of multiple independent variants[5]

    2. Long QT Syndrome

    LQTS is an IAS with an estimated prevalence of 1 in 2000. LQTS is characterized by electrocardiographically corrected QT (QTc) interval prolongation in the absence of a secondary cause for prolonged QTc, such as drugs or electrolyte disturbances. This arrhythmogenic disease is associated with ventricular arrhythmias, particularly torsade des pointes, leading to syncope and SCD. Further, LQTS is a common cause of sudden-infant-death syndrome[4]. LQTS can also be diagnosed in an individual with a risk score (modified Schwartz score) of >3.5 or upon identification of an unequivocally pathogenic variant in a LQTS-related gene.

    There are currently more than 25 genes associated with congenital LQTS, and comprehensive genetic analysis, including copy-number variants (CNV), identifies the genetic risk in nearly 85% of cases. However, more than 75% of cases are associated with rare nonsynonymous variants in genes encoding potassium or sodium ion channels (KCNQ1, KCNH2, and SCN5A). Current guidelines recommend analysis of only these three genes[6], and a recent international study concluded that only these three genes are linked to LQTS[7]. However, four other genes (CALM1, CALM2, CALM3, and TRDN) have strong causality for LQTS, but with atypical features such as sinus bradycardia or atrioventricular block, QT prolongation, seizures, or developmental delay in infancy or early childhood. Therefore, both congenital and acquired (typically drug-induced) LQTS represent distinct but intertwined arrhythmogenic disorders characterized by QT interval prolongation[8].

    3. Brugada Syndrome

    BrS is a rare IAS with a prevalence of 1 in 2500 characterized by electrocardiographic ST-segment elevation with successive negative T waves in at least one right precordial lead without structural cardiac abnormalities. A characteristic Type 1 Brugada pattern, observed spontaneously or induced during drug challenge, is considered definitively diagnostic. The most severe clinical symptom of BrS is ventricular fibrillation and SCD, which can be the first manifestation of the disease. Further, BrS is a main cause of SCD in children and young adults, although some patients remain asymptomatic for life[4]. Currently, nearly 30 genes have been linked to BrS, and most follow an autosomal dominant pattern of inheritance, although some studies support autosomal recessive[9] or X-linked inheritance[10].

    Comprehensive genetic analysis identifies genetic associations in nearly 35% of BrS cases, and up to 30% of genetic alterations are in SCN5A. Current guidelines recommend analysis of SCN5A as the most cost-effective approach[6]. SCN5A is considered pathogenic[11] despite only a few nonsynonymous variants that are considered deleterious[12]. Beyond SCN5A, pathogenic variants associated with BrS are in four minor genes: SLMAP, SEMA3A, SCNN1A, and SCN2B[13].

    4. Catecholaminergic Polymorphic Ventricular Tachycardia

    CPVT is a very rare (prevalence of 1 in 10,000) highly lethal IAS with a 30% mortality rate in untreated patients. It is characterized by adrenergic stimulated polymorphic ventricular tachycardia in the presence of a structurally normal heart. CPVT is usually diagnosed in patients younger than 40 years old[14]. The diagnostic hallmark is induced ventricular arrhythmias during exercise, particularly bidirectional ventricular tachycardia. A key feature of CPVT is a normal baseline electrocardiogram and echocardiogram. Without exercise stress testing, diagnosis can be missed[15].

    Nowadays, nine genes are associated with CPVT, and genetic alteration (noncommon variants and CNV) is a potential cause in almost 65% of cases, although 60% of cases are attributed to rare nonsynonymous variants in the cardiac ryanodine receptor (RYR2)[16]. Current guidelines recommend analysis of RYR2 in CPVT diagnosis[6]. Further, a recent international calmodulinopathy registry identified that nearly 28% of patients diagnosed with CPVT had alterations in calmodulin genes (mainly CALM2). All CALM–CPVT patients were symptomatic with early age of onset (around 6 years old)[17]. Identification of a pathogenic variant implies that genetic testing should be extended to first-degree relatives since CPVT is highly lethal.

    5. Short QT Syndrome

    Short QT syndrome (SQTS) is a very rare entity, with a prevalence of 1 in 10,000. SQTS is associated with paroxysmal atrial and ventricular fibrillation, syncope, and SCD, and is characterized by a short QT interval on the electrocardiogram, lack of normal changes in QT interval with heart rate, peaked T waves (particularly in precordial leads), and short or absent ST segments. The most common initial symptom is cardiac arrest in one-third of cases. Lethal episodes usually occur in infants and young children with no structural heart abnormalities[18]. SQTS is a genetically heterogeneous disease with eight associated genes. Comprehensive genetic analysis identified a genetic cause in 40% of cases, with most diagnosed cases resulting from alterations in KCNH2, KCNQ1, and KCNJ2. Current guidelines recommend analysis of these three genes[6]. Our group recently reported that rare variants in other genes are associated with electrical alterations concomitant with shortened QT intervals, but do not guarantee a diagnosis of SQTS[19]. Thus, other genetic alterations may explain cases without definitive genetic diagnosis. Additional large studies are needed, but low prevalence and high mortality rates impede comprehensive genotype–phenotype studies.

    The entry is from 10.3390/jcm9061866


    1. Douglas P. Zipes; Hein J. J. Wellens; Sudden Cardiac Death. Circulation 1998, 98, 2334-2351, 10.1161/01.cir.98.21.2334.
    2. Richard D. Bagnall; Robert G. Weintraub; Jodie Ingles; Johan Duflou; Laura Yeates; Lien Lam; Andrew M. Davis; Tina Thompson; Vanessa Connell; Jennie Wallace; et al. A Prospective Study of Sudden Cardiac Death among Children and Young Adults. New England Journal of Medicine 2016, 374, 2441-2452, 10.1056/nejmoa1510687.
    3. Connie R. Bezzina; Najim Lahrouchi; Silvia G. Priori; Genetics of Sudden Cardiac Death. Circulation Research 2015, 116, 1919-1936, 10.1161/circresaha.116.304030.
    4. Mohita Singh; Daniel P. Morin; Mark S. Link; Sudden cardiac death in Long QT syndrome (LQTS), Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT). Progress in Cardiovascular Diseases 2019, 62, 227-234, 10.1016/j.pcad.2019.05.006.
    5. Monica Coll; Alexandra Pérez-Serra; Jesus Mates; Bernat Del Olmo; Marta Puigmulé; Anna Fernández-Falgueras; Anna Iglesias; Ferran Picó; Laura Lopez; Ramon Brugada; et al. Incomplete Penetrance and Variable Expressivity: Hallmarks in Channelopathies Associated with Sudden Cardiac Death. Biology 2017, 7, 3, 10.3390/biology7010003.
    6. Silvia Giuliana Priori; Carina Blomström-Lundqvist; CardioPulse Articles2015 European Society of Cardiology Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death summarized by co-chairs‘Ten Commandments' of 2015 European Society of Cardiology Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac deathAdolfo J. de Bold PhD OC FRSC: a pioneer in cardiovascular medicineNatriuretic peptides in 2015Teachable moment or missed opportunity?. European Heart Journal 2015, 36, 2757-2762, 10.1093/eurheartj/ehv445.
    7. Arnon Adler; Valeria Novelli; Ahmad S. Amin; Emanuela Abiusi; Melanie Care; Eline A. Nannenberg; Harriet Feilotter; Simona Amenta; Daniela Mazza; Hennie Bikker; et al. An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation 2020, 141, 418-428, 10.1161/circulationaha.119.043132.
    8. John R. Giudicessi; Dan M. Roden; Arthur A.M. Wilde; Michael J. Ackerman; Classification and Reporting of Potentially Proarrhythmic Common Genetic Variation in Long QT Syndrome Genetic Testing.. Circulation 2018, 137, 619-630, 10.1161/CIRCULATIONAHA.117.030142.
    9. Alexandre Janin; Francis Bessière; Tudor Georgescu; Valérie Chanavat; Philippe Chevalier; Gilles Millat; TRPM4 mutations to cause autosomal recessive and not autosomal dominant Brugada type 1 syndrome. European Journal of Medical Genetics 2019, 62, 103527, 10.1016/j.ejmg.2018.08.008.
    10. Jens-Peter David; Ulrike Lisewski; Shawn M. Crump; Thomas A. Jepps; Elke Bocksteins; Nicola Wilck; Janine Lossie; Torsten K. Roepke; Nicole Schmitt; Geoffrey W. Abbott; et al. Deletion in mice of X‐linked, Brugada syndrome–and atrial fibrillation–associated Kcne5 augments ventricular K v currents and predisposes to ventricular arrhythmia. The FASEB Journal 2018, 33, 2537-2552, 10.1096/fj.201800502r.
    11. S. Mohsen Hosseini; Raymond Kim; Sharmila Udupa; Gregory Costain; Rebekah Jobling; Eriskay Liston; Seema M. Jamal; Marta Szybowska; Chantal F. Morel; Sarah Bowdin; et al. Reappraisal of Reported Genes for Sudden Arrhythmic Death. Circulation 2018, 138, 1195-1205, 10.1161/circulationaha.118.035070.
    12. Nathan C. Denham; Charles M. Pearman; Wern Yew Ding; Johan Waktare; Dhiraj Gupta; Richard Snowdon; Mark Hall; Robert Cooper; Simon Modi; Derick Todd; et al. Systematic re-evaluation of SCN5A variants associated with Brugada syndrome. Journal of Cardiovascular Electrophysiology 2018, 30, 118-127, 10.1111/jce.13740.
    13. Oscar Campuzano; Georgia Sarquella‐Brugada; Anna Fernandez‐Falgueras; Sergi Cesar; Monica Coll; Jesus Mates; Elena Arbelo; Alexandra Perez‐Serra; Bernat Del Olmo; Paloma Jordá; et al. Genetic interpretation and clinical translation of minor genes related to Brugada syndrome. Human Mutation 2019, 40, 749-764, 10.1002/humu.23730.
    14. Chan W. Kim; Wilbert S. Aronow; Tanya Dutta; Daniel Frenkel; William H. Frishman; Catecholaminergic Polymorphic Ventricular Tachycardia. Cardiology in Review 2020, null, null, 10.1097/crd.0000000000000302.
    15. Marwan M Refaat; Mostafa Hotait; Zian H. Tseng; Utility of the Exercise Electrocardiogram Testing in Sudden Cardiac Death Risk Stratification. Annals of Noninvasive Electrocardiology 2014, 19, 311-318, 10.1111/anec.12191.
    16. Matthew J. Wleklinski; Prince J. Kannankeril; Bjorn C. Knollmann; Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia. The Journal of Physiology 2020, 598, 2817-2834, 10.1113/jp276757.
    17. Lia Crotti; Carla Spazzolini; David J Tester; Alice Ghidoni; Alban-Elouen Baruteau; Britt-Maria Beckmann; Elijah R Behr; Jeffrey S Bennett; Connie R Bezzina; Zahurul A Bhuiyan; et al. Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry. European Heart Journal 2019, 40, 2964-2975, 10.1093/eurheartj/ehz311.
    18. Oscar Campuzano; Georgia Sarquella-Brugada; Sergi Cesar; Elena Arbelo; Josep Brugada; Ramon Brugada; Recent Advances in Short QT Syndrome. Frontiers in Cardiovascular Medicine 2018, 5, 149, 10.3389/fcvm.2018.00149.
    19. Oscar Campuzano; Anna Fernandez-Falgueras; Ximena Lemus Maulen; Georgia Sarquella-Brugada; Sergi Cesar; Monica Coll; Jesus Mates; Elena Arbelo; Paloma Jordà; Alexandra Pérez-Serra; et al. Short QT Syndrome: A Comprehensive Genetic Interpretation and Clinical Translation of Rare Variants.. Journal of Clinical Medicine 2019, 8, 1035, 10.3390/jcm8071035.
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