Curr Cardiol Rep (2015) 17:53 DOI 10.1007/s11886-015-0606-8
INVASIVE ELECTROPHYSIOLOGY AND PACING (EK HEIST, SECTION EDITOR)
Genetics of Sudden Cardiac Death Marwan M. Refaat 1,3 & Mostafa Hotait 1 & Barry London 2
# Springer Science+Business Media New York 2015
Abstract Sudden cardiac death (SCD) is defined by the World Health Organization (WHO) as death within 1 h of symptom onset (witnessed) or within 24 h of being observed alive and symptom free (unwitnessed). It affects more than 3 million people annually worldwide and affects approximately 1/1000 people each year in the USA. Familial studies of syndromes with Mendelian inheritance, candidate genes analyses, and genome-wide association studies (GWAS) have helped our understanding of the genetics of SCD. We will review the genetics of arrhythmogenic hereditary syndromes with Mendelian inheritance from familial studies with structural heart disease (hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic cardiomyopathy) as well as primary electrical causes (long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome). In addition, we will review the genetics of intermediate phenotypes for SCD such as coronary artery disease and electrocardiographic variables (QT interval, QRS duration, and RR interval). Finally, we will review rare and common variants that are associated with SCD in the
This article is part of the Topical Collection on Invasive Electrophysiology and Pacing * Marwan M. Refaat [email protected] 1
Department of Internal Medicine (Cardiology Division), American University of Beirut Medical Center, Beirut, Lebanon
2
Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA
3
Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
general population and were identified from candidate gene analyses and GWAS. Our understanding of the genetics of SCD will improve by the use of next-generation sequencing/ whole-exome sequencing as well as whole-genome sequencing which have the potential to discover unsuspected common and rare genetic variants that might be associated with SCD. Keywords Sudden cardiac death . Arrhythmogenic hereditary syndromes . Genetics . Genome-wide association studies . Cardiomyopathies . Hypertrophic cardiomyopathy . Dilated cardiomyopathy . Arrhythmogenic right ventricular cardiomyopathy/dysplasia . Long QT syndrome . Short QT syndrome . Brugada syndrome . Catecholaminergic polymorphic ventricular tachycardia
Introduction Sudden cardiac death (SCD), defined by the World Health Organization (WHO) as death within 1 h of symptom onset (witnessed) or within 24 h of being observed alive and symptom free (unwitnessed), remains a major public health problem and accounts for 200,000 to 450,000 deaths annually in the USA, which equates to 15 to 20 % of all deaths and 50 % of overall cardiac mortality [1–3]. Although significant progress has been made to understand SCD, it continues to be a devastating event due to its occurrence in individuals without previously diagnosed heart disease and the fact that 60 % of cases occur outside the hospital setting [3]. Due to the variety of causes of this cardiac collapse and the very small subset of patients being under observation or close monitoring, the exact underlying mechanism usually remains a big challenge [3]. Sudden death is usually thought to be due to interactions between a substrate (underlying disease) and a triggering event that is responsible for an electric instability. Despite a
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spectrum of etiologies, this instability is believed to often start with electrical reentry propagating into ventricular tachycardia and multiple localized areas of microcircuits that lead to ventricular fibrillation and subsequent asystole. Coronary heart disease (CHD) is considered the most common substrate for SCD accounting for 75–80 % of all cases, but only 13 % of CHD patients will have sudden cardiac arrest [1]. A recent study from San Francisco with a comprehensive review of medical examiner investigation and autopsy on the majority of the suspected SCD cases (gold standard to diagnose SCD) showed that significant CHD contributes only to 39 % of sudden arrhythmic death [4]. Studies conducted to identify the potential association between SCD and history of SCD in first-degree relative show a 1.6- to 1.8-fold increase in SCD susceptibility [5]. There is a twofold increase in SCD risk if an individual had one parent who died suddenly and a ninefold increase if both parents died suddenly; this was independent of family history of myocardial infarction [2]. In addition, rare variants with strong effects have been identified in cardiac conduction diseases that are associated with increased risk of ventricular arrhythmias and SCD. Furthermore, discovery of novel mutations involved in some arrhythmogenic syndromes and their impact on basic electrophysiology raised the possibility of their implication in SCD risk. Our review will stress the progress made so far in studying the genetics of inheritable diseases and the polymorphisms involved in SCD. We will review the genetics of arrhythmogenic hereditary syndromes with Mendelian inheritance from familial studies with structural heart disease (hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic cardiomyopathy) as well as primary electrical causes (long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome). In addition, we will review the genetics of intermediate phenotypes for SCD such as coronary artery disease and electrocardiographic variables (QT interval, QRS duration, and RR interval). Finally, we will review rare and common variants that are associated with SCD in the general population and were identified from candidate gene analyses and genome-wide association studies. Our understanding of the genetics of SCD will improve by the use of nextgeneration sequencing/whole-exome sequencing as well as whole-genome sequencing, which have the potential to discover unsuspected common and rare genetic variants that might be associated with SCD.
The Genetic and Molecular Basis of the Rare Monogenic Diseases Predisposing to SCD We will present in this section genetic variants identified from familial studies to cause SCD via structural cardiomyopathies (such as hypertrophic cardiomyopathy, dilated cardiomyopathy,
Curr Cardiol Rep (2015) 17:53
arrhythmogenic cardiomyopathy, restrictive cardiomyopathy, and left ventricular noncompaction cardiomyopathy) and primary electrical diseases (such as long QT syndrome, short QT syndrome, J-wave syndromes [Brugada syndrome and early repolarization syndrome (or Haïssaguerre syndrome)], and catecholaminergic polymorphic ventricular tachycardia). The genes involved in inherited cardiomyopathies include sarcomeric genes in hypertrophic cardiomyopathy and restrictive cardiomyopathy which lead to diastolic dysfunction, genes involved in the linkage of the sarcomere to the sarcolemma in dilated cardiomyopathy which lead to systolic function, and the desmosome genes in arrhythmogenic cardiomyopathy which bind myocytes together. Left ventricular noncompaction cardiomyopathy (LVNC) is an overlap disorder and it appears that any of the cardiomyopathy genes can be involved depending on the specific form of the LVNC.
Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease of myocontractile sarcomeric proteins leading to myocardial hypertrophy and fibrosis [6]. Local fibrosis and scarring provide the substrate for electrical heterogeneity that puts subjects at a higher risk for arrhythmia and makes them more susceptible to ventricular tachycardia/fibrillation. HCM is clearly familial in half of the cases and exhibits an autosomal-dominant pattern of inheritance with variable penetrance [6]. HCM is the most prevalent cardiovascular genetic disease affecting 1 in 500 of otherwise healthy young individuals and is the most common inherited predisposition to SCD in the young accounting for up to 48 % of sudden death [6]. More than 450 mutations have been identified in genes encoding sarcomeric proteins of the thick and thin filaments, Z-disc, and the intercalated disc. As HCM exhibits genotypic and phenotypic heterogeneity, the risk of sudden death has been linked to the underlying mutation in addition to the extent of hypertrophy. The bulk of mutations are reported in eight myofilament-associated genes including β-myosin heavy chain (MYH7) and myosin binding protein-C (MYBPC3), which account for 30–40 % of all cases [6]. Cardiac troponin T (TNNT2), tropomyosin (TPM1), cardiac troponin I (TNNI3), cardiac actin (ACTC), and the myosin light chains (MYL3, MYL2) represent only 1–5 % of cases [6, 7]. Previous studies have shown that some mutations in the βmyosin heavy chain gene (Arg403Gln, Arg453Gln, and Arg719Trp) have nearly complete penetrance and lead to a severe early-onset disease with a high risk of SCD [8]. Moreover, troponin T mutations generally exhibit mild to no ventricular hypertrophy and abnormal blood pressure responses to exercise, yet subjects have poor prognosis and increased risk of sudden death. Other mutations that have been associated with HCM and cardiomyopathies with apparent hypertrophy
Curr Cardiol Rep (2015) 17:53
are in calcium-induced sarcoplasmic reticulum calcium release genes [such as sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), ryanodine receptor 2 (RyR2), and junctophilin 2 (JPH2)] and in genes encoding mitochondrial and lysosomal proteins [AMP-dependent protein kinase (PRKAG2), lysosomal-associated membrane protein 2 (LAMP2), and αgalactosidase A (GLA) causing Fabry disease] which lead to storage and metabolic cardiomyopathies. Though previous studies reported a benign prognosis of patients with apical HCM (~3 % of patients with HCM), recent studies reported the association of apical HCM with SCD [9]. Previous reports also showed that subjects having double mutations exhibit a more severe form of the disease than patients with single gene defects and are more prone for sudden cardiac death [10]. This highly malignant disease with its significant risk of SCD and the underlying genetic involvement necessitates genetic screening in subjects with positive family history.
Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is another significant contributor to sudden cardiac death. It is an inherited cardiac muscle disease affecting the right ventricle predominantly (and can affect the left ventricle as well) with a prevalence between 1 in 5000 and 1 in 2000 in the general population and accounting for 5 % of unexplained sudden death in some populations [6]. The disease is characterized by the gradual loss of muscle in the right ventricle free wall progressing from the epicardium to endocardium [6]. Myocyte loss with subsequent fibroadipose replacement leads to intraventricular conduction delay and major electrical instability, with reentrant conduction of right ventricle origin being the underlying cause of ventricular tachycardia having the observed left bundle branch block morphology [6]. ARVC is difficult to diagnose as it has a broad spectrum of clinical manifestations, and sudden death is the first presenting symptom in 23 % of patients. Endurance exercise and frequent exercise increase the age-related penetrance and the arrhythmic risk in ARVC/D. Previous studies have demonstrated an autosomaldominant inheritance with incomplete penetrance in half of ARVC cases. After publishing the first chromosomal locus to be linked to the disease in 1994, other molecular genetic studies successfully provided insights to the genetic heterogeneity and their association with desmosomal adhesion proteins [6]. In addition to plakophilin-2 (PKP-2) gene mutations that account for more than 40 % of ARVC cases, desmoplakin (DSP), plakoglobin (JUP), desmoglein-2 (DSG-2), and desmocollin-2 (DSC-2) are the major proteins responsible for maintaining continuous cell-to-cell adhesion [6]. Impairment of these intercellular junctions and, thus, myocytes mechanical
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coupling are considered the primary underlying molecular defects. Other non-desmosomal proteins have also been reported to play a significant role in the pathogenesis of ARVC: ryanodine receptor 2 (cardiac) [RyR2], transforming growth factor β-3 [TGF-β3], transmembrane 43 [TMEM43] whose mutation leads to a deleterious clinical phenotype (ARVC-5/ Newfoundland mutation), titin [TTN], desmin [DES], lamin A/ C [LMNA], phospholamban [PLN], and LIM (Lin11, Isl-1, and Mec-3) domain binding 3 [LDB3] [6, 7]. ARVC emerged as a merely desmosomal disease, yet ongoing genetic studies continue to discover new nondesmosomal genes playing a significant role in the pathophysiological pathway of the disease. Another form of arrhythmogenic cardiomyopathy is the left-dominant arrhythmogenic cardiomyopathy (LDAC) with fibroadipose replacement of the left ventricle. LDAC was first described in SCD autopsies and is seen in families with desmoplakin mutations. The high risk of sudden cardiac death and the familial background of arrhythmogenic cardiomyopathy enforce the need for thorough comprehensive screening of all possible candidates.
Dilated Cardiomyopathy Dilated cardiomyopathy (DCM) is a cardiac muscle disease characterized by a poorly contracting enlarged heart chamber. It is the most common type of cardiomyopathies, and various etiologies have been attributed to the disease including ischemia, viral/immunologic, idiopathic/familial, and alcoholic/ toxic causes [11]. The prevalence of the idiopathic/familial form of disease is estimated to be 1:2000 in the USA accounting for 20 % of all cases with a predominantly autosomaldominant inheritance pattern with age-dependent penetrance [7, 11, 12]. In addition to the progressive worsening of systolic function and ultimately heart failure, DCM has been reported to predispose patients to arrhythmic sudden cardiac death. Mutations in at least 50 single genes have been identified to cause DCM and most involve proteins that are implicated in links between the sarcomere and the sarcolemma with the nuclear envelope structure and cytoskeletal complex [11]. The DCM genes implicated in the sarcolemmal-sarcomerenuclear envelope coupling mainly encode proteins involved in force generation (thick filament), force transmission, and energy production. Sarcomeric mutations were identified in more than 10 % of cases (this is much higher now that titin and its interacting partners are included; perhaps 30 %), and the commonest genes involved encode the β-myosin heavy chain (MYH7), troponin (I and C), tropomyosin, and cardiac actin [11, 13]. The largest human protein, TTN, acts as a stretch sensor playing a major part in sarcomere assembly and signal transmission. MYH7 and TTN are the commonest gene mutations among sarcomere and structural mutations, respectively [13]. Nuclear lamins are intermediate filaments
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forming the nuclear lamina that maintain nuclear structure during mitosis [13]. The LMNA gene encodes the A-type lamins (lamin A and lamin C), essential protein in the nuclear envelope assembly, and is one of the common genetic causes of DCM as it accounts for 8 % of familial cases [13]. Mutations in the LMNA gene predisposes to electrical instability and severe conduction disease in 90 % of carriers, which in turn puts patients on high risk for sudden cardiac death (in 50 % of the cases) before the onset of heart failure [13]. Mutations in emerin (which codes for a protein that anchors at the inner nuclear membrane of the cardiomyocyte and interacts with lamins and the nucleoplasm) lead to Emery-Dreifuss muscular dystrophy (EDMD)-dilated cardiomyopathy. The ribonucleic acid binding motif protein 20 (RBM20) is a member of serine/arginine-rich protein family and is involved in selective cardiac splicing. Recent studies have shown that RBM20 is linked with a malignant clinical course of DCM [13, 14]. Another recent DCM candidate gene is nebulette (NEBL), which encodes a protein essential in thin filament alignment connecting them to Z-disc [15]. In addition to the mentioned genes, many others have been identified to predispose carriers to dilated cardiomyopathy. As genetic studies continue to identify novel mutations linked to this highly genetic complex disease, genetic screening in the familial DCM should be performed.
Curr Cardiol Rep (2015) 17:53
peaks in early recovery, after which it gradually deceases into late recovery while the QTc intervals in LQT2 patients increases as the recovery period progresses [19•]. Common variants have also been shown to influence the QT interval and sudden death. The NOS1AP gene that encodes nitric oxide synthase 1 adaptor protein has been shown to be involved in myocardial repolarization. Variants of NOS1AP modulate the risk in LQT syndrome, and half of them were not previously implicated in repolarization [1, 2]. Three separate studies were conducted to investigate the link between NOS1AP gene variants and SCD and identified that two intronic variants are associated with SCD even after controlling for QT interval [2]. This association was validated to carry a 30 % increase in SCD risk in white participants, but no significance was observed in African-American subjects [2, 20]. The S1103Y variant in the cardiac sodium channel gene (SCN5A) is common in African Americans with 13 % being heterozygous, and it increases the arrhythmia risk by more than eightfold in carrier subjects [20, 21]. The SCN5AS1103Y variant was responsible for abnormal sodium channel inactivation leading to increased susceptibility to early afterdepolarizations. There is an increased risk for ventricular arrhythmias and sudden death reaching a 24-fold greater risk of sudden death in SCN5A-S1103Y homozygotes [20].
Brugada Syndrome Long QT Syndrome Arrhythmogenic syndromes such as long QT syndrome (LQTS) display great genetic heterogeneity, and the relationship between symptoms, genotype, and QT interval is not always clear [6]. Of the subjects, 30–50 % become symptomatic presenting with syncope and 3–5 % of patients present with cardiac arrest as the initial manifestation of the disease [16]. LQTS can result from loss-of-function mutations in potassium channel genes (such as KCNQ1, KCNH2, KCNE1, KCNE2, and KCNJ2) or gain-of-function mutations in sodium or calcium channel genes (such as SCN5A and CACNA1C) [13, 17, 18] (Table 1). Autosomal-dominant (Romano-Ward syndrome and Andersen-Tawil syndrome) and autosomalrecessive patterns (Jervell and Lange-Nielsen syndrome) have been described to be the mode of inheritance in LQT syndrome, with the autosomal-dominant pattern being predominant. More than 500 mutations in 13 genes have been reported to be responsible for the disease, and 75 % of all cases were caused by mutations in only 5 genes (KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2) coding cardiac channels responsible for cardiac action potential [6]. Exercise testing was shown to unmask concealed LQTS, particularly LQT1, even in the presence of beta-blockers that are known to obscure the LQT1 diagnostic profile during the epinephrine QT stress test [19•]. The QTc prolongation of LQT1 patients
Brugada syndrome (BrS) is an autosomal-dominant genetic disorder with incomplete penetrance and is associated with high risk of sudden cardiac death [22]. It affects predominantly middle-aged men with a mean age of diagnosis around 40 years and is mostly diagnosed by accidental ECG findings. Patients are at high risk for SCD with cardiac event rate per year of 0.5 % in asymptomatic patients, 1.9 % in patients with syncope, and 7.7 % in patients with aborted SCD [22]. The syndrome is estimated to be responsible for up to 12 % of all sudden deaths and 20 % of SCD among patients with structurally normal hearts [22–25]. The syndrome has a genetic basis, and several mutations have been identified in genes encoding subunits of cardiac sodium, potassium, and calcium channels, as well as in genes involved in the trafficking or regulation of these channels. Hundreds of variants in more than 25 genes have been associated with BrS [22, 24–28]. The first gene mutation to be identified as responsible for Brugada syndrome was SCN5A which is also associated with LQTS type 3. After screening, SCN5A mutations are present in 25 % of patients with BrS. Patients show clinical signs of conduction slowing that is demonstrated by PR and QRS prolongation. The glycerol-3-phosphate dehydrogenase 1-like GPD1L gene responsible for trafficking of sodium channels has also been shown to cause Brugada syndrome via reduced sodium current [29]. A list of the genes involved in BrS is
Curr Cardiol Rep (2015) 17:53 Table 1 Causative genes in long QT syndrome
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Locus
Gene
Protein
Current
LQT1 LQT2 LQT3 LQT4 LQT5
KCNQ1 KCNH2 SCN5A ANK2 KCNE1
Kv7.1 α HERG/Kv11.1 α Nav1.5 α Ankyrin-B minK β
↓ IKs ↓ IKr ↑ INa,L ↓ INa,K ATPase/↓INCX ↓ IKs
LQT6 LQT7 Andersen-Tawil LQT8 Timothy LQT9 LQT10 LQT11 LQT12 LQT13 JLNS1a (80 % cases) JLNS2a (20 % cases)
KCNE2 KCNJ2 CACNA1C CAV3 SCN4B AKAP9 SNTA1 KCNJ5 KCNQ1 KCNE1
MiRP1 β IRK1, Kir2.1 α Cav1.2 α1c Caveolin-3 NaV1.5 β4 Yotiao α-1-syntrophin GIRK4/KIR3.4 Kv7.1 α minK β
↓ IKr ↓ IK1 ↑ ICa,L ↑ INa ↑ INa ↓ IKs ↑ INa ↓ IK1 ↓ IKs ↓ IKs
a
Chromosome 11p15.5 7q35 3p21 4q25 21q22.1 21q22.1 17q23 12p13.3 3p25 11q23 7q21-22 20q11.21 11q24.3 11p15.5 21q22.1
Jervell and Lange-Nielsen Syndrome (JLNS), autosomal recessive syndrome with hearing deficit
INa,L late component of the sodium channel current
found in Table 2. Approximately 70 % of BrS cases are still genotype negative.
Catecholaminergic Polymorphic Ventricular Tachycardia Catecholaminergic polymorphic ventricular tachycardia (CPVT) is another rare, yet malignant, heritable syndrome referred to as the familial polymorphic ventricular tachycardia because of its distinctive continuous alternation of the QRS morphology and axis [6]. It presents as syncope, polymorphic VT, and SCD that are triggered by physical exertion or emotional stress. It is considered a highly lethal disease associated with a 30 % risk of SCD below the age of 30 and reaching 50 % by the age of 40 in untreated subjects [30]. It is identified as the underlying cause of sudden death in 13 % of patients without heart disease [16]. The challenging part is that affected individuals have a normal resting ECG and no structural heart abnormalities, but manifests a bidirectional ventricular tachycardia and QRS alternation. As family history of sudden death was evident in 30 % of cases, investigators studied the genetic basis of the disease and the variants responsible for this clinical entity. RyR2, CASQ2, KCNJ2, TRDN, CALM1, and ANK2 genes are involved in cardiac intracellular calcium hemostasis and have been associated with CPVT, the classical bidirectional VT, and primary VF with non-prolonged QT intervals. Up to 70 % of patients with CPVT display mutations in one of the three genes: RyR2, KCNJ2, and CASQ2 (Table 3). RyR2 encodes a large protein that forms the Ca2+ release channel in sarcoplasmic reticulum and is essential in
the excitation-contraction coupling regulation [6]. RyR2 variants are transmitted in an autosomal-dominant pattern with 80 % penetrance [6]. More than 60 mutations in this gene have been identified, and one-fifth of carriers had sudden death as their first clinical presentation of the disease [6, 16, 31]. Mutations in the cardiac calsequestrin gene, CASQ2, are much less frequent and are transmitted in an autosomal recessive manner [6]. Calsequestrin is a calcium-binding protein in the sarcoplasmic reticulum and is also a major participant in the excitation-contraction regulation [6]. Patients who test positive for mutations in the abovementioned genes are predisposed to an earlier onset and more aggressive form of the disease. In the light of the high rates of SCD in untreated patients, pre-symptomatic diagnosis and genetic testing are invaluable for the implementation of primary prevention therapeutic strategies.
Short QT Syndrome Short QT syndrome (SQTS) is a recently described disease of cardiac ion channels that is characterized by persistently short QT intervals (QTc
INVASIVE ELECTROPHYSIOLOGY AND PACING (EK HEIST, SECTION EDITOR)
Genetics of Sudden Cardiac Death Marwan M. Refaat 1,3 & Mostafa Hotait 1 & Barry London 2
# Springer Science+Business Media New York 2015
Abstract Sudden cardiac death (SCD) is defined by the World Health Organization (WHO) as death within 1 h of symptom onset (witnessed) or within 24 h of being observed alive and symptom free (unwitnessed). It affects more than 3 million people annually worldwide and affects approximately 1/1000 people each year in the USA. Familial studies of syndromes with Mendelian inheritance, candidate genes analyses, and genome-wide association studies (GWAS) have helped our understanding of the genetics of SCD. We will review the genetics of arrhythmogenic hereditary syndromes with Mendelian inheritance from familial studies with structural heart disease (hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic cardiomyopathy) as well as primary electrical causes (long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome). In addition, we will review the genetics of intermediate phenotypes for SCD such as coronary artery disease and electrocardiographic variables (QT interval, QRS duration, and RR interval). Finally, we will review rare and common variants that are associated with SCD in the
This article is part of the Topical Collection on Invasive Electrophysiology and Pacing * Marwan M. Refaat [email protected] 1
Department of Internal Medicine (Cardiology Division), American University of Beirut Medical Center, Beirut, Lebanon
2
Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA
3
Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
general population and were identified from candidate gene analyses and GWAS. Our understanding of the genetics of SCD will improve by the use of next-generation sequencing/ whole-exome sequencing as well as whole-genome sequencing which have the potential to discover unsuspected common and rare genetic variants that might be associated with SCD. Keywords Sudden cardiac death . Arrhythmogenic hereditary syndromes . Genetics . Genome-wide association studies . Cardiomyopathies . Hypertrophic cardiomyopathy . Dilated cardiomyopathy . Arrhythmogenic right ventricular cardiomyopathy/dysplasia . Long QT syndrome . Short QT syndrome . Brugada syndrome . Catecholaminergic polymorphic ventricular tachycardia
Introduction Sudden cardiac death (SCD), defined by the World Health Organization (WHO) as death within 1 h of symptom onset (witnessed) or within 24 h of being observed alive and symptom free (unwitnessed), remains a major public health problem and accounts for 200,000 to 450,000 deaths annually in the USA, which equates to 15 to 20 % of all deaths and 50 % of overall cardiac mortality [1–3]. Although significant progress has been made to understand SCD, it continues to be a devastating event due to its occurrence in individuals without previously diagnosed heart disease and the fact that 60 % of cases occur outside the hospital setting [3]. Due to the variety of causes of this cardiac collapse and the very small subset of patients being under observation or close monitoring, the exact underlying mechanism usually remains a big challenge [3]. Sudden death is usually thought to be due to interactions between a substrate (underlying disease) and a triggering event that is responsible for an electric instability. Despite a
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spectrum of etiologies, this instability is believed to often start with electrical reentry propagating into ventricular tachycardia and multiple localized areas of microcircuits that lead to ventricular fibrillation and subsequent asystole. Coronary heart disease (CHD) is considered the most common substrate for SCD accounting for 75–80 % of all cases, but only 13 % of CHD patients will have sudden cardiac arrest [1]. A recent study from San Francisco with a comprehensive review of medical examiner investigation and autopsy on the majority of the suspected SCD cases (gold standard to diagnose SCD) showed that significant CHD contributes only to 39 % of sudden arrhythmic death [4]. Studies conducted to identify the potential association between SCD and history of SCD in first-degree relative show a 1.6- to 1.8-fold increase in SCD susceptibility [5]. There is a twofold increase in SCD risk if an individual had one parent who died suddenly and a ninefold increase if both parents died suddenly; this was independent of family history of myocardial infarction [2]. In addition, rare variants with strong effects have been identified in cardiac conduction diseases that are associated with increased risk of ventricular arrhythmias and SCD. Furthermore, discovery of novel mutations involved in some arrhythmogenic syndromes and their impact on basic electrophysiology raised the possibility of their implication in SCD risk. Our review will stress the progress made so far in studying the genetics of inheritable diseases and the polymorphisms involved in SCD. We will review the genetics of arrhythmogenic hereditary syndromes with Mendelian inheritance from familial studies with structural heart disease (hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic cardiomyopathy) as well as primary electrical causes (long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome). In addition, we will review the genetics of intermediate phenotypes for SCD such as coronary artery disease and electrocardiographic variables (QT interval, QRS duration, and RR interval). Finally, we will review rare and common variants that are associated with SCD in the general population and were identified from candidate gene analyses and genome-wide association studies. Our understanding of the genetics of SCD will improve by the use of nextgeneration sequencing/whole-exome sequencing as well as whole-genome sequencing, which have the potential to discover unsuspected common and rare genetic variants that might be associated with SCD.
The Genetic and Molecular Basis of the Rare Monogenic Diseases Predisposing to SCD We will present in this section genetic variants identified from familial studies to cause SCD via structural cardiomyopathies (such as hypertrophic cardiomyopathy, dilated cardiomyopathy,
Curr Cardiol Rep (2015) 17:53
arrhythmogenic cardiomyopathy, restrictive cardiomyopathy, and left ventricular noncompaction cardiomyopathy) and primary electrical diseases (such as long QT syndrome, short QT syndrome, J-wave syndromes [Brugada syndrome and early repolarization syndrome (or Haïssaguerre syndrome)], and catecholaminergic polymorphic ventricular tachycardia). The genes involved in inherited cardiomyopathies include sarcomeric genes in hypertrophic cardiomyopathy and restrictive cardiomyopathy which lead to diastolic dysfunction, genes involved in the linkage of the sarcomere to the sarcolemma in dilated cardiomyopathy which lead to systolic function, and the desmosome genes in arrhythmogenic cardiomyopathy which bind myocytes together. Left ventricular noncompaction cardiomyopathy (LVNC) is an overlap disorder and it appears that any of the cardiomyopathy genes can be involved depending on the specific form of the LVNC.
Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease of myocontractile sarcomeric proteins leading to myocardial hypertrophy and fibrosis [6]. Local fibrosis and scarring provide the substrate for electrical heterogeneity that puts subjects at a higher risk for arrhythmia and makes them more susceptible to ventricular tachycardia/fibrillation. HCM is clearly familial in half of the cases and exhibits an autosomal-dominant pattern of inheritance with variable penetrance [6]. HCM is the most prevalent cardiovascular genetic disease affecting 1 in 500 of otherwise healthy young individuals and is the most common inherited predisposition to SCD in the young accounting for up to 48 % of sudden death [6]. More than 450 mutations have been identified in genes encoding sarcomeric proteins of the thick and thin filaments, Z-disc, and the intercalated disc. As HCM exhibits genotypic and phenotypic heterogeneity, the risk of sudden death has been linked to the underlying mutation in addition to the extent of hypertrophy. The bulk of mutations are reported in eight myofilament-associated genes including β-myosin heavy chain (MYH7) and myosin binding protein-C (MYBPC3), which account for 30–40 % of all cases [6]. Cardiac troponin T (TNNT2), tropomyosin (TPM1), cardiac troponin I (TNNI3), cardiac actin (ACTC), and the myosin light chains (MYL3, MYL2) represent only 1–5 % of cases [6, 7]. Previous studies have shown that some mutations in the βmyosin heavy chain gene (Arg403Gln, Arg453Gln, and Arg719Trp) have nearly complete penetrance and lead to a severe early-onset disease with a high risk of SCD [8]. Moreover, troponin T mutations generally exhibit mild to no ventricular hypertrophy and abnormal blood pressure responses to exercise, yet subjects have poor prognosis and increased risk of sudden death. Other mutations that have been associated with HCM and cardiomyopathies with apparent hypertrophy
Curr Cardiol Rep (2015) 17:53
are in calcium-induced sarcoplasmic reticulum calcium release genes [such as sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), ryanodine receptor 2 (RyR2), and junctophilin 2 (JPH2)] and in genes encoding mitochondrial and lysosomal proteins [AMP-dependent protein kinase (PRKAG2), lysosomal-associated membrane protein 2 (LAMP2), and αgalactosidase A (GLA) causing Fabry disease] which lead to storage and metabolic cardiomyopathies. Though previous studies reported a benign prognosis of patients with apical HCM (~3 % of patients with HCM), recent studies reported the association of apical HCM with SCD [9]. Previous reports also showed that subjects having double mutations exhibit a more severe form of the disease than patients with single gene defects and are more prone for sudden cardiac death [10]. This highly malignant disease with its significant risk of SCD and the underlying genetic involvement necessitates genetic screening in subjects with positive family history.
Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is another significant contributor to sudden cardiac death. It is an inherited cardiac muscle disease affecting the right ventricle predominantly (and can affect the left ventricle as well) with a prevalence between 1 in 5000 and 1 in 2000 in the general population and accounting for 5 % of unexplained sudden death in some populations [6]. The disease is characterized by the gradual loss of muscle in the right ventricle free wall progressing from the epicardium to endocardium [6]. Myocyte loss with subsequent fibroadipose replacement leads to intraventricular conduction delay and major electrical instability, with reentrant conduction of right ventricle origin being the underlying cause of ventricular tachycardia having the observed left bundle branch block morphology [6]. ARVC is difficult to diagnose as it has a broad spectrum of clinical manifestations, and sudden death is the first presenting symptom in 23 % of patients. Endurance exercise and frequent exercise increase the age-related penetrance and the arrhythmic risk in ARVC/D. Previous studies have demonstrated an autosomaldominant inheritance with incomplete penetrance in half of ARVC cases. After publishing the first chromosomal locus to be linked to the disease in 1994, other molecular genetic studies successfully provided insights to the genetic heterogeneity and their association with desmosomal adhesion proteins [6]. In addition to plakophilin-2 (PKP-2) gene mutations that account for more than 40 % of ARVC cases, desmoplakin (DSP), plakoglobin (JUP), desmoglein-2 (DSG-2), and desmocollin-2 (DSC-2) are the major proteins responsible for maintaining continuous cell-to-cell adhesion [6]. Impairment of these intercellular junctions and, thus, myocytes mechanical
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coupling are considered the primary underlying molecular defects. Other non-desmosomal proteins have also been reported to play a significant role in the pathogenesis of ARVC: ryanodine receptor 2 (cardiac) [RyR2], transforming growth factor β-3 [TGF-β3], transmembrane 43 [TMEM43] whose mutation leads to a deleterious clinical phenotype (ARVC-5/ Newfoundland mutation), titin [TTN], desmin [DES], lamin A/ C [LMNA], phospholamban [PLN], and LIM (Lin11, Isl-1, and Mec-3) domain binding 3 [LDB3] [6, 7]. ARVC emerged as a merely desmosomal disease, yet ongoing genetic studies continue to discover new nondesmosomal genes playing a significant role in the pathophysiological pathway of the disease. Another form of arrhythmogenic cardiomyopathy is the left-dominant arrhythmogenic cardiomyopathy (LDAC) with fibroadipose replacement of the left ventricle. LDAC was first described in SCD autopsies and is seen in families with desmoplakin mutations. The high risk of sudden cardiac death and the familial background of arrhythmogenic cardiomyopathy enforce the need for thorough comprehensive screening of all possible candidates.
Dilated Cardiomyopathy Dilated cardiomyopathy (DCM) is a cardiac muscle disease characterized by a poorly contracting enlarged heart chamber. It is the most common type of cardiomyopathies, and various etiologies have been attributed to the disease including ischemia, viral/immunologic, idiopathic/familial, and alcoholic/ toxic causes [11]. The prevalence of the idiopathic/familial form of disease is estimated to be 1:2000 in the USA accounting for 20 % of all cases with a predominantly autosomaldominant inheritance pattern with age-dependent penetrance [7, 11, 12]. In addition to the progressive worsening of systolic function and ultimately heart failure, DCM has been reported to predispose patients to arrhythmic sudden cardiac death. Mutations in at least 50 single genes have been identified to cause DCM and most involve proteins that are implicated in links between the sarcomere and the sarcolemma with the nuclear envelope structure and cytoskeletal complex [11]. The DCM genes implicated in the sarcolemmal-sarcomerenuclear envelope coupling mainly encode proteins involved in force generation (thick filament), force transmission, and energy production. Sarcomeric mutations were identified in more than 10 % of cases (this is much higher now that titin and its interacting partners are included; perhaps 30 %), and the commonest genes involved encode the β-myosin heavy chain (MYH7), troponin (I and C), tropomyosin, and cardiac actin [11, 13]. The largest human protein, TTN, acts as a stretch sensor playing a major part in sarcomere assembly and signal transmission. MYH7 and TTN are the commonest gene mutations among sarcomere and structural mutations, respectively [13]. Nuclear lamins are intermediate filaments
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forming the nuclear lamina that maintain nuclear structure during mitosis [13]. The LMNA gene encodes the A-type lamins (lamin A and lamin C), essential protein in the nuclear envelope assembly, and is one of the common genetic causes of DCM as it accounts for 8 % of familial cases [13]. Mutations in the LMNA gene predisposes to electrical instability and severe conduction disease in 90 % of carriers, which in turn puts patients on high risk for sudden cardiac death (in 50 % of the cases) before the onset of heart failure [13]. Mutations in emerin (which codes for a protein that anchors at the inner nuclear membrane of the cardiomyocyte and interacts with lamins and the nucleoplasm) lead to Emery-Dreifuss muscular dystrophy (EDMD)-dilated cardiomyopathy. The ribonucleic acid binding motif protein 20 (RBM20) is a member of serine/arginine-rich protein family and is involved in selective cardiac splicing. Recent studies have shown that RBM20 is linked with a malignant clinical course of DCM [13, 14]. Another recent DCM candidate gene is nebulette (NEBL), which encodes a protein essential in thin filament alignment connecting them to Z-disc [15]. In addition to the mentioned genes, many others have been identified to predispose carriers to dilated cardiomyopathy. As genetic studies continue to identify novel mutations linked to this highly genetic complex disease, genetic screening in the familial DCM should be performed.
Curr Cardiol Rep (2015) 17:53
peaks in early recovery, after which it gradually deceases into late recovery while the QTc intervals in LQT2 patients increases as the recovery period progresses [19•]. Common variants have also been shown to influence the QT interval and sudden death. The NOS1AP gene that encodes nitric oxide synthase 1 adaptor protein has been shown to be involved in myocardial repolarization. Variants of NOS1AP modulate the risk in LQT syndrome, and half of them were not previously implicated in repolarization [1, 2]. Three separate studies were conducted to investigate the link between NOS1AP gene variants and SCD and identified that two intronic variants are associated with SCD even after controlling for QT interval [2]. This association was validated to carry a 30 % increase in SCD risk in white participants, but no significance was observed in African-American subjects [2, 20]. The S1103Y variant in the cardiac sodium channel gene (SCN5A) is common in African Americans with 13 % being heterozygous, and it increases the arrhythmia risk by more than eightfold in carrier subjects [20, 21]. The SCN5AS1103Y variant was responsible for abnormal sodium channel inactivation leading to increased susceptibility to early afterdepolarizations. There is an increased risk for ventricular arrhythmias and sudden death reaching a 24-fold greater risk of sudden death in SCN5A-S1103Y homozygotes [20].
Brugada Syndrome Long QT Syndrome Arrhythmogenic syndromes such as long QT syndrome (LQTS) display great genetic heterogeneity, and the relationship between symptoms, genotype, and QT interval is not always clear [6]. Of the subjects, 30–50 % become symptomatic presenting with syncope and 3–5 % of patients present with cardiac arrest as the initial manifestation of the disease [16]. LQTS can result from loss-of-function mutations in potassium channel genes (such as KCNQ1, KCNH2, KCNE1, KCNE2, and KCNJ2) or gain-of-function mutations in sodium or calcium channel genes (such as SCN5A and CACNA1C) [13, 17, 18] (Table 1). Autosomal-dominant (Romano-Ward syndrome and Andersen-Tawil syndrome) and autosomalrecessive patterns (Jervell and Lange-Nielsen syndrome) have been described to be the mode of inheritance in LQT syndrome, with the autosomal-dominant pattern being predominant. More than 500 mutations in 13 genes have been reported to be responsible for the disease, and 75 % of all cases were caused by mutations in only 5 genes (KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2) coding cardiac channels responsible for cardiac action potential [6]. Exercise testing was shown to unmask concealed LQTS, particularly LQT1, even in the presence of beta-blockers that are known to obscure the LQT1 diagnostic profile during the epinephrine QT stress test [19•]. The QTc prolongation of LQT1 patients
Brugada syndrome (BrS) is an autosomal-dominant genetic disorder with incomplete penetrance and is associated with high risk of sudden cardiac death [22]. It affects predominantly middle-aged men with a mean age of diagnosis around 40 years and is mostly diagnosed by accidental ECG findings. Patients are at high risk for SCD with cardiac event rate per year of 0.5 % in asymptomatic patients, 1.9 % in patients with syncope, and 7.7 % in patients with aborted SCD [22]. The syndrome is estimated to be responsible for up to 12 % of all sudden deaths and 20 % of SCD among patients with structurally normal hearts [22–25]. The syndrome has a genetic basis, and several mutations have been identified in genes encoding subunits of cardiac sodium, potassium, and calcium channels, as well as in genes involved in the trafficking or regulation of these channels. Hundreds of variants in more than 25 genes have been associated with BrS [22, 24–28]. The first gene mutation to be identified as responsible for Brugada syndrome was SCN5A which is also associated with LQTS type 3. After screening, SCN5A mutations are present in 25 % of patients with BrS. Patients show clinical signs of conduction slowing that is demonstrated by PR and QRS prolongation. The glycerol-3-phosphate dehydrogenase 1-like GPD1L gene responsible for trafficking of sodium channels has also been shown to cause Brugada syndrome via reduced sodium current [29]. A list of the genes involved in BrS is
Curr Cardiol Rep (2015) 17:53 Table 1 Causative genes in long QT syndrome
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Locus
Gene
Protein
Current
LQT1 LQT2 LQT3 LQT4 LQT5
KCNQ1 KCNH2 SCN5A ANK2 KCNE1
Kv7.1 α HERG/Kv11.1 α Nav1.5 α Ankyrin-B minK β
↓ IKs ↓ IKr ↑ INa,L ↓ INa,K ATPase/↓INCX ↓ IKs
LQT6 LQT7 Andersen-Tawil LQT8 Timothy LQT9 LQT10 LQT11 LQT12 LQT13 JLNS1a (80 % cases) JLNS2a (20 % cases)
KCNE2 KCNJ2 CACNA1C CAV3 SCN4B AKAP9 SNTA1 KCNJ5 KCNQ1 KCNE1
MiRP1 β IRK1, Kir2.1 α Cav1.2 α1c Caveolin-3 NaV1.5 β4 Yotiao α-1-syntrophin GIRK4/KIR3.4 Kv7.1 α minK β
↓ IKr ↓ IK1 ↑ ICa,L ↑ INa ↑ INa ↓ IKs ↑ INa ↓ IK1 ↓ IKs ↓ IKs
a
Chromosome 11p15.5 7q35 3p21 4q25 21q22.1 21q22.1 17q23 12p13.3 3p25 11q23 7q21-22 20q11.21 11q24.3 11p15.5 21q22.1
Jervell and Lange-Nielsen Syndrome (JLNS), autosomal recessive syndrome with hearing deficit
INa,L late component of the sodium channel current
found in Table 2. Approximately 70 % of BrS cases are still genotype negative.
Catecholaminergic Polymorphic Ventricular Tachycardia Catecholaminergic polymorphic ventricular tachycardia (CPVT) is another rare, yet malignant, heritable syndrome referred to as the familial polymorphic ventricular tachycardia because of its distinctive continuous alternation of the QRS morphology and axis [6]. It presents as syncope, polymorphic VT, and SCD that are triggered by physical exertion or emotional stress. It is considered a highly lethal disease associated with a 30 % risk of SCD below the age of 30 and reaching 50 % by the age of 40 in untreated subjects [30]. It is identified as the underlying cause of sudden death in 13 % of patients without heart disease [16]. The challenging part is that affected individuals have a normal resting ECG and no structural heart abnormalities, but manifests a bidirectional ventricular tachycardia and QRS alternation. As family history of sudden death was evident in 30 % of cases, investigators studied the genetic basis of the disease and the variants responsible for this clinical entity. RyR2, CASQ2, KCNJ2, TRDN, CALM1, and ANK2 genes are involved in cardiac intracellular calcium hemostasis and have been associated with CPVT, the classical bidirectional VT, and primary VF with non-prolonged QT intervals. Up to 70 % of patients with CPVT display mutations in one of the three genes: RyR2, KCNJ2, and CASQ2 (Table 3). RyR2 encodes a large protein that forms the Ca2+ release channel in sarcoplasmic reticulum and is essential in
the excitation-contraction coupling regulation [6]. RyR2 variants are transmitted in an autosomal-dominant pattern with 80 % penetrance [6]. More than 60 mutations in this gene have been identified, and one-fifth of carriers had sudden death as their first clinical presentation of the disease [6, 16, 31]. Mutations in the cardiac calsequestrin gene, CASQ2, are much less frequent and are transmitted in an autosomal recessive manner [6]. Calsequestrin is a calcium-binding protein in the sarcoplasmic reticulum and is also a major participant in the excitation-contraction regulation [6]. Patients who test positive for mutations in the abovementioned genes are predisposed to an earlier onset and more aggressive form of the disease. In the light of the high rates of SCD in untreated patients, pre-symptomatic diagnosis and genetic testing are invaluable for the implementation of primary prevention therapeutic strategies.
Short QT Syndrome Short QT syndrome (SQTS) is a recently described disease of cardiac ion channels that is characterized by persistently short QT intervals (QTc
