Human Genomics and Its Impact on Arrhythmias

doi:10.1016/j.tcm.2004.01.001

Trends in Cardiovascular Medicine

Volume 14, Issue 3, April 2004, Pages 112-116

https://doi.org/10.1016/j.tcm.2004.01.001 Get rights and content

Abstract

Investigation of families with monogenic arrhythmia syndromes has identified genes whose further study has proven extraordinarily valuable in further understanding variability in cardiac electrophysiology and its response to exogenous stressors. One lesson being learned from this work is that individuals from the same kindred with the same disease-associated DNA variant may nevertheless display strikingly different phenotypes. Further, common function-altering polymorphisms are being identified in these and other genes controlling cardiac excitability. These findings, combined with the recognition that very common arrhythmia syndromes (such as atrial fibrillation or sudden arrhythmic death) include a genetic component, raise the prospect that analysis of genomic variability among individuals and populations may in the future be used to manage patients

Section snippets

Arrhythmia Genetics and Variable Penetrance

One important step in moving from rare familial arrhythmia syndromes to arrhythmia genomics has been the increasing recognition that the penetrance of these apparently monogenic diseases is highly variable (Priori et al. 1999). That is, within a specific affected kindred, individuals with a manifest phenotype (e.g., marked QT prolongation and high risk for sudden death) may coexist with other individuals who carry the identical mutation and yet have no manifest phenotype. It has been assumed,

Arrhythmogenic Mutations Are More Common than Previously Thought

Understanding long QT syndrome (LQTS) molecular genetics and defining the phenomenon of incomplete penetrance has allowed for an interesting thought problem with regard to the frequency of arrhythmogenic mutations in the general population. The starting point is the molecular genetics of the JLN syndrome, characterized by marked QT prolongation, a high risk for sudden death, and congenital deafness. Work over the last decade has identified JLN as a recessive disorder, with affected individuals

Expanding Candidate Modulators of the Arrhythmogenic Phenotype: Substrates and Triggers

The phenotypic spectrum of these monogenic arrhythmia syndromes thus extends from the mutation carrier with no manifest abnormal phenotype to patients with severe electrocardiographic abnormalities and high risk for arrhythmias. Interestingly, however, even in the latter group the vast majority of heartbeats are, in fact, normal. This finding reflects the prevalent paradigm for arrhythmogenesis: that the development of an arrhythmia represents an interplay between an arrhythmia-prone substrate

Drug-Induced Ventricular Fibrillation and SCN5A

The interplay between arrhythmia substrates and arrhythmia triggers is one example of a more general gene–environment interaction problem. The LQT1 mechanism is an example of an environmental stressor that elicits an arrhythmia in the susceptible myocardium. Another is “unmasking” of the Brugada syndrome electrocardiogram by challenge with sodium channel blocking drugs. Indeed, it was this clinical observation that identified SCN5A as a candidate for this form of idiopathic or familial

Genetics of Drug-Induced QT Prolongation

Another environmental “stressor” that can provoke arrhythmias in some patients is drug administration. The Brugada syndrome is one example, and administration of QT-prolonging drugs to provoke the “drug-induced” LQTS, characterized by Torsades de Pointes, is another. The concept of “repolarization reserve” posits that individuals vary in the multiple mechanisms that protect against exaggerated QT prolongation (and Torsades de Pointes) with drug challenge; some of this variability may be

Common Arrhythmias Include a Genetic Component

Evidence from large clinical trials points to a role for family history in mediating risk for sudden death Friedlander et al., 1998, Jouven et al., 1999. Whether this represents a heretofore much more prominent role for monogenic arrhythmia syndrome variants, or a role for polymorphism sets, in mediating the interaction between arrhythmia triggers such as coronary occlusion and the arrhythmogenic substrate is not known.

The most commonly treated arrhythmia in the Western world is atrial

Genomic Approaches to Common Arrhythmia Problems

Taken together, the basic and clinical studies defining rare monogenic arrhythmia syndromes and the epidemiology of common arrhythmias support the idea that sets of DNA variants define the arrhythmia-prone substrate and its response to arrhythmogenic environmental stressors (Spooner et al. 2001). Accomplishing the goal of identifying these sets is a major challenge. It seems likely that the fundamental approach will be to compare genomic information in subjects with arrhythmias (e.g., sudden

Acknowledgements

This work was supported in part by grants from the United States Public Health Service (HL46681, HL49989, HL65962). D.M.R. is the holder of the William Stokes Chair in Experimental Therapeutics, a gift from the Dai-ichi Corporation.

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Cited by (37)

The future of sudden cardiac death research
2017, Progress in Pediatric Cardiology
Citation Excerpt :
Unfortunately, despite these major advances, the cause of SCD in at least two-third of cases is still unknown [2]. Moreover, the use of genetic testing to identify family members at the highest risk for preventive measures and prophylactic treatment is hampered by the fact that for a given family member carrying the familial mutation does not automatically mean that he or she will develop disease [4–5]. It remains largely elusive why relatives carrying the same (identical) mutation display large variability in disease severity ranging from SCD at young age all the way to lifelong asymptomatic state.
Sudden unexplained death (SUD) in the young is a rare but tragic event. As genetic cardiac causes underlie the majority of SUD cases, surviving family members with the same genetic substrate as their deceased relative may be at increased risk. Presently, the diagnostic strategy to young SUD victims and their families is yet not standardized, the underlying aetiology in an important fraction of cases is still unravelled, and risk prediction in the genetically affected relatives is difficult due the variable expressivity of disease-causing mutations. In this review, we describe an ideal approach to SUD that is currently feasible but unfortunately not routinely followed in the clinical practice. We also discuss recent advancements in genetic technology and novel insights in the pathomechanism of genetic diseases that provide new opportunities for the future of sudden cardiac death research and management.
Mutational analysis of mitochondrial DNA in Brugada syndrome
2016, Cardiovascular Pathology
Citation Excerpt :
In fact, to date, mutations in 17 other genes [6], each responsible for a very low percentage of Brugada cases, have been described. At present, the emerging view of arrhythmia genomics suggests that BrS is a complex disorder in which the cosegregation of different mutations or genetic variants can contribute to the clinical phenotype [7–9]. It is difficult to pin down the exact incidence of BrS in the general population, although it is estimated to affect from 5 to 20 in every 10,000 people worldwide.
Brugada syndrome (BrS) is a primary electrical disease associated with an increased risk of sudden cardiac death due to ventricular fibrillation. This pathology has nuclear heterogeneous genetic origins, and at present, molecular diagnostic tests on nuclear DNA cover only 30% of BrS patients. The aim of this study was to assess the possible involvement of mitochondrial (mt) DNA variants in BrS since their etiological role in several cardiomyopathies has already been described.
The whole mt genome of BrS patients was sequenced and analyzed. A specific mtDNA mutation responsible for BrS can be excluded, but BrS patient d-loop was found to be more polymorphic than that of control cases (P= 0.003). Moreover, there appears to be an association between patients with the highest number of variants (n> 20) and four mt Single Nucleotide Polymorphism (SNPs) (T4216C, A11251G, C15452A, T16126C) and the most severe BrS phenotype (P= 0.002).
The high substitution rate found in BrS patient mtDNA is unlikely to be the primary cause of the disease, but it could represent an important cofactor in the manifestation of the BrS phenotype.
Evidence suggesting that a specific mtDNA allelic combination and a high number of mtDNA SNPs may be associated with more severe cases of BrS represents the starting point for further cohort studies aiming to test whether this mt genetic condition could be a genetic modulator of the BrS clinical phenotype.
Multifocal ectopic Purkinje-related premature contractions: A new SCN5A-related cardiac channelopathy
2012, Journal of the American College of Cardiology
The aim of this study was to describe a new familial cardiac phenotype and to elucidate the electrophysiological mechanism responsible for the disease.
Mutations in several genes encoding ion channels, especially SCN5A, have emerged as the basis for a variety of inherited cardiac arrhythmias.
Three unrelated families comprising 21 individuals affected by multifocal ectopic Purkinje-related premature contractions (MEPPC) characterized by narrow junctional and rare sinus beats competing with numerous premature ventricular contractions with right and/or left bundle branch block patterns were identified.
Dilated cardiomyopathy was identified in 6 patients, atrial arrhythmias were detected in 9 patients, and sudden death was reported in 5 individuals. Invasive electrophysiological studies demonstrated that premature ventricular complexes originated from the Purkinje tissue. Hydroquinidine treatment dramatically decreased the number of premature ventricular complexes. It normalized the contractile function in 2 patients. All the affected subjects carried the c.665G>A transition in the SCN5A gene. Patch-clamp studies of resulting p.Arg222Gln (R222Q) Nav1.5 revealed a net gain of function of the sodium channel, leading, in silico, to incomplete repolarization in Purkinje cells responsible for premature ventricular action potentials. In vitro and in silico studies recapitulated the normalization of the ventricular action potentials in the presence of quinidine.
A new SCN5A-related cardiac syndrome, MEPPC, was identified. The SCN5A mutation leads to a gain of function of the sodium channel responsible for hyperexcitability of the fascicular-Purkinje system. The MEPPC syndrome is responsive to hydroquinidine.
Diplotype analysis of the human cardiac sodium channel regulatory region in Japanese cases of sudden death by unknown causes
2009, Legal Medicine
Citation Excerpt :
Such disease-associated mutations could disrupt sodium channel function via multiple molecular mechanisms, such as synthesis of defective sodium channels because of a reduced expression of sodium channel membranes [14]. However, the role of DNA variants within SCN5A transcriptional control has not been determined thus far [19–22]. The SCN5A gene core promoter includes multiple positive and negative cis-acting elements that extending into intron 1 and DNA polymorphisms [23].
Inherited mutations in the human cardiac sodium channel (SCN5A) gene cause arrhythmogenic diseases such as tachyarrhythmia and bradyarrhythmia. Moreover, mutation subsets in the coding region impair SCN5A function, potentially leading to sudden cardiac death (SCD). In the present study, we performed diplotype analysis of the regulatory region of the SCN5A gene in Japanese people who died suddenly because of an unknown cause (sudden death group; n = 70) and controls (n = 112). There were no significant differences at six polymorphic loci between the groups. However, 38 diplotypes of 6-nucleotide polymorphism variants were identified. One of these diplotypes—Dip.D (CTG–TC/CCG–TC)—occurred significantly more frequently in the sudden death group than in the controls (p < 0.01, OR = 5.18, 95% CI: 1.38–19.45). Dip.D has two variants (T-1062C and T-847G), and while it is unclear whether these directly affect mRNA expression, a common polymorphism in this region modulates SCN5A expression in vitro. Our results thus suggest that the transcription of the SCN5A Dip.D variant may be associated with arrhythmogenic diseases that can induce sudden death.
SCN5A Mutation associated with acute myocardial infarction
2009, Legal Medicine
Ventricular tachycardia and fibrillation (VT/VF) complicating Brugada syndrome, a genetic disorder linked to SCN5A mutations, and VF complicating acute myocardial infarction (AMI) have both been linked to phase 2 reentry. Because of these mechanistic similarities in arrhythmogenesis, we examined the contribution of SCN5A mutations to VT/VF complicating AMI. Nineteen consecutive patients developing VF during AMI were enrolled. Wild-type (WT) and mutant SCN5A genes were co-expressed with SCN1B in TSA201 cells and studied using whole-cell patch-clamp techniques. One missense mutation (G400A) in SCN5A was detected in a conserved region among the cohort of 19 patients. A H558R polymorphism was detected on the same allele. Unlike the other 18 patients who each developed 1-2 VF episodes during acute MI, the mutation carrier developed six episodes of VT/VF within the first 12 hours. All VT/VF episodes were associated with ST segment changes and were initiated by short-coupled extrasystoles. We describe the first sodium channel mutation to be associated with the development of an arrhythmic storm during acute ischemia. These findings suggest that a loss of function in SCN5A may predispose to ischemia induced arrhythmic storm. These results could be very useful for forensic implications regarding genetic screening in relatives.
Genetic predisposition and cellular basis for ischemia-induced ST-segment changes and arrhythmias
2007, Journal of Electrocardiology
Recent reports have highlighted the importance of a family history of sudden death as a risk for ventricular fibrillation (VF) in patients experiencing acute myocardial infarction (AMI), pointing to the possibility of a genetic predisposition. This report briefly reviews 2 recent studies designed to examine the hypothesis that there is a genetic predisposition to the development of arrhythmias associated with AMI. Ventricular tachycardia and VF (VT/VF) complicating AMI as well as arrhythmias associated with Brugada syndrome, a genetic disorder linked to SCN5A mutations, have both been linked to phase 2 reentry. Because of these mechanistic similarities in arrhythmogenesis, we examined the contribution of SCN5A mutations to VT/VF complicating AMI in patients developing VF during AMI. A missense mutation in SCN5A was found in a patient who developed an arrhythmic electrical storm during an evolving myocardial infarction. All VT/VF episodes were associated with ST-segment changes and were initiated by short-coupled extrasystoles. G400A mutation and H558R polymorphism were on the same allele, and functional expression in TSA201 demonstrated loss of function of sodium channel activity. These results suggest that a subclinical mutation in SCN5A resulting in a loss of function may predispose to life-threatening arrhythmias during acute ischemia. In another cohort of patients who developed long-QT intervals and torsade de pointes arrhythmias in days 2 to 11 after an AMI, a genetic screening of all long-QT genes was performed. Of 8 patients in this group, 6 (75%) displayed the same polymorphism in KCNH2, which encodes the α-subunit of the rapidly activating delayed rectifier potassium current, I_Kr. The K897T polymorphism was detected in only 3 of 14 patients with uncomplicated myocardial infarction and has been detected in 33% of the white population. Expression of this polymorphism has previously been shown to cause a loss of function in HERG current consistent with the long-QT phenotype. These observations suggest a genetic predisposition to the development of long-QT intervals and torsade de pointes in the days after an AMI. These preliminary studies provide support for the hypothesis that there is a genetic predisposition to the type and severity of arrhythmias that develop during and after an AMI, and that additional studies are warranted.

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Brief ReviewHuman Genomics and Its Impact on Arrhythmias

Abstract

Section snippets

Arrhythmia Genetics and Variable Penetrance

Arrhythmogenic Mutations Are More Common than Previously Thought

Expanding Candidate Modulators of the Arrhythmogenic Phenotype: Substrates and Triggers

Drug-Induced Ventricular Fibrillation and SCN5A

Genetics of Drug-Induced QT Prolongation

Common Arrhythmias Include a Genetic Component

Genomic Approaches to Common Arrhythmia Problems

Acknowledgements

J Am Coll Cardiol

J Am Coll Cardiol

Cell

Am J Hum Genet

J Am Coll Cardiol

J Am Coll Cardiol

Novel mechanism for Brugada syndrome: defective surface localization of an SCN5A mutant (R1432G)

Circ Res

Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)

J Clin Invest

Identification of a genetic locus for familial atrial fibrillation

N Engl J Med

Increased mortality due to encainide or flecainide in a randomized trial of arrhythmia suppression after myocardial infarction

N Engl J Med

Genetic basis and molecular mechanism for idiopathic-ventricular fibrillation

Nature

KCNQ1 gain-of-function mutation in familial atrial fibrillation

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KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome

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Clinical, genetic, and biophysical characterization of a homozygous HERG mutation causing severe neonatal long QT syndrome

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Brief Review
Human Genomics and Its Impact on Arrhythmias