Brief ReviewHuman Genomics and Its Impact on Arrhythmias
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 CardiologyCitation 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.
Mutational analysis of mitochondrial DNA in Brugada syndrome
2016, Cardiovascular PathologyCitation 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.
Multifocal ectopic Purkinje-related premature contractions: A new SCN5A-related cardiac channelopathy
2012, Journal of the American College of CardiologyDiplotype analysis of the human cardiac sodium channel regulatory region in Japanese cases of sudden death by unknown causes
2009, Legal MedicineCitation 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].
SCN5A Mutation associated with acute myocardial infarction
2009, Legal MedicineGenetic predisposition and cellular basis for ischemia-induced ST-segment changes and arrhythmias
2007, Journal of Electrocardiology