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Six founder mutations contribute to sudden cardiac arrest
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Six rare genetic variants were more prevalent in those with sudden cardiac arrest than in the general population, according to new research.
“This finding provides proof of concept for the notion that rare genetic variants contribute to some extent to [sudden cardiac arrest] risk in the community,” Annalisa Milano, PhD, and colleagues wrote in Circulation: Cardiovascular Genetics.
Milano, from the department of clinical and experimental cardiology, Amsterdam Medical Center, University of Amsterdam, and colleagues investigated the involvement of rare genetic variants in risk for sudden cardiac arrest on a population-level basis. According to the study background, common variants known to increase susceptibility to ventricular fibrillation have been linked to increased risk for sudden cardiac arrest, but whether they contribute to elevated sudden cardiac arrest risk in the community was not known.
The researchers analyzed the prevalence of six Dutch founder mutations that had been linked to some form of cardiomyopathy or electrical disease in unselected Dutch victims of sudden cardiac arrest. Of those, PLN-p.Arg14del is associated with dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy; MYBPC3-p.Trp792fsX17, MYBPC3-p.Arg943X and MYBPC3-p.Pro955fsX95 are associated with hypertrophic cardiomyopathy; PKP2-p.Arg79X is associated with arrhythmogenic right ventricular cardiomyopathy; and the Chr7q36 idiopathic ventricular fibrillation risk-haplotype is associated with ventricular fibrillation.
The researchers compared the prevalence of the six mutations in 1,440 people with sudden cardiac arrest from the ARREST study with 1,379 healthy Dutch matched controls from the Amsterdam area and 500 people from the Genome of the Netherlands (GoNL) study. They also compared the prevalence of PLN-p.Arg14del between those from ARREST and 8,261 people from the PREVEND study of inhabitants of Groningen, the Netherlands, where the mutation is believed to have originated.
They found that the cohort of people with sudden cardiac arrest had higher prevalence of the six mutations compared with the healthy matched controls (1.1% vs. 0.4%; Mantel-Haenszel test, P = .028), compared with the GoNL population (1.1% vs. 0%; P < .02).
They also found that the PLN-p.Arg14del mutation was more prevalent in the ARREST population than in the PREVEND population (0.56% vs. 0.07%; Fisher exact test, P < .0003).
The findings “are consistent with previous insights that these mutations are pathogenic and contribute importantly to [sudden cardiac arrest] in young individuals without acquired causes for [sudden cardiac arrest],” Milano and colleagues wrote. – by Erik Swain
Disclosure: The researchers report no relevant financial disclosures.
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