EP News—Section Editors: T. Jared Bunch, Penelope A. Boyden, N.A. Mark Estes III, Erica S. Zado| Volume 14, ISSUE 9, P1425, September 2017

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  • Erica S. Zado
    Address reprint requests and correspondence: Ms Erica S. Zado, Section of Cardiac Electrophysiology, Cardiovascular Division, Hospital of the University of Pennsylvania, Founders 9, 3400 Spruce St, Philadelphia, PA 19104.
    Section of Cardiac Electrophysiology, Cardiovascular Division, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
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      Using information obtained in the CASPER (Cardiac Arrest Survivors with Preserved Ejection fraction Registry), Mellor et al (Circ Cardiovasc Genet 2017;10:e001686, PMID 28600387) sought to identify genes and clinical factors associated with sudden cardiac death (SCD) in patients without clinically obvious cardiac abnormalities. This national (Canadian) registry enrolled SCD survivors with documented ventricular tachycardia (VT) or ventricular fibrillation requiring cardioversion or defibrillation. In addition, subjects needed to have a normal left ventricular ejection fraction and no significant coronary artery disease (no stenosis >50%). Those with known causes of SCD, such as a long QT on the resting electrocardiogram, Brugada syndrome, hypertrophic cardiomyopathy, and reversible causes such as hypokalemia or drug overdose, were excluded. Clinical testing included echocardiogram, exercise testing, cardiac magnetic resonance imaging, procainamide and epinephrine infusion, and, in 174 patients, genetic testing. Decision to perform genetic testing and the type of genetic was at the discretion of the investigating physician. The investigators assessed all the genetic results and reclassified variants on the basis of the most up-to-date information. Of these 174 undergoing genetic testing, a pathogenic mutation was found in 29 patients (17%) and there were 70 variants of unknown significance (VUSs) in 32 patients (18%). Genes associated with long QT syndrome (LQTS) and arrhythmogenic right ventricular cardiomyopathy (ARVC) were the most frequently identified pathogenic variants. Interestingly, despite the registry excluding patients with significant cardiomyopathy, 11 (6%) patients had a pathogenic gene associated with cardiomyopathy. Both family history of sudden death and a history of syncope predicted presence of pathogenic mutation. The 174 patients were classified as phenotype positive (n = 72 [41%]) or phenotype negative after clinical testing. Phenotype-positive patients were more likely to have a pathogenic variant identified (25% vs 11%). Pathogenic mutations and VUSs were found much more frequently when broad, multiphenotype gene panels were used, especially in phenotype-negative patients. The authors conclude that in patients without a definite clinical phenotype presenting with unexplained SCD, a significant number will have a pathologic genetic variant found on genetic testing. Both family history and syncope predict a positive test, and broader panels yield higher results. However, the authors caution that investigation of VUSs takes time and specialized knowledge, and therefore genetic testing in these patients should be done at centers with that expertise.
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