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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Published online: July 19, 2017