Is Careful Assessment of Rare Variants in the RYR2 Gene Piercing the Guidelines’ Strong Armor?
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See Article by Kapplinger and Pundi et al
All inherited cardiac channelopathies have their diagnostic hallmark. In the case of catecholaminergic polymorphic ventricular tachycardia (CPVT), this is bidirectional ventricular tachycardia during exercise. If all patients with clinical suspicion of CPVT had this diagnostic feature during an exercise stress test in the setting of a structurally normal heart and normal resting ECG, a CPVT clinical diagnosis could easily be established. Unfortunately, in everyday clinical practice, the next new patient coming to medical attention is unlikely to be a textbook case. And this is where genetics come in.
The genetic revolution of the mid-1990s with the first breakthrough discoveries of the genetic substrate underlying inherited arrhythmia syndromes seemed to promise a land where the void created by reduced penetrance and variable expressivity would be filled by a firm genetic diagnosis. Largely, this is indeed what happened and genetics have truly had a major impact on clinical management,1 but from this to a genetic panacea, it is a long way.
A crucial element that was missing in the early days of the genetic revolution was human genome variability. Early scientific reports used 50 to 100 controls to cross-check any genetic finding before assigning it pathogenicity. Who would dare say that now, in the era of the 1000 Genomes Project and of the Exome (ExAC) and Genome Aggregation Consortiums (gnomAD)?2 By now, it is in fact well appreciated that rare genetic variation is paradoxically a rather common finding and that this also holds true for the main CPVT-causative gene, the ryanodine receptor 2 (RYR2).3,4 Just as the next new patient is probably not a textbook case, so the next rare or even novel RYR2 variant identified on genetic testing is not a certainly pathogenic variant either. Unfortunately, this …