Background The rapid expansion of genetic testing has led to increased utilization of clinical whole exome sequencing (WES). Clinicians and genetic researchers are being faced with assessing risk of disease vulnerability from incidentally identified genetic variants which is typified by variants found in genes associated with sudden death-predisposing CPVT. We sought to determine whether incidentally identified variants in genes associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) from WES clinical testing represent disease-associated biomarkers. Methods and Results CPVT-associated genes RYR2 and CASQ2 variants were identified in one of the world’s largest collections of clinical WES referral tests (N = 6517, Baylor Miraca Genetics Laboratories) and compared to a control cohort of ostensibly healthy individuals (N = 60,706) and a case cohort of CPVT cases (N = 155). Within the WES cohort, the rate of rare variants in CPVT-associated genes was 8.8% compared to 6.0% among controls and 60.0% among cases. There was a predominance of variants of undetermined significance (VUS, 97.7%). Following protein topology mapping, WES variants colocalized more frequently to residues with variants found in controls compared to cases. Retrospective clinical evaluation of individuals referred to our institution with WES-positive variants demonstrated no evidence of clinical CPVT in individuals with a low pre-test clinical suspicion for CPVT. Conclusions The prevalence of incidentally CPVT-associated variants is ~9% among WES tests. VUSs in CPVT-associated genes in WES genetic testing, in the absence of clinical suspicion for CPVT, are unlikely to represent markers of CPVT pathogenicity.

The prevalence of incidentally identified LQTS-associated variants is ∼38% among WES tests. These variants most likely represent benign healthy background genetic variation rather than disease-associated mutations.

S ARS-CoV-2 infection has been associated with cardiovascular disease in children, but which children need cardiac evaluation is unclear . We describe our experience evaluating 206 children for cardiac disease following S ARS-CoV-2 infection (one of whom had ventricular ectopy) and propose a new guideline for management of these children. Routine cardiac screening after S ARS-CoV-2 infection in children without any cardiac signs or symptoms does not appear to be high yield.