Interpreting Incidentally Identified Variants in Genes Associated With Catecholaminergic Polymorphic Ventricular Tachycardia in a Large Cohort of Clinical Whole-Exome Genetic Test Referrals

Abstract

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.

Year in Review in Cardiac Electrophysiology

“…Landstrom et al 29 demonstrated in whole-exome sequencing, incidentally identified catecholaminergic polymorphic VT-associated variants showed a 9% prevalence, but these variants were of undetermined significance, and in the absence of a clinical suspicion of catecholaminergic polymorphic VT, are unlikely to represent markers of true catecholaminergic polymorphic VT pathogenicity.…”

Incidentally identified genetic variants in arrhythmogenic right ventricular cardiomyopathy‐associated genes among children undergoing exome sequencing reflect healthy population variation

“…These results demonstrate that variant frequency in the WES cohort, similar to the control cohort, was driven by contributions from variants in genes that are rarely associated with ARVC cases. Given evidence that disease-specific S:N calculations can distinguish background genetic noise from true pathologic variant burden, this analysis was applied to each gene locus (Landstrom et al, 2017(Landstrom et al, , 2018 Figure 3).…”

“…We have previously shown that amino acid-level S:N can distinguish incidentally identified from pathologic variants based on primary sequence location in genes associated with cardiac channelopathic disease (Landstrom et al, 2017(Landstrom et al, , 2018. We applied this methodology to ARVC-associated gene products.…”

A 14‐year‐old in heart failure with multiple cardiomyopathy variants illustrates a role for signal‐to‐noise analysis in gene test re‐interpretation

“…The same gene can also cause multiple cardiomyopathy subtypes, as seen in TTN (ARVC, DCM, LVNC), LMNA (DCM, HCM, restrictive cardiomyopathy), and DSP (ARVC, DCM) . Further, while increasingly expansive clinical gene testing has allowed more sensitive detection of variants, there has been a rapid increase in the number of “variants of unknown significance” (VUSs) and increased uncertainty in test interpretation . Two phenomenon known to result in non‐Mendelian inheritance of genetic disease further complicate the analysis: (a) Compound heterozygosity whereby two different mutant alleles in the same gene can cause disease in a heterozygous state and (b) multigenic disease whereby multiple mutant alleles in different genes cause disease when each in isolation is insufficient.…”

“…1,4,5 Further, while increasingly expansive clinical gene testing has allowed more sensitive detection of variants, there has been a rapid increase in the number of "variants of unknown significance" (VUSs) and increased uncertainty in test interpretation. 10 Two phenomenon known to result in non-Mendelian inheritance of genetic disease further complicate the analysis: (a) Compound heterozygosity whereby two different mutant alleles in the same gene can cause disease in a heterozygous state and (b) multigenic disease whereby multiple mutant alleles in different genes cause disease when each in isolation is insufficient. Here, we present a case of mixed cardiomyopathy, with pathologically confirmed characteristics of DCM, ARVC, and LVNC, in the context of multiple VUSs in PKP2, PKP4, SYNE2, and TTN.…”