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

Publication ,  Journal Article
Landstrom, AP; Dailey-Schwartz, AL; Rosenfeld, JA; Yang, Y; McLean, MJ; Miyake, CY; Valdes, SO; Fan, Y; Allen, HD; Penny, DJ; Kim, JJ
Published in: Circ Arrhythm Electrophysiol
April 2017

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 catecholaminergic polymorphic ventricular tachycardia (CPVT). We sought to determine whether incidentally identified variants in genes associated with 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 with 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 with 6.0% among controls and 60.0% among cases. There was a predominance of variants of undetermined significance (97.7%). After protein topology mapping, WES variants colocalized more frequently to residues with variants found in controls compared with 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 pretest clinical suspicion for CPVT. CONCLUSIONS: The prevalence of incidentally identified CPVT-associated variants is ≈9% among WES tests. Variants of undetermined significances in CPVT-associated genes in WES genetic testing, in the absence of clinical suspicion for CPVT, are unlikely to represent markers of CPVT pathogenicity.

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Published In

Circ Arrhythm Electrophysiol

DOI

EISSN

1941-3084

Publication Date

April 2017

Volume

10

Issue

4

Location

United States

Related Subject Headings

  • Tachycardia, Ventricular
  • Ryanodine Receptor Calcium Release Channel
  • Risk Factors
  • Retrospective Studies
  • Referral and Consultation
  • Predictive Value of Tests
  • Phenotype
  • Mutation
  • Male
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Landstrom, A. P., Dailey-Schwartz, A. L., Rosenfeld, J. A., Yang, Y., McLean, M. J., Miyake, C. Y., … Kim, J. J. (2017). Interpreting Incidentally Identified Variants in Genes Associated With Catecholaminergic Polymorphic Ventricular Tachycardia in a Large Cohort of Clinical Whole-Exome Genetic Test Referrals. Circ Arrhythm Electrophysiol, 10(4). https://doi.org/10.1161/CIRCEP.116.004742
Landstrom, Andrew P., Andrew L. Dailey-Schwartz, Jill A. Rosenfeld, Yaping Yang, Margaret J. McLean, Christina Y. Miyake, Santiago O. Valdes, et al. “Interpreting Incidentally Identified Variants in Genes Associated With Catecholaminergic Polymorphic Ventricular Tachycardia in a Large Cohort of Clinical Whole-Exome Genetic Test Referrals.Circ Arrhythm Electrophysiol 10, no. 4 (April 2017). https://doi.org/10.1161/CIRCEP.116.004742.
Landstrom AP, Dailey-Schwartz AL, Rosenfeld JA, Yang Y, McLean MJ, Miyake CY, et al. Interpreting Incidentally Identified Variants in Genes Associated With Catecholaminergic Polymorphic Ventricular Tachycardia in a Large Cohort of Clinical Whole-Exome Genetic Test Referrals. Circ Arrhythm Electrophysiol. 2017 Apr;10(4).
Landstrom, Andrew P., et al. “Interpreting Incidentally Identified Variants in Genes Associated With Catecholaminergic Polymorphic Ventricular Tachycardia in a Large Cohort of Clinical Whole-Exome Genetic Test Referrals.Circ Arrhythm Electrophysiol, vol. 10, no. 4, Apr. 2017. Pubmed, doi:10.1161/CIRCEP.116.004742.
Landstrom AP, Dailey-Schwartz AL, Rosenfeld JA, Yang Y, McLean MJ, Miyake CY, Valdes SO, Fan Y, Allen HD, Penny DJ, Kim JJ. Interpreting Incidentally Identified Variants in Genes Associated With Catecholaminergic Polymorphic Ventricular Tachycardia in a Large Cohort of Clinical Whole-Exome Genetic Test Referrals. Circ Arrhythm Electrophysiol. 2017 Apr;10(4).

Published In

Circ Arrhythm Electrophysiol

DOI

EISSN

1941-3084

Publication Date

April 2017

Volume

10

Issue

4

Location

United States

Related Subject Headings

  • Tachycardia, Ventricular
  • Ryanodine Receptor Calcium Release Channel
  • Risk Factors
  • Retrospective Studies
  • Referral and Consultation
  • Predictive Value of Tests
  • Phenotype
  • Mutation
  • Male
  • Humans