title: 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 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.
  
  
  RESULTS
  CPVT-associated genesRYR2andCASQ2variants 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.
authors.affiliation: From the Department of Pediatrics, Section of Pediatric Cardiology (A.P.L., A.L.D.-S., C.Y.M., S.O.V., Y.F., H.D.A., D.J.P., J.J.K.) and Cardiovascular Research Institute (A.P.L., M.J.M.), Baylor College of Medicine, Houston, TX; and Baylor Miraca Genetics Laboratories, Houston, TX (J.A.R., Y.Y.). landstro@bcm.edu jjkim@texaschildrens.org.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Landstrom
authors.affiliation: From the Department of Pediatrics, Section of Pediatric Cardiology (A.P.L., A.L.D.-S., C.Y.M., S.O.V., Y.F., H.D.A., D.J.P., J.J.K.) and Cardiovascular Research Institute (A.P.L., M.J.M.), Baylor College of Medicine, Houston, TX; and Baylor Miraca Genetics Laboratories, Houston, TX (J.A.R., Y.Y.).
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Dailey-Schwartz
authors.affiliation: From the Department of Pediatrics, Section of Pediatric Cardiology (A.P.L., A.L.D.-S., C.Y.M., S.O.V., Y.F., H.D.A., D.J.P., J.J.K.) and Cardiovascular Research Institute (A.P.L., M.J.M.), Baylor College of Medicine, Houston, TX; and Baylor Miraca Genetics Laboratories, Houston, TX (J.A.R., Y.Y.).
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: From the Department of Pediatrics, Section of Pediatric Cardiology (A.P.L., A.L.D.-S., C.Y.M., S.O.V., Y.F., H.D.A., D.J.P., J.J.K.) and Cardiovascular Research Institute (A.P.L., M.J.M.), Baylor College of Medicine, Houston, TX; and Baylor Miraca Genetics Laboratories, Houston, TX (J.A.R., Y.Y.).
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: From the Department of Pediatrics, Section of Pediatric Cardiology (A.P.L., A.L.D.-S., C.Y.M., S.O.V., Y.F., H.D.A., D.J.P., J.J.K.) and Cardiovascular Research Institute (A.P.L., M.J.M.), Baylor College of Medicine, Houston, TX; and Baylor Miraca Genetics Laboratories, Houston, TX (J.A.R., Y.Y.).
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: McLean
authors.affiliation: From the Department of Pediatrics, Section of Pediatric Cardiology (A.P.L., A.L.D.-S., C.Y.M., S.O.V., Y.F., H.D.A., D.J.P., J.J.K.) and Cardiovascular Research Institute (A.P.L., M.J.M.), Baylor College of Medicine, Houston, TX; and Baylor Miraca Genetics Laboratories, Houston, TX (J.A.R., Y.Y.).
authors.forename: Christina Y
authors.initials: CY
authors.lastname: Miyake
authors.affiliation: From the Department of Pediatrics, Section of Pediatric Cardiology (A.P.L., A.L.D.-S., C.Y.M., S.O.V., Y.F., H.D.A., D.J.P., J.J.K.) and Cardiovascular Research Institute (A.P.L., M.J.M.), Baylor College of Medicine, Houston, TX; and Baylor Miraca Genetics Laboratories, Houston, TX (J.A.R., Y.Y.).
authors.forename: Santiago O
authors.initials: SO
authors.lastname: Valdes
authors.affiliation: From the Department of Pediatrics, Section of Pediatric Cardiology (A.P.L., A.L.D.-S., C.Y.M., S.O.V., Y.F., H.D.A., D.J.P., J.J.K.) and Cardiovascular Research Institute (A.P.L., M.J.M.), Baylor College of Medicine, Houston, TX; and Baylor Miraca Genetics Laboratories, Houston, TX (J.A.R., Y.Y.).
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Fan
authors.affiliation: From the Department of Pediatrics, Section of Pediatric Cardiology (A.P.L., A.L.D.-S., C.Y.M., S.O.V., Y.F., H.D.A., D.J.P., J.J.K.) and Cardiovascular Research Institute (A.P.L., M.J.M.), Baylor College of Medicine, Houston, TX; and Baylor Miraca Genetics Laboratories, Houston, TX (J.A.R., Y.Y.).
authors.forename: Hugh D
authors.initials: HD
authors.lastname: Allen
authors.affiliation: From the Department of Pediatrics, Section of Pediatric Cardiology (A.P.L., A.L.D.-S., C.Y.M., S.O.V., Y.F., H.D.A., D.J.P., J.J.K.) and Cardiovascular Research Institute (A.P.L., M.J.M.), Baylor College of Medicine, Houston, TX; and Baylor Miraca Genetics Laboratories, Houston, TX (J.A.R., Y.Y.).
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Penny
authors.affiliation: From the Department of Pediatrics, Section of Pediatric Cardiology (A.P.L., A.L.D.-S., C.Y.M., S.O.V., Y.F., H.D.A., D.J.P., J.J.K.) and Cardiovascular Research Institute (A.P.L., M.J.M.), Baylor College of Medicine, Houston, TX; and Baylor Miraca Genetics Laboratories, Houston, TX (J.A.R., Y.Y.). landstro@bcm.edu jjkim@texaschildrens.org.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Kim
mesh_terms: D002155:Calsequestrin / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D059472:Exome; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D014644:Genetic Variation; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D011237:Predictive Value of Tests; D012017:Referral and Consultation; D012189:Retrospective Studies; D012307:Risk Factors; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics; D017180:Tachycardia, Ventricular / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: C443109:CASQ2 protein, human; D002155:Calsequestrin; D005819:Genetic Markers; D019837:Ryanodine Receptor Calcium Release Channel
keywords: Casq2; RyR2; catecholamingeric polymorphic ventricular tachycardia; exome; genetic testing; genetics; variant of undetermined significance