Yield of the RYR2 Genetic Test in Suspected Catecholaminergic Polymorphic Ventricular Tachycardia and Implications for Test Interpretation

Jamie D. Kapplinger, Krishna N. Pundi, Nicholas Larson, Thomas E. Callis, David J. Tester, Hennie Bikker, Arthur A.M. Wilde, Michael John Ackerman

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

BACKGROUND: Pathogenic RYR2 variants account for ≈60% of clinically definite cases of catecholaminergic polymorphic ventricular tachycardia. However, the rate of rare benign RYR2 variants identified in the general population remains a challenge for genetic test interpretation. Therefore, we examined the results of the RYR2 genetic test among patients referred for commercial genetic testing and examined factors impacting variant interpretability. METHODS: Frequency and location comparisons were made for RYR2 variants identified among 1355 total patients of varying clinical certainty and 60 706 Exome Aggregation Consortium controls. The impact of the clinical phenotype on the yield of RYR2 variants was examined. Six in silico tools were assessed using patient- and control-derived variants. RESULTS: A total of 18.2% (218/1200) of patients referred for commercial testing hosted rare RYR2 variants, statistically less than the 59% (46/78) yield among clinically definite cases, resulting in a much higher potential genetic false discovery rate among referrals considering the 3.2% background rate of rare, benign RYR2 variants. Exclusion of clearly putative pathogenic variants further complicates the interpretation of the next novel RYR2 variant. Exonic/topologic analyses revealed overrepresentation of patient variants in exons covering only one third of the protein. In silico tools largely failed to show evidence toward enhancement of variant interpretation. CONCLUSIONS: Current expert recommendations have resulted in increased use of RYR2 genetic testing in patients with questionable clinical phenotypes. Using the largest to date catecholaminergic polymorphic ventricular tachycardia patient versus control comparison, this study highlights important variables in the interpretation of variants to overcome the 3.2% background rate that confounds RYR2 variant interpretation.

Original languageEnglish (US)
Pages (from-to)e001424
JournalCirculation. Genomic and precision medicine
Volume11
Issue number2
DOIs
StatePublished - Feb 1 2018
Externally publishedYes

Fingerprint

Genetic Testing
Computer Simulation
Exome
Phenotype
Polymorphic catecholergic ventricular tachycardia
Exons
Referral and Consultation
Population
Proteins

Keywords

  • cardiologist
  • exons
  • genetic testing
  • phenotype
  • uncertainty

Cite this

Yield of the RYR2 Genetic Test in Suspected Catecholaminergic Polymorphic Ventricular Tachycardia and Implications for Test Interpretation. / Kapplinger, Jamie D.; Pundi, Krishna N.; Larson, Nicholas; Callis, Thomas E.; Tester, David J.; Bikker, Hennie; Wilde, Arthur A.M.; Ackerman, Michael John.

In: Circulation. Genomic and precision medicine, Vol. 11, No. 2, 01.02.2018, p. e001424.

Research output: Contribution to journalArticle

Kapplinger, Jamie D. ; Pundi, Krishna N. ; Larson, Nicholas ; Callis, Thomas E. ; Tester, David J. ; Bikker, Hennie ; Wilde, Arthur A.M. ; Ackerman, Michael John. / Yield of the RYR2 Genetic Test in Suspected Catecholaminergic Polymorphic Ventricular Tachycardia and Implications for Test Interpretation. In: Circulation. Genomic and precision medicine. 2018 ; Vol. 11, No. 2. pp. e001424.
@article{3100fdaf4a084e52a46a883d7f4435d7,
title = "Yield of the RYR2 Genetic Test in Suspected Catecholaminergic Polymorphic Ventricular Tachycardia and Implications for Test Interpretation",
abstract = "BACKGROUND: Pathogenic RYR2 variants account for ≈60{\%} of clinically definite cases of catecholaminergic polymorphic ventricular tachycardia. However, the rate of rare benign RYR2 variants identified in the general population remains a challenge for genetic test interpretation. Therefore, we examined the results of the RYR2 genetic test among patients referred for commercial genetic testing and examined factors impacting variant interpretability. METHODS: Frequency and location comparisons were made for RYR2 variants identified among 1355 total patients of varying clinical certainty and 60 706 Exome Aggregation Consortium controls. The impact of the clinical phenotype on the yield of RYR2 variants was examined. Six in silico tools were assessed using patient- and control-derived variants. RESULTS: A total of 18.2{\%} (218/1200) of patients referred for commercial testing hosted rare RYR2 variants, statistically less than the 59{\%} (46/78) yield among clinically definite cases, resulting in a much higher potential genetic false discovery rate among referrals considering the 3.2{\%} background rate of rare, benign RYR2 variants. Exclusion of clearly putative pathogenic variants further complicates the interpretation of the next novel RYR2 variant. Exonic/topologic analyses revealed overrepresentation of patient variants in exons covering only one third of the protein. In silico tools largely failed to show evidence toward enhancement of variant interpretation. CONCLUSIONS: Current expert recommendations have resulted in increased use of RYR2 genetic testing in patients with questionable clinical phenotypes. Using the largest to date catecholaminergic polymorphic ventricular tachycardia patient versus control comparison, this study highlights important variables in the interpretation of variants to overcome the 3.2{\%} background rate that confounds RYR2 variant interpretation.",
keywords = "cardiologist, exons, genetic testing, phenotype, uncertainty",
author = "Kapplinger, {Jamie D.} and Pundi, {Krishna N.} and Nicholas Larson and Callis, {Thomas E.} and Tester, {David J.} and Hennie Bikker and Wilde, {Arthur A.M.} and Ackerman, {Michael John}",
year = "2018",
month = "2",
day = "1",
doi = "10.1161/CIRCGEN.116.001424",
language = "English (US)",
volume = "11",
pages = "e001424",
journal = "Circulation. Genomic and precision medicine",
issn = "1942-325X",
publisher = "Lippincott Williams and Wilkins Ltd.",
number = "2",

}

TY - JOUR

T1 - Yield of the RYR2 Genetic Test in Suspected Catecholaminergic Polymorphic Ventricular Tachycardia and Implications for Test Interpretation

AU - Kapplinger, Jamie D.

AU - Pundi, Krishna N.

AU - Larson, Nicholas

AU - Callis, Thomas E.

AU - Tester, David J.

AU - Bikker, Hennie

AU - Wilde, Arthur A.M.

AU - Ackerman, Michael John

PY - 2018/2/1

Y1 - 2018/2/1

N2 - BACKGROUND: Pathogenic RYR2 variants account for ≈60% of clinically definite cases of catecholaminergic polymorphic ventricular tachycardia. However, the rate of rare benign RYR2 variants identified in the general population remains a challenge for genetic test interpretation. Therefore, we examined the results of the RYR2 genetic test among patients referred for commercial genetic testing and examined factors impacting variant interpretability. METHODS: Frequency and location comparisons were made for RYR2 variants identified among 1355 total patients of varying clinical certainty and 60 706 Exome Aggregation Consortium controls. The impact of the clinical phenotype on the yield of RYR2 variants was examined. Six in silico tools were assessed using patient- and control-derived variants. RESULTS: A total of 18.2% (218/1200) of patients referred for commercial testing hosted rare RYR2 variants, statistically less than the 59% (46/78) yield among clinically definite cases, resulting in a much higher potential genetic false discovery rate among referrals considering the 3.2% background rate of rare, benign RYR2 variants. Exclusion of clearly putative pathogenic variants further complicates the interpretation of the next novel RYR2 variant. Exonic/topologic analyses revealed overrepresentation of patient variants in exons covering only one third of the protein. In silico tools largely failed to show evidence toward enhancement of variant interpretation. CONCLUSIONS: Current expert recommendations have resulted in increased use of RYR2 genetic testing in patients with questionable clinical phenotypes. Using the largest to date catecholaminergic polymorphic ventricular tachycardia patient versus control comparison, this study highlights important variables in the interpretation of variants to overcome the 3.2% background rate that confounds RYR2 variant interpretation.

AB - BACKGROUND: Pathogenic RYR2 variants account for ≈60% of clinically definite cases of catecholaminergic polymorphic ventricular tachycardia. However, the rate of rare benign RYR2 variants identified in the general population remains a challenge for genetic test interpretation. Therefore, we examined the results of the RYR2 genetic test among patients referred for commercial genetic testing and examined factors impacting variant interpretability. METHODS: Frequency and location comparisons were made for RYR2 variants identified among 1355 total patients of varying clinical certainty and 60 706 Exome Aggregation Consortium controls. The impact of the clinical phenotype on the yield of RYR2 variants was examined. Six in silico tools were assessed using patient- and control-derived variants. RESULTS: A total of 18.2% (218/1200) of patients referred for commercial testing hosted rare RYR2 variants, statistically less than the 59% (46/78) yield among clinically definite cases, resulting in a much higher potential genetic false discovery rate among referrals considering the 3.2% background rate of rare, benign RYR2 variants. Exclusion of clearly putative pathogenic variants further complicates the interpretation of the next novel RYR2 variant. Exonic/topologic analyses revealed overrepresentation of patient variants in exons covering only one third of the protein. In silico tools largely failed to show evidence toward enhancement of variant interpretation. CONCLUSIONS: Current expert recommendations have resulted in increased use of RYR2 genetic testing in patients with questionable clinical phenotypes. Using the largest to date catecholaminergic polymorphic ventricular tachycardia patient versus control comparison, this study highlights important variables in the interpretation of variants to overcome the 3.2% background rate that confounds RYR2 variant interpretation.

KW - cardiologist

KW - exons

KW - genetic testing

KW - phenotype

KW - uncertainty

UR - http://www.scopus.com/inward/record.url?scp=85050704284&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85050704284&partnerID=8YFLogxK

U2 - 10.1161/CIRCGEN.116.001424

DO - 10.1161/CIRCGEN.116.001424

M3 - Article

VL - 11

SP - e001424

JO - Circulation. Genomic and precision medicine

JF - Circulation. Genomic and precision medicine

SN - 1942-325X

IS - 2

ER -