Association of Arrhythmia-Related Genetic Variants With Phenotypes Documented in Electronic Medical Records

Van Driest, Sara L.; Wells, Quinn S.; Stallings, Sarah; Bush, William S.; Gordon, Adam; Nickerson, Deborah A.; Kim, Jerry H.; Crosslin, David R.; Jarvik, Gail P.; Carrell, David S.; Ralston, James D.; Larson, Eric B.; Bielinski, Suzette J.; Olson, Janet E.; Ye, Zi; Kullo, Iftikhar J.; Abul-Husn, Noura S.; Scott, Stuart A.; Bottinger, Erwin; Almoguera, Berta; Connolly, John; Chiavacci, Rosetta; Hakonarson, Hakon; Rasmussen-Torvik, Laura J.; Pan, Vivian; Persell, Stephen D.; Smith, Maureen; Chisholm, Rex L.; Kitchner, Terrie E.; He, Max M.; Brilliant, Murray H.; Wallace, John R.; Doheny, Kimberly F.; Shoemaker, M. Benjamin; Li, Rongling; Manolio, Teri A.; Callis, Thomas E.; Macaya, Daniela; Williams, Marc S.; Carey, David; Kapplinger, Jamie D.; Ackerman, Michael J.; Ritchie, Marylyn D.; Denny, Joshua C.; Roden, Dan M.

doi:10.1001/jama.2015.17701

Cited by 170Cardiac electrophysiology and arrhythmiasGenomics and Rare DiseasesGenetic Associations and Epidemiology

Association of Arrhythmia-Related Genetic Variants With Phenotypes Documented in Electronic Medical Records

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Van Driest, Sara L., Wells, Quinn S., Stallings, Sarah, Bush, William S., Gordon, Adam, Nickerson, Deborah A., Kim, Jerry H., Crosslin, David R. +37 more·2016·JAMA

DOI 10.1001/jama.2015.17701PMC PMC4758131

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Abstract

IMPORTANCE: Large-scale DNA sequencing identifies incidental rare variants in established Mendelian disease genes, but the frequency of related clinical phenotypes in unselected patient populations is not well established. Phenotype data from electronic medical records (EMRs) may provide a resource to assess the clinical relevance of rare variants. OBJECTIVE: To determine the clinical phenotypes from EMRs for individuals with variants designated as pathogenic by expert review in arrhythmia susceptibility genes. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study included 2022 individuals recruited for nonantiarrhythmic drug exposure phenotypes from October 5, 2012, to September 30, 2013, for the Electronic Medical Records and Genomics Network Pharmacogenomics project from 7 US academic medical centers. Variants in SCN5A and KCNH2, disease genes for long QT and Brugada syndromes, were assessed for potential pathogenicity by 3 laboratories with ion channel expertise and by comparison with the ClinVar database. Relevant phenotypes were determined from EMRs, with data available from 2002 (or earlier for some sites) through September 10, 2014. EXPOSURES: One or more variants designated as pathogenic in SCN5A or KCNH2. MAIN OUTCOMES AND MEASURES: Arrhythmia or electrocardiographic (ECG) phenotypes defined by International Classification of Diseases, Ninth Revision (ICD-9) codes, ECG data, and manual EMR review. RESULTS: Among 2022 study participants (median age, 61 years [interquartile range, 56-65 years]; 1118 [55%] female; 1491 [74%] white), a total of 122 rare (minor allele frequency <0.5%) nonsynonymous and splice-site variants in 2 arrhythmia susceptibility genes were identified in 223 individuals (11% of the study cohort). Forty-two variants in 63 participants were designated potentially pathogenic by at least 1 laboratory or ClinVar, with low concordance across laboratories (Cohen κ = 0.26). An ICD-9 code for arrhythmia was found in 11 of 63 (17%) variant carriers vs 264 of 1959 (13%) of those without variants (difference, +4%; 95% CI, -5% to +13%; P = .35). In the 1270 (63%) with ECGs, corrected QT intervals were not different in variant carriers vs those without (median, 429 vs 439 milliseconds; difference, -10 milliseconds; 95% CI, -16 to +3 milliseconds; P = .17). After manual review, 22 of 63 participants (35%) with designated variants had any ECG or arrhythmia phenotype, and only 2 had corrected QT interval longer than 500 milliseconds. CONCLUSIONS AND RELEVANCE: Among laboratories experienced in genetic testing for cardiac arrhythmia disorders, there was low concordance in designating SCN5A and KCNH2 variants as pathogenic. In an unselected population, the putatively pathogenic genetic variants were not associated with an abnormal phenotype. These findings raise questions about the implications of notifying patients of incidental genetic findings.

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The remaining 29 are suggested to be due to a combination of incomplete penetrance, late onset of disease, mild symptoms not seeking medical attention, unrecognised technical issues with sequencing or annotation, or dubious evidence to support the gene-phenotype assignment.
“We suggest that the remaining 29 are due to a combination of incomplete penetrance[12–16], late onset of disease (i.e. not yet having occurred), individuals with mild symptoms not seeking medical attention, unrecognised technical issues with sequencing or annotation (e.g. tissue specific alternative splicing), or dubious evidence to support the gene-phenotype assignment”
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Authors: Van Driest, S. L., Wells, Q. S., Stallings, S., Bush, W. S., Gordon, A., Nickerson, D. A., Kim, J. H., Crosslin, D. R., Jarvik, G. P., Carrell, D. S., Ralston, J. D., Larson, E. B., Bielinski, S. J., Olson, J. E., Ye, Z., Kullo, I. J., Abul-Husn, N. S., Scott, S. A., Bottinger, E., Almoguera, B., Connolly, J., Chiavacci, R., Hakonarson, H., Rasmussen-Torvik, L. J., Pan, V., Persell, S. D., Smith, M., Chisholm, R. L., Kitchner, T. E., He, M. M., Brilliant, M. H., Wallace, J. R., Doheny, K. F., Shoemaker, M. B., Li, R., Manolio, T. A., Callis, T. E., Macaya, D., Williams, M. S., Carey, D., Kapplinger, J. D., Ackerman, M. J., Ritchie, M. D., Denny, J. C., & Roden, D. M.
Affiliations: Vanderbilt University Medical Center, Nashville, Tennessee
Vanderbilt University Medical Center (US)
Case Western Reserve University (US)
University of Washington, Seattle
University of Washington (US)
Kaiser Permanente Washington Health Research Institute (US)
Mayo Clinic (US)
Icahn School of Medicine at Mount Sinai, New York, New York
Icahn School of Medicine at Mount Sinai (US)
Children's Hospital of Philadelphia (US)
Northwestern University Feinberg School of Medicine, Chicago, Illinois
Northwestern University (US)
Marshfield Clinic Research Foundation (US)
Pennsylvania State University (US)
Johns Hopkins University (US)
National Institutes of Health (US)
Transgenomic (United States) (US)
GeneDx, Gaithersburg, Maryland
Geisinger Health System (US)
Corresponding author: Roden, Dan M.
ORCID: Wells, Quinn S.
Stallings, Sarah
Bush, William S.
Nickerson, Deborah A.
Crosslin, David R.
Jarvik, Gail P.
Carrell, David S.
Ralston, James D.
Larson, Eric B.
Bielinski, Suzette J.
Olson, Janet E.
Ye, Zi
Kullo, Iftikhar J.
Scott, Stuart A.
Almoguera, Berta
Connolly, John
Hakonarson, Hakon
Pan, Vivian
Persell, Stephen D.
Smith, Maureen
Chisholm, Rex L.
He, Max M.
Brilliant, Murray H.
Wallace, John R.
Doheny, Kimberly F.
Shoemaker, M. Benjamin
Manolio, Teri A.
Callis, Thomas E.
Macaya, Daniela
Williams, Marc S.
Carey, David
Ackerman, Michael J.
Ritchie, Marylyn D.
Denny, Joshua C.
Roden, Dan M.
Venue: JAMA
Publisher: American Medical Association (AMA)
Published: 2016-01-05
Volume: 315
Issue: 1
Pages: 47
ISSN: 0002-9955 (ISSN-L)
0098-7484
DOI: 10.1001/jama.2015.17701
PMC: PMC4758131
OpenAlex: W2227098102
Cited by: 170
References: 38
Citations by year: 2026: 2 · 2025: 6 · 2024: 8 · 2023: 5 · 2022: 9 · 2021: 14 · 2020: 19 · 2019: 21 · 2018: 28 · 2017: 26 · 2016: 31
FWCI: 29.10
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: JAMA (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Children's Hospital of Philadelphia
National Institutes of Health (UL1TR000427, UL1TR000445)
National Institute on Aging (R01AG034676, U01AG006781)
National Heart, Lung, and Blood Institute (U19HL069757, F30HL127904)
National Human Genome Research Institute (U01HG006385, U01HG006379, U01HG006830, U01HG008657, U01HG008701, U01HG004438, U01HG006375, U01HG008673, U01HG008672, U01HG006380, U01HG006382, U01HG006828, U01HG005137, U01HG006378, U01HG008684, U01HG006388, U01HG006389)
National Cancer Institute (R01CA138461)
National Institute of General Medical Sciences (U19GM61388, R01-GM-28157, U19GM061388, R01GM028157, U01GM097119, K23GM104401, T32GM007454, T32GM082773)
National Center for Advancing Translational Sciences
Topics: Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords: rare variants, SCN5A, KCNH2, long QT syndrome, Brugada syndrome, pathogenicity assessment, clinical phenotype, cardiac arrhythmias, electrocardiographic abnormalities, electronic health records, pharmacogenomics, ClinVar, Mendelian disease genes, ICD-9 codes, genotype-phenotype correlation
MeSH terms: ERG1 Potassium Channel, Aged, Aged, 80 and over, Alleles, Arrhythmias, Cardiac, Female, Genetic Testing, Heterozygote, Humans, Laboratories, Male, Middle Aged, Phenotype, Prospective Studies, Random Allocation, Genetic Variation, Statistics, Nonparametric, Genetic Predisposition to Disease, Mutation, Missense, Genomics, Incidental Findings, Ether-A-Go-Go Potassium Channels, Brugada Syndrome, Young Adult, Electronic Health Records, NAV1.5 Voltage-Gated Sodium Channel

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