TY - JOUR
T1 - Association of arrhythmia-related genetic variants with phenotypes documented in electronic medical records
AU - Van Driest, Sara L.
AU - Wells, Quinn S.
AU - Stallings, Sarah
AU - Bush, William S.
AU - Gordon, Adam
AU - Nickerson, Deborah A.
AU - Kim, Jerry H.
AU - Crosslin, David R.
AU - Jarvik, Gail P.
AU - Carrell, David S.
AU - Ralston, James D.
AU - Larson, Eric B.
AU - Bielinski, Suzette J.
AU - Olson, Janet E.
AU - Ye, Zi
AU - Kullo, Iftikhar J.
AU - Abul-Husn, Noura S.
AU - Scott, Stuart A.
AU - Bottinger, Erwin
AU - Almoguera, Berta
AU - Connolly, John
AU - Chiavacci, Rosetta
AU - Hakonarson, Hakon
AU - Rasmussen-Torvik, Laura J.
AU - Pan, Vivian
AU - Persell, Stephen D.
AU - Smith, Maureen
AU - Chisholm, Rex L.
AU - Kitchner, Terrie E.
AU - He, Max M.
AU - Brilliant, Murray H.
AU - Wallace, John R.
AU - Doheny, Kimberly F.
AU - Shoemaker, M. Benjamin
AU - Li, Rongling
AU - Manolio, Teri A.
AU - Callis, Thomas E.
AU - Macaya, Daniela
AU - Williams, Marc S.
AU - Carey, David
AU - Kapplinger, Jamie D.
AU - Ackerman, Michael J.
AU - Ritchie, Marylyn D.
AU - Denny, Joshua C.
AU - Roden, Dan M.
N1 - Funding Information:
All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Larson reported having received royalties from UpToDate. Dr Persell reported having received grants from Pfizer. Dr Ackerman reported having consulted for Boston Scientific, Gilead Sciences, Medtronic, and St Jude Medical and having received along with Mayo Clinic Ventures sales-based royalties from Transgenomic for their FAMILION-LQTS and FAMILION-CPVT genetic tests. The eMERGE Network was initiated and funded by the National Human Genome Research Institute (NHGRI) through the following grants: U01HG006828 (Cincinnati Children''s Hospital Medical Center/Boston Children''s Hospital); U01HG006830 (Children''s Hospital of Philadelphia); U01HG006389 (Essentia Institute of Rural Health, Marshfield Clinic Research Foundation, and Pennsylvania State University); U01HG006382 (Geisinger Clinic); U01HG006375 (Group Health Cooperative, University of Washington); U01HG006379 (Mayo Clinic); U01HG006380 (Icahn School of Medicine at Mount Sinai); U01HG006388 (Northwestern University); U01HG006378 (Vanderbilt University Medical Center); and U01HG006385 (Vanderbilt University Medical Center serving as the Coordinating Center). Additional support was provided by National Center for Advancing Translational Sciences (NCATS) grant UL1TR000427 (University ofWisconsin, Marshfield Clinic); National Institute on Aging grant UO1AG006781 (Group Health Cooperative, University ofWashington); NHGRI grant U01HG004438 (Johns Hopkins School of Medicine); NCATS grant UL1TR000445 (Vanderbilt University Medical Center); National Institute of General Medical Sciences grants U19GM61388, R01GM28157, U01HG005137, R01CA138461, R01AG034676; and theWindland Smith Rice Comprehensive Sudden Cardiac Death Program (Mayo Clinic). The sequencing platform was developed by the next-generation sequencing centers of the Pharmacogenomics Research Network supported by National Institutes of Health grants U19GM61388, U19HL069757, and U01GM097119.
Publisher Copyright:
Copyright © 2016 American Medical Association. All rights reserved.
PY - 2016/1/5
Y1 - 2016/1/5
N2 - 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.
AB - 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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U2 - 10.1001/jama.2015.17701
DO - 10.1001/jama.2015.17701
M3 - Article
C2 - 26746457
AN - SCOPUS:84953297333
SN - 0098-7484
VL - 315
SP - 47
EP - 57
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
IS - 1
ER -