HHS Public Access Author manuscript Author Manuscript

JAMA. Author manuscript; available in PMC 2017 January 05. Published in final edited form as: JAMA. 2016 January 5; 315(1): 47–57. doi:10.1001/jama.2015.17701.

Association of arrhythmia-related genetic variants with phenotypes documented in electronic medical records

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Sara L. Van Driest, M.D., Ph.D.1, Quinn S. Wells, M.D., Pharm.D., M.S.C.I.1, Sarah Stallings, Ph.D.1, William S. Bush, Ph.D., M.S.1,2, Adam Gordon, Ph.D.3, Deborah A. Nickerson, Ph.D. 3, Jerry H. Kim, MD.3, David R. Crosslin, Ph.D.3, Gail P. Jarvik, M.D., Ph.D.3, David S. Carrell, Ph.D.4, James Ralston, M.D., M.P.H.4, Eric B. Larson, M.D., M.P.H.4, Suzette J. Bielinski, Ph.D.5, Janet E. Olson, Ph.D.5, Zi Ye, M.D., Ph.D.5, Iftikhar J. Kullo, M.D.5, Noura S. Abul-Husn, M.D., Ph.D.6, Stuart A. Scott, Ph.D.6, Erwin Bottinger, M.D.6, Berta Almoguera, Ph.D.7, John Connolly, Ph.D.7, Rosetta Chiavacci, B.S.N., C.C.R.C.7, Hakon Hakonarson, M.D., Ph.D.7,8, Laura J. Rasmussen-Torvik, Ph.D.9, Vivian Pan, M.S., C.G.C.9, Stephen D. Persell, M.D., M.P.H.9, Maureen Smith, M.S., C.G.C.9, Rex L. Chisholm, Ph.D.9, Terrie E. Kitchner, C.C.R.P10, Max M. He, Ph.D.10, Murray H. Brilliant, Ph.D.10, John R. Wallace, M.S.11, Kimberly F. Doheny, Ph.D.12, M. Benjamin Shoemaker, M.D., M.S.C.I.1, Rongling Li, M.D., Ph.D., M.P.H.13, Teri A. Manolio, M.D., Ph.D.13, Thomas E. Callis, Ph.D.14, Daniela Macaya, M.Q.C., F.A.C.M.G.15, Marc S. Williams, M.D.16, David Carey, Ph.D.16, Jamie D. Kapplinger, B.A.5, Michael J. Ackerman, M.D., Ph.D.5, Marylyn D. Ritchie, Ph.D. 11,16, Joshua C. Denny, M.D., M.S.1, and Dan M. Roden, M.D.1 1Vanderbilt

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2Case

University Medical Center, Nashville, TN

Western Reserve University, Cleveland, OH

3University 4Group

of Washington, Seattle, WA

Health Research Institute, Seattle, WA

5Mayo

Clinic, Rochester, MN

6Icahn

School of Medicine at Mount Sinai, New York, NY

7The

Children’s Hospital of Philadelphia, Philadelphia, PA

8The

Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

9Northwestern

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10Marshfield 11The

University Feinberg School of Medicine, Chicago, IL

Clinic Research Foundation, Marshfield, WI

Pennsylvania State University, University Park, PA

Corresponding Author: Dan Roden, 2215B Garland Avenue, Room 1285, Nashville, Tennessee 37232-0575, Phone: (615) 322-0067; Fax: (615) 343-4522; [email protected]. Role of the Funder/Sponsor: NHGRI program staff participated with eMERGE investigators in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication, and are accordingly included as authors. DISCLOSURES MJA and Mayo Clinic Ventures receive sales-based royalties from Transgenomic for their FAMILION-LQTS and FAMILION-CPVT genetic tests.

Van Driest et al. 12Johns

Page 2

Hopkins School of Medicine, Baltimore, MD

Author Manuscript

13National

Human Genome Research Institute, National Institutes of Health, Bethesda, MD

14Transgenomic, 15GeneDx,

New Haven, CT

Gaithersburg, MD

16Geisinger

Health System, Danville, PA

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 may provide a resource to assess the clinical relevance of rare variants.

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Objective—To determine the clinical phenotypes from electronic medical records in 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 non-antiarrhythmic drug exposure phenotypes from 10/5/2012 to 9/30/2013 for the Electronic Medical Records and Genomics Network Pharmacogenomics project from seven US academic medical centers. Variants in SCN5A and KCNH2, disease genes for long QT and Brugada Syndromes, were assessed for potential pathogenicity by three laboratories with ion channel expertise and the ClinVar database. Relevant phenotypes were determined from electronic medical records, with data available through 9/10/2014. Exposure—One or more variants designated as pathogenic in SCN5A or KCNH2.

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Main Outcome Measures—Arrhythmia or electrocardiographic (ECG) phenotypes defined by ICD9 codes, ECG data, and manual electronic medical record review.

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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 0.99

Atrial Fibrillation

92 (5%)

88 (4%)

4 (6%)

0.53

Conduction Disorder

6 (0.3%)

6 (0.3%)

0 (0%)

>0.99

Any Arrhythmia Code

275 (14%)

264 (13%)

11 (17%)

0.35

ECG Parametersb

1270 (63%)

1234 (63%)

36 (57%)

0.36

Maximum Heart Rate (bpm) a

76 (65–90)

76 (65–90)

73 (65–82)

0.11

Maximum PR Interval (ms) a

164 (150–182)

164 (150–182)

172 (151–193)

0.24

Maximum QRS Interval (ms) a

92 (86–102)

92 (86–100)

92 (85–104)

0.78

Raceb

200 msb

135 (7%)

130 (7%)

5 (8%)

0.58

QRS Interval > 120 msb

82 (4%)

81 (4%)

1 (2%)

0.73

QTc > 500 msb

71 (4%)

70 (4%)

1 (2%)

0.72

a

Median (interquartile range), p-value from Wilcoxon rank-sum (Mann-Whitney) test comparing variant carriers to non-carriers;

b

N (%), p-value from Fisher exact test comparing variant carriers to non-carriers;

c Calculated as the difference in years between the first and last EMR data points available for assessment; QTc - QT interval corrected for heart rate using Bazett’s formula (QTc = QT/√(RR in seconds); EMR – Electronic Medical Records; bpm – beats per minute; ms - milliseconds

Author Manuscript Author Manuscript Author Manuscript JAMA. Author manuscript; available in PMC 2017 January 05.

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

Large-scale DNA sequencing identifies incidental rare variants in established Mendelian disease genes, but the frequency of related clinical phenotype...
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