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Original Investigation |

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

Sara L. Van Driest, MD, PhD1; Quinn S. Wells, MD, PharmD, MSCI1; Sarah Stallings, PhD1; William S. Bush, PhD, MS1,2; Adam Gordon, PhD3; Deborah A. Nickerson, PhD3; Jerry H. Kim, MD3; David R. Crosslin, PhD3; Gail P. Jarvik, MD, PhD3; David S. Carrell, PhD4; James D. Ralston, MD, MPH4; Eric B. Larson, MD, MPH4; Suzette J. Bielinski, PhD5; Janet E. Olson, PhD5; Zi Ye, MD, PhD5; Iftikhar J. Kullo, MD5; Noura S. Abul-Husn, MD, PhD6; Stuart A. Scott, PhD6; Erwin Bottinger, MD6; Berta Almoguera, PhD7; John Connolly, PhD7; Rosetta Chiavacci, BSN, CCRC7; Hakon Hakonarson, MD, PhD7,8; Laura J. Rasmussen-Torvik, PhD, MPH9; Vivian Pan, MS, CGC9; Stephen D. Persell, MD, MPH9; Maureen Smith, MS, CGC9; Rex L. Chisholm, PhD9; Terrie E. Kitchner, CCRP10; Max M. He, PhD10; Murray H. Brilliant, PhD10; John R. Wallace, MS11; Kimberly F. Doheny, PhD12; M. Benjamin Shoemaker, MD, MCSI1; Rongling Li, MD, PhD, MPH13; Teri A. Manolio, MD, PhD13; Thomas E. Callis, PhD14; Daniela Macaya, MQC15; Marc S. Williams, MD16; David Carey, PhD16; Jamie D. Kapplinger, BA5; Michael J. Ackerman, MD, PhD5; Marylyn D. Ritchie, PhD11,16; Joshua C. Denny, MD, MS1; Dan M. Roden, MD1
[+] Author Affiliations
1Vanderbilt University Medical Center, Nashville, Tennessee
2Case Western Reserve University, Cleveland, Ohio
3University of Washington, Seattle
4Group Health Research Institute, Seattle, Washington
5Mayo Clinic, Rochester, Minnesota
6Icahn School of Medicine at Mount Sinai, New York, New York
7The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
8Perelman School of Medicine, University of Pennsylvania, Philadelphia
9Northwestern University Feinberg School of Medicine, Chicago, Illinois
10Marshfield Clinic Research Foundation, Marshfield, Wisconsin
11Pennsylvania State University, University Park
12Johns Hopkins School of Medicine, Baltimore, Maryland
13National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
14Transgenomic, New Haven, Connecticut
15GeneDx, Gaithersburg, Maryland
16Geisinger Health System, Danville, Pennsylvania
JAMA. 2016;315(1):47-57. doi:10.1001/jama.2015.17701.
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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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Figure 1.
Rare Variants Identified in SCN5A

A, All 81 rare (minor allele frequency <0.5%) missense variants in the study population are designated as circles with the single-letter amino acid code for the reference sequence on the protein structure33,34 of the encoded voltage-activated sodium channel. Variants in orange (n = 32) were designated as pathogenic or likely pathogenic by ClinVar or at least 1 of the 3 expert laboratories.

B, Variant classification by ClinVar and the 3 independent expert laboratories, with pathogenic or likely pathogenic designation indicated in red, for the 32 rare variants with at least 1 such designation. The numbers of participants with each variant and phenotypes are shown below. Totals for each row are listed to the right. One participant had both SCN5A-D1243N and KCNH2-T983I, designated with an asterisk.

C, Arrhythmia and electrocardiographic (ECG) phenotypes, indicated in blue, identified through electronic medical record and ECG review of all participants with 1 or more putatively pathogenic variants; aggregated data from Tables 1, 2, and 3 are shown. Lines above join the phenotype to the variant identified. Electronic medical records were searched using International Classification of Diseases, Ninth Revision (ICD-9) codes and keywords for each phenotype (listed in eTable 2 in the Supplement), with manual review of the record to confirm accuracy. All available ECG tracings were reviewed by 2 cardiologists using the criteria in eTable 3. No individuals were identified with Brugada syndrome or cardiac pacing. For long QT syndrome, light blue denotes corrected QT interval (QTc) of 450-500 milliseconds for males or 460-500 milliseconds for females, while dark blue indicates at least 1 ECG with QTc longer than 500 milliseconds. AV indicates atrioventricular.

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Figure 2.
Rare Variants Identified in KCNH2

A, All 41 rare (minor allele frequency <0.5%) variants in the study population are designated as circles (missense variants) or a blue diamond (splice-site variant at position 150645629) with the single-letter amino acid code for the reference sequence on the protein structure33,35 of the encoded voltage-activated potassium channel, Kv11.1 (sometimes called HERG). Variants in orange (n = 10) were designated as pathogenic or likely pathogenic by ClinVar or at least 1 of the 3 expert laboratories.

B, Variant classification by ClinVar and the 3 independent expert laboratories, with pathogenic or likely pathogenic designation indicated in red, for the 10 rare variants with at least 1 such designation. The numbers of participants with each variant and phenotypes are shown below. Totals for each row are listed to the right. One participant had both SCN5A-D1243N and KCNH2-T983I, designated with an asterisk.

C, Arrhythmia and electrocardiographic (ECG) phenotypes, indicated in blue, identified through electronic medical record and ECG review of all participants with 1 or more putatively pathogenic variants; aggregated data from Tables 1, 2, and 3 are shown. Lines above join the phenotype to the variant identified. Electronic medical records were searched using International Classification of Diseases, Ninth Revision (ICD-9) codes and keywords for each phenotype (listed in eTable 2 in the Supplement), with manual review of the record to confirm accuracy. All available ECG tracings were reviewed by 2 cardiologists using the criteria in eTable 3. No individuals were identified with Brugada syndrome or cardiac pacing. For long QT syndrome, light blue denotes corrected QT interval of 450-500 milliseconds for males or 460-500 milliseconds for females. AV indicates atrioventricular; cNBD, cyclic nucleotide binding domain.

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