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

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.

Figure 1

Rare variant identification, characterization, and phenotyping. A) Variants identified in SCN5A. Top: All 81 rare [Minor Allele Frequency (MAF) < 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 structure^, of the encoded voltage-activated sodium channel, Nav1.5. Variants in yellow (N=32) were designated as pathogenic or likely pathogenic by ClinVar or at least one of the three independent expert laboratories. Middle: Variant classification by ClinVar and the three independent expert laboratories, with pathogenic or likely pathogenic designation indicated in red, for the 32 rare variants with at least one such designation. The total number of variants designated by each site is shown in parentheses. The number of participants with each variant is indicated below each variant, and the number of participants with each variant and phenotypes are shown beneath the variant count. Totals for each row are listed in parentheses. One participant had both SCN5A-D1243N and KCNH2-T983I, designated with a *. Bottom: Arrhythmia and electrocardiographic phenotypes, indicated in blue, identified through electronic medical record and electrocardiogram review of all participants with one or more putatively pathogenic variant. Lines above join the phenotype to the variant identified. For Long QT, light blue denotes corrected QT interval (QTc) of 450–500ms for males or 460–500ms for females, while dark blue indicates at least one electrocardiogram with QTc > 500ms. B) Rare variants identified in KCNH2. Top: All 41 rare 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 structure^, of the encoded voltage-activated potassium channel, Kv11.1 (sometimes called HERG). Variants in yellow (N=10) were designated as pathogenic or likely pathogenic by ClinVar or at least one of the three independent expert laboratories. Middle: Variant classification by ClinVar and the three independent expert laboratories, with pathogenic or likely pathogenic designation indicated in red, for the 10 rare variants with at least one such designation. The total number of variants designated by each site is shown in parentheses. The number of participants with each variant is indicated below the boxes. The number of participants with each variant and phenotypes are shown beneath the variant count. Totals for each row are listed in parentheses. One participant had both SCN5A-D1243N and KCNH2-T983I, designated with a *. Bottom: Arrhythmia and electrocardiographic phenotypes, indicated in blue, identified through electronic medical record and electrocardiogram review of all participants with one or more putatively pathogenic variant. Lines above join the phenotype to the variant identified. For Long QT, light blue denotes QTc of 450–500ms for males or 460–500ms for females. AV – Atrioventricular; cNBD – cyclic nucleotide binding domain.

Figure 1

Rare variant identification, characterization, and phenotyping. A) Variants identified in SCN5A. Top: All 81 rare [Minor Allele Frequency (MAF) < 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 structure^, of the encoded voltage-activated sodium channel, Nav1.5. Variants in yellow (N=32) were designated as pathogenic or likely pathogenic by ClinVar or at least one of the three independent expert laboratories. Middle: Variant classification by ClinVar and the three independent expert laboratories, with pathogenic or likely pathogenic designation indicated in red, for the 32 rare variants with at least one such designation. The total number of variants designated by each site is shown in parentheses. The number of participants with each variant is indicated below each variant, and the number of participants with each variant and phenotypes are shown beneath the variant count. Totals for each row are listed in parentheses. One participant had both SCN5A-D1243N and KCNH2-T983I, designated with a *. Bottom: Arrhythmia and electrocardiographic phenotypes, indicated in blue, identified through electronic medical record and electrocardiogram review of all participants with one or more putatively pathogenic variant. Lines above join the phenotype to the variant identified. For Long QT, light blue denotes corrected QT interval (QTc) of 450–500ms for males or 460–500ms for females, while dark blue indicates at least one electrocardiogram with QTc > 500ms. B) Rare variants identified in KCNH2. Top: All 41 rare 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 structure^, of the encoded voltage-activated potassium channel, Kv11.1 (sometimes called HERG). Variants in yellow (N=10) were designated as pathogenic or likely pathogenic by ClinVar or at least one of the three independent expert laboratories. Middle: Variant classification by ClinVar and the three independent expert laboratories, with pathogenic or likely pathogenic designation indicated in red, for the 10 rare variants with at least one such designation. The total number of variants designated by each site is shown in parentheses. The number of participants with each variant is indicated below the boxes. The number of participants with each variant and phenotypes are shown beneath the variant count. Totals for each row are listed in parentheses. One participant had both SCN5A-D1243N and KCNH2-T983I, designated with a *. Bottom: Arrhythmia and electrocardiographic phenotypes, indicated in blue, identified through electronic medical record and electrocardiogram review of all participants with one or more putatively pathogenic variant. Lines above join the phenotype to the variant identified. For Long QT, light blue denotes QTc of 450–500ms for males or 460–500ms for females. AV – Atrioventricular; cNBD – cyclic nucleotide binding domain.