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Cited by 192Cardiac electrophysiology and arrhythmiasAtrial Fibrillation Management and OutcomesGenomics and Rare Diseases

The DOI matches its Crossref record; 49 of the 51 references it cites were found in a registry or an index.

Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes

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Yoneda, Zachary T., Anderson, Katherine C., Quintana, Joseph A., O’Neill, Matthew J., Sims, Richard A., Glazer, Andrew M., Shaffer, Christian M., Crawford, Diane M., Stricker, Thomas, Ye, Fei, Wells, Quinn, Stevenson, Lynne W., Michaud, Gregory F., Darbar, Dawood, Lubitz, Steven A., Ellinor, Patrick T., Roden, Dan M., Shoemaker, M. Benjamin·2021·JAMA Cardiology
DOI 10.1001/jamacardio.2021.3370PMC PMC8427496
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Abstract

Importance: Early-onset atrial fibrillation (AF) can be the initial manifestation of a more serious underlying inherited cardiomyopathy or arrhythmia syndrome. Objective: To examine the results of genetic testing for early-onset AF. Design, Setting, and Participants: This prospective, observational cohort study enrolled participants from an academic medical center who had AF diagnosed before 66 years of age and underwent whole genome sequencing through the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine program. Participants were enrolled from November 23, 1999, to June 2, 2015. Data analysis was performed from October 24, 2020, to March 11, 2021. Exposures: Rare variants identified in a panel of 145 genes that are included on cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories. Main Outcomes and Measures: Sequencing data were analyzed using an automated process followed by manual review by a panel of independent, blinded reviewers. The primary outcome was classification of rare variants using American College of Medical Genetics and Genomics criteria: benign, likely benign, variant of undetermined significance, likely pathogenic, or pathogenic. Disease-associated variants were defined as pathogenic/likely pathogenic variants in genes associated with autosomal dominant or X-linked dominant disorders. Results: Among 1293 participants (934 [72.2%] male; median [interquartile range] age at enrollment, 56 [48-61] years; median [interquartile range] age at AF diagnosis, 50 [41-56] years), genetic testing identified 131 participants (10.1%) with a disease-associated variant, 812 (62.8%) with a variant of undetermined significance, 92 (7.1%) as heterozygous carriers for an autosomal recessive disorder, and 258 (20.0%) with no suspicious variant. The likelihood of a disease-associated variant was highest in participants with AF diagnosed before the age of 30 years (20 of 119 [16.8%; 95% CI, 10.0%-23.6%]) and lowest after the age of 60 years (8 of 112 [7.1%; 95% CI, 2.4%-11.9%]). Disease-associated variants were more often associated with inherited cardiomyopathy syndromes compared with inherited arrhythmias. The most common genes were TTN (n = 38), MYH7 (n = 18), MYH6 (n = 10), LMNA (n = 9), and KCNQ1 (n = 8). Conclusions and Relevance: In this cohort study, genetic testing identified a disease-associated variant in 10% of patients with early-onset AF (the percentage was higher if diagnosed before the age of 30 years and lower if diagnosed after the age of 60 years). Most pathogenic/likely pathogenic variants are in genes associated with cardiomyopathy. These results support the use of genetic testing in early-onset AF.

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Figure 1. The Comprehensive Arrhythmia and Cardiomyopathy Gene Panel Genes were selected from commercial panels. A total of 145 genes were included; 87 were included only on the cardiomyopathy gene panel, 36 only on the arrhythmia gene panel, and 22 on both.
Figure 1. The Comprehensive Arrhythmia and Cardiomyopathy Gene Panel Genes were selected from commercial panels. A total of 145 genes were included; 87 were included only on the cardiomyopathy gene panel, 36 only on the arrhythmia gene panel, and 22 on both.CC BY · PubMed Central
Figure 2. Results of Genetic Testing in Early-Onset Atrial Fibrillation (AF) for Genes Associated With Arrhythmia and Cardiomyopathy Syndromes Variants are classified according to standard American College of Medical Genetics and Genomics criteria. AD indicates autosomal dominant; AR, autosomal recessive; P/LP, pathogenic/likely pathogenic; VUS, variant of undetermined significance; XLD, X-linked dominant; XLR, X-linked recessive.
Figure 2. Results of Genetic Testing in Early-Onset Atrial Fibrillation (AF) for Genes Associated With Arrhythmia and Cardiomyopathy Syndromes Variants are classified according to standard American College of Medical Genetics and Genomics criteria. AD indicates autosomal dominant; AR, autosomal recessive; P/LP, pathogenic/likely pathogenic; VUS, variant of undetermined significance; XLD, X-linked dominant; XLR, X-linked recessive.CC BY · PubMed Central
Figure 3. Prevalence of Disease-Associated Variants and Genetic Overlap With Inherited Cardiomyopathy and Arrhythmia Syndromes A, Prevalence of disease-associated rare variants according to age at atrial fibrillation (AF) diagnosis presented by age groups. Error bars indicate bootstrapped 95% CIs. B, Prevalence of disease-associated rare variants presented as a continuous variable (cubic spline graph, P = .02 for the association between age and presence of disease-associated variant based on the F test). C, The genetic overlap between disease-associated variants and specific inherited cardiomyopathy and arrhythmia syndromes. Shaded in blue is the proportion of variants in major disease genes for each disorder. AC (ARVC) indicates arrhythmogenic cardiomyopathy (arrhythmogenic right ventricular cardiomyopathy); CPVT, catecholaminergic polymorphic ventricular tachycardia; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LQTS, long QT syndrome.
Figure 3. Prevalence of Disease-Associated Variants and Genetic Overlap With Inherited Cardiomyopathy and Arrhythmia Syndromes A, Prevalence of disease-associated rare variants according to age at atrial fibrillation (AF) diagnosis presented by age groups. Error bars indicate bootstrapped 95% CIs. B, Prevalence of disease-associated rare variants presented as a continuous variable (cubic spline graph, P = .02 for the association between age and presence of disease-associated variant based on the F test). C, The genetic overlap between disease-associated variants and specific inherited cardiomyopathy and arrhythmia syndromes. Shaded in blue is the proportion of variants in major disease genes for each disorder. AC (ARVC) indicates arrhythmogenic cardiomyopathy (arrhythmogenic right ventricular cardiomyopathy); CPVT, catecholaminergic polymorphic ventricular tachycardia; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LQTS, long QT syndrome.CC BY · PubMed Central
Figure 4. Breakdown According to the Most Prevalent Genes A, Pathogenic/likely pathogenic (P/LP) variants in autosomal dominant disorders. B, Variants of undetermined significance (VUSs); only loss-of-function variants in TTN are reported. C, Heterozygous P/LP variants in autosomal recessive (AR) disorders.
Figure 4. Breakdown According to the Most Prevalent Genes A, Pathogenic/likely pathogenic (P/LP) variants in autosomal dominant disorders. B, Variants of undetermined significance (VUSs); only loss-of-function variants in TTN are reported. C, Heterozygous P/LP variants in autosomal recessive (AR) disorders.CC BY · PubMed Central

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Authors
Yoneda, Z. T., Anderson, K. C., Quintana, J. A., O’Neill, M. J., Sims, R. A., Glazer, A. M., Shaffer, C. M., Crawford, D. M., Stricker, T., Ye, F., Wells, Q., Stevenson, L. W., Michaud, G. F., Darbar, D., Lubitz, S. A., Ellinor, P. T., Roden, D. M., & Shoemaker, M. B.
Affiliations
  • Vanderbilt University Medical Center (US)
  • Vanderbilt University (US)
  • University of Illinois Chicago (US)
  • Broad Institute (US)
Corresponding author
Shoemaker, M. Benjamin
ORCID
Venue
JAMA Cardiology
Publisher
American Medical Association (AMA)
Published
2021-12-01
Volume
6
Issue
12
Pages
1371
ISSN
2380-6583 (ISSN-L)
DOI
10.1001/jamacardio.2021.3370
PMC
PMC8427496
OpenAlex
W3196904047
Cited by
192
References
51
Citations by year
2026: 46 · 2025: 42 · 2024: 43 · 2023: 32 · 2022: 28 · 2021: 1
FWCI
17.43
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • JAMA Cardiology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • American Heart Association (18SFRN34110082)
  • National Institutes of Health (UL1TR002243)
  • National Heart, Lung, and Blood Institute (R01HL140074, K24HL105780, R01HL155197)
  • National Human Genome Research Institute (K99HG010904)
  • National Institute of General Medical Sciences (T32GM007347, T32GM152284)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Atrial Fibrillation Management and Outcomes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
early-onset atrial fibrillation, rare variants, familial cardiomyopathy, inherited arrhythmia, genetic testing, variant interpretation, autosomal recessive disorder, whole genome sequencing, pathogenic variants, genetic counseling
MeSH terms
Whole Genome Sequencing, Adult, Aged, Atrial Fibrillation, Female, Follow-Up Studies, Humans, Male, Middle Aged, Cardiomyopathies, Prospective Studies, Registries, United States, Prevalence, Precision Medicine

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