Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes
Open accessAbstract
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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There is a strong association between AF and genes KCNA5, SCN5A, and TTN, while LMNA and KCNQ1 present a weaker association with AF.
“There is a strong association between AF and genes such as KCNA5, SCN5A and TTN, while genes like LMNA and KCNQ1 present a weaker association with AF [35,36,37,38].”
From Atrial Fibrillation in Elite Athletes: A Comprehensive Review of the Literature (2024) · cites this paper as [36]
The Discussion’s “Prevalence of Disease-Associated Variants in Individual Genes” section reports that TTN variants were the most common among patients with early-onset AF (27% of disease-associated variants), while LMNA and KCNQ1 each accounted for 6%. That supports a narrower comparison of variant frequencies, not a comparison of the genes’ strength of association with AF. The passages found do not establish the claimed strong associations for KCNA5 or SCN5A. (LLM, conf=0.88)
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Prevalence of deleterious variants in cardiomyopathy genes in early-onset atrial fibrillation
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Galanti, K., Dabbagh, G. S., Ricci, F., Gallina, S., Giansante, R., Jacob, R., Obeng-Gyimah, E. K., Cooper, L. T., Prasad, S., Birnie, D. H., et al. (2025) · ESC Heart Failure · doi:10.1002/ehf2.15307 · Cited by 3 · see citing works
- 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)
- 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
- hybrid
- doi.org
- 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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