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Yoneda ZT, Anderson KC, Quintana JA, et al. Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes. JAMA Cardiol. 2021;6(12):1371-1379doi: 10.1001/jamacardio.2021.3370.
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. (2021). Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes. JAMA cardiology, 6(12), 1371-1379. https://doi.org/10.1001/jamacardio.2021.3370
Yoneda, Zachary T, et al. "Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes." JAMA cardiology vol. 6,12 (2021): 1371-1379. doi: https://doi.org/10.1001/jamacardio.2021.3370
Yoneda ZT, Anderson KC, Quintana JA, O'Neill MJ, Sims RA, Glazer AM, Shaffer CM, Crawford DM, Stricker T, Ye F, Wells Q, Stevenson LW, Michaud GF, Darbar D, Lubitz SA, Ellinor PT, Roden DM, Shoemaker MB. Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes. JAMA Cardiol. 2021 Dec 01;6(12):1371-1379. doi: 10.1001/jamacardio.2021.3370. PMID: 34495297; PMCID: PMC8427496.
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JAMA Cardiol. 2021 Dec 01;6(12):1371-1379. doi: 10.1001/jamacardio.2021.3370.

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

JAMA cardiology

Zachary T Yoneda, Katherine C Anderson, Joseph A Quintana, Matthew J O'Neill, Richard A Sims, Andrew M Glazer, Christian M Shaffer, Diane M Crawford, Thomas Stricker, Fei Ye, Quinn Wells, Lynne W Stevenson, Gregory F Michaud, Dawood Darbar, Steven A Lubitz, Patrick T Ellinor, Dan M Roden, M Benjamin Shoemaker

Affiliations

  1. Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
  2. Vanderbilt University School of Medicine, Nashville, Tennessee.
  3. Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
  4. Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
  5. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.
  6. Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago.
  7. Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  8. Cardiovascular Research Center, Massachusetts General Hospital, Boston.
  9. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
  10. Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee.

PMID: 34495297 PMCID: PMC8427496 DOI: 10.1001/jamacardio.2021.3370

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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