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

Authors, Journal, Affiliations, Type, DOI

• Authors: 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
• Journal: JAMA Cardiology, December 2021, Vol. 6, No. 12
• Affiliations: Vanderbilt University Medical Center (primary); University of Illinois at Chicago; Broad Institute of MIT and Harvard; Massachusetts General Hospital
• Type of study: Prospective, observational cohort study
• DOI: 10.1001/jamacardio.2021.3370

Overview

This study enrolled 1293 patients with early-onset atrial fibrillation (AF diagnosed before age 66) who underwent whole-genome sequencing through the NHLBI TOPMed program, analyzed against 145 genes from commercial cardiomyopathy and arrhythmia panels. Disease-associated (pathogenic/likely pathogenic) variants were identified in 10.1% of all participants, rising to 16.8% in those diagnosed before age 30. The vast majority of pathogenic variants were in cardiomyopathy genes — particularly TTN, MYH7, MYH6, and LMNA — rather than channelopathy genes, suggesting early-onset AF frequently represents the first clinical manifestation of an underlying inherited cardiomyopathy.

Keywords

Atrial fibrillation, early-onset, rare variants, whole genome sequencing, cardiomyopathy, arrhythmia, pathogenic, ACMG, genetic testing, TTN, TOPMed

Key Takeaways

Background and Rationale

• Genetic testing is currently not guideline-recommended for AF, but recent data suggest early-onset AF is enriched for rare disease-associated variants.
• Prior single-center work (Goodyer 2019, n=25) found 24% carried a P/LP variant on a commercial arrhythmia/cardiomyopathy panel — comparable to the diagnostic yield in dilated cardiomyopathy (~25%).
• TTN loss-of-function variants were previously found in 2.1% of all early-onset AF patients, rising to 6.5% of those diagnosed before age 30 (Choi 2018).
• This study was designed to determine the yield of genetic testing across a large cohort using ACMG classification standards to simulate clinical practice.

Methods

• 1293 participants from the Vanderbilt AF and Vanderbilt AF Ablation Registries; enrolled 1999–2015.
• Whole-genome sequencing via TOPMed; analysis of 145 genes drawn from commercial arrhythmia/cardiomyopathy panels (AmbryGenetics, GeneDx, Invitae) current as of June 2020.
• 87 genes on cardiomyopathy panel only, 36 on arrhythmia panel only, 22 on both.
• Automated ACMG variant classification (Franklin, Genoox) followed by manual review by two independent blinded reviewers; disagreements resolved by a third expert (interobserver agreement 91.8%, κ=0.848).
• Participants assigned to mutually exclusive groups by highest-priority variant: Group 1 (P/LP for AD/XLD disorder) → Group 4 (no suspicious variant).

Results — Overall Variant Yield

• Group 1 (disease-associated): 131 participants (10.1%) — P/LP variant in autosomal dominant or X-linked dominant gene.
• Group 2 (VUS): 812 participants (62.8%) — variant of undetermined significance only.
• Group 3 (AR carrier): 92 participants (7.1%) — heterozygous carrier for autosomal recessive disorder; 82 of these carried an HFE (hemochromatosis) variant.
• Group 4 (no suspicious variant): 258 participants (20.0%).
• Participants with disease-associated variants had significantly higher rates of heart failure (27.5% vs. ~15%) and heart failure with reduced ejection fraction (15.3% vs. 6.6–7.3%), suggesting these variants confer susceptibility to LV dysfunction.

Results — Age-Related Prevalence

• Yield was highest in youngest patients: 16.8% (20/119) for AF diagnosed before age 30, vs. 7.1% (8/112) for age 60–65.
• A continuous cubic spline analysis confirmed a nonlinear inverse relationship between age at AF diagnosis and disease-associated variant prevalence (P=.02).
• Multivariable logistic regression: OR 1.26 per decade of earlier diagnosis (95% CI, 1.07–1.48; P=.005), adjusting for sex, race, and ethnicity.
• No significant age association was found for VUS-only group (Group 2), suggesting age dependency is specific to truly pathogenic variants.
• The authors suggest genetic testing could reasonably be considered for patients diagnosed with AF up to age 60, with a stronger recommendation for those diagnosed before age 30.

Results — Genetic Overlap With Inherited Syndromes

• Cardiomyopathy syndromes dominated: DCM 7.2% (93 participants), HCM 3.3% (43), AC/ARVC 2.9% (37).
• Channelopathy overlap was far lower: LQTS 0.9% (12), Brugada syndrome 0.2% (2), CPVT 0.1% (1).
• Restricting to major disease genes (ClinGen strong/definitive evidence): DCM 5.3%, HCM 2.1%, AC/ARVC 0.4%, LQTS 0.9%, Brugada 0.2%, CPVT 0.1%.
• This suggests early-onset AF overlaps far more with inherited cardiomyopathy than with channelopathies.

Results — Most Prevalent Genes

• 141 P/LP variants in 34 genes; top 5:
  • TTN: 38 variants (27% of P/LP variants); median AF diagnosis age 44 years
  • MYH7: 18 variants (13%); median AF diagnosis age 48 years
  • MYH6: 10 variants (7%); median AF diagnosis age 43 years
  • LMNA: 9 variants (6%); median AF diagnosis age 52 years
  • KCNQ1: 8 variants (6%); median AF diagnosis age 43 years
• VUSs (n=1979) were most common in TTN (98 loss-of-function VUSs), SCN10A (86), FLNC (81), RYR2 (66).
• VUS count per individual significantly associated with transcript length — a systematic artifact of large genes.

Discussion

• Early-onset AF overlapping with cardiomyopathy genes may represent an "atrial myopathy" subtype (Goette 2017), where genetic substrate drives AF through structural atrial disease rather than primary ion channel dysfunction.
• Future questions: Do patients with early-onset AF and cardiomyopathy variants develop HF, ventricular arrhythmias, and stroke at elevated rates? Could early genetic identification allow disease-modifying intervention?
• Study population was predominantly of European ancestry (95.7% White); a separate report found 7% P/LP yield in African/Hispanic patients — similar but data remains limited.
• Practical implication: results support establishing an inherited heart disease clinic pathway for patients with early-onset AF, with genetic counseling and commercial cardiomyopathy/arrhythmia panel testing.

Limitations

• Single-center cohort (Vanderbilt); referral bias possible.
• Predominately European ancestry — generalizability uncertain.
• Gene panel is commercial, not AF-specific; many genes have varying levels of ClinGen evidence.
• VUS interpretation inconsistent across laboratories; high VUS rate (62.8%) is a clinical challenge.
• Temporal relationship between genetic variant detection and AF onset vs. cardiomyopathy onset was not established.

Key Concepts Mentioned

• concepts/Early-Onset-Atrial-Fibrillation — central subject; defined as AF diagnosed before age 66
• concepts/Genetic-Testing-in-AF — clinical rationale, age cutoff, and yield of testing
• concepts/Arrhythmogenic-Cardiomyopathy — major overlap category with early-onset AF

Key Entities Mentioned

• entities/TTN — most common gene harboring P/LP variants (27%)
• entities/MYH7 — second most common (13%); HCM-associated
• entities/MYH6 — third (7%); α-myosin, atrium-predominant
• entities/LMNA — 6% of P/LP variants; arrhythmogenic DCM with early AF
• entities/KCNQ1 — 6% of P/LP variants; LQT1 gene
• entities/FLNC — common VUS gene; AC/DCM overlap
• entities/RYR2 — common VUS gene; CPVT gene
• entities/Atrial-Fibrillation — primary clinical phenotype
• entities/ARVC — genetic overlap syndrome (2.9%)

Limitations of the Document

• The optimal age cutoff for recommending genetic testing in AF remains undefined — this paper suggests up to age 60 but prior proposals used 45 years.
• High VUS rate (62.8%) is a major clinical challenge; no validated AF-specific gene panel exists to reduce VUS burden.
• Whether early identification of cardiomyopathy variants in AF patients leads to disease-modifying management changes is not established.
• Temporal relationship (does variant cause AF, or does AF precede cardiomyopathy?) remains unresolved.
• Population is predominantly European — variant pathogenicity databases are less well-characterized for non-European populations.

Wiki Pages Updated

• wiki/sources/eoaf-jama-2021.md (created)
• wiki/entities/TTN.md (created)
• wiki/entities/MYH7.md (created)
• wiki/entities/MYH6.md (created)
• wiki/concepts/Early-Onset-Atrial-Fibrillation.md (created)
• wiki/concepts/Genetic-Testing-in-AF.md (created)
• wiki/entities/Atrial-Fibrillation.md (updated)
• wiki/entities/KCNQ1.md (updated)
• wiki/entities/LMNA.md (updated)
• wiki/entities/FLNC.md (updated)
• wiki/entities/ARVC.md (updated)
• wiki/entities/RYR2.md (updated)
• wiki/index.md (updated)
• wiki/log.md (updated)