Genetic testing in early-onset atrial fibrillation

Authors, Journal, Affiliations, Type, DOI

• Authors: Shinwan Kany, Sean J. Jurgens, Joel T. Rämö, Ingrid E. Christophersen, Michiel Rienstra, Mina K. Chung, Morten S. Olesen, Michael J. Ackerman, Elizabeth M. McNally, Christopher Semsarian, Renate B. Schnabel, Arthur A.M. Wilde, Emelia J. Benjamin, Heidi L. Rehm, Paulus Kirchhof, Connie R. Bezzina, Dan M. Roden, M. Benjamin Shoemaker, Patrick T. Ellinor (co-last)
• Journal: European Heart Journal (2024), Volume 45, pp. 3111–3123
• Affiliations: Broad Institute of MIT and Harvard, Massachusetts General Hospital, University Heart and Vascular Center Hamburg-Eppendorf, Amsterdam UMC, University of Helsinki, Mayo Clinic, Northwestern University, University of Sydney, Vanderbilt University Medical Center, and others
• Type: State of the Art Review
• DOI: https://doi.org/10.1093/eurheartj/ehae298

Overview

This review summarises evidence for genetic testing in early-onset AF (EOAF), showing that ~4–11% of EOAF patients carry pathogenic or likely pathogenic (P/LP) variants — predominantly in cardiomyopathy genes (TTN, MYBPC3, LMNA, PKP2, RBM20, MYH7) — making AF a potential early sentinel of heritable ventricular disease. The 2023 ACC/AHA guidelines issued a first-ever Class IIb recommendation for genetic testing in AF ≤45 years without obvious risk factors; current ESC guidelines do not yet include this recommendation. A major challenge is that ~60% of tested patients carry a VUS, demanding careful pre-test counselling and restriction of panels to high-confidence genes. AF can temporally precede ventricular cardiomyopathy in ~50% of TTNtv carriers, underscoring the need for longitudinal surveillance.

Keywords

Genetic testing • Atrial fibrillation • Cardiomyopathy • Rare variants • Cascade testing

Key Takeaways

Genetic Architecture of AF

• AF has a complex polygenic architecture; GWAS has identified hundreds of common variant loci (PITX2, ZFHX3, KCNN3, SCN5A, TTN, MYH6 among others)
• Polygenic risk scores (PRS) for AF are promising but lack proven clinical utility
• Rare variants with large effect sizes — identified via WES/WGS — are the principal focus of genetic testing in EOAF

Genetic Yield in Early-Onset AF

• Yield of P/LP variants is inversely related to age of AF onset: ~10% at onset <66 years, ~10–16% at onset <45 years, up to 24% in some highly selected series (mean age ~27 years)
• In the largest study (Yoneda et al., n=1293): 10.1% carried P/LP variants; highest yield for TTN (3%), followed by MYH7, MYH6, LMNA, KCNQ1
• ~7% of EOAF cases carry variants in high-confidence cardiomyopathy/arrhythmia genes; ~4% carry readily-reportable ACMG truncating variants (TTN, LMNA, MYBPC3, KCNQ1, DSP, SCN5A)
• P/LP cardiomyopathy variant carriers with EOAF have an increased risk of death (HR 1.5, 95% CI 1.0–2.1) over ~10 years, driven by cardiomyopathy-related death and SCD

Key Genes Implicated in EOAF

• TTN: Most common gene; TTNtv in 4.7–6.5% of EOAF onset <40 years; 16% in familial AF; AF may precede ventricular cardiomyopathy in ~50% of TTNtv carriers who develop both
• MYBPC3: Truncating variants (HCM gene) enriched in EOAF
• LMNA: AF and atrial myopathy often precede ventricular manifestations by years to decades
• PKP2: Truncating variants (ARVC gene) enriched in EOAF; exercise restriction in PKP2 carriers
• RBM20: Truncating variants associated with EOAF and larger atrial volumes
• MYH7: Associated with higher AF incidence in HCM; MYH7 missense variants enriched in EOAF
• SCN5A (GOF): Associated with LQTS and EOAF kindreds; loss-of-function relates to Brugada syndrome (frequent atrial arrhythmia)
• KCNQ1 (GOF and LOF): Both gain- and loss-of-function variants co-segregate with EOAF; associated with QT abnormalities (LQTS, short QT syndrome) and SCD in some cases
• KCNA5: Atrial-specific ion channel; co-segregates with lone EOAF in small families (limited replication)
• MYL4: Rare atrial-specific gene; genetic primary atrial myopathy and EOAF described

Temporality of AF and Ventricular Cardiomyopathy

• AF is not always a consequence of overt cardiomyopathy in rare variant carriers — it can precede ventricular manifestations
• In LMNA carriers: AF and atrial myopathy often precede ventricular DCM by years to decades
• In UK Biobank TTNtv analysis: AF preceded ventricular cardiomyopathy in ~50% of individuals who ultimately developed both
• In Latvian EOAF study: 5/13 P/LP cardiomyopathy variant carriers with initially normal echocardiography later showed ventricular enlargement on MRI

Polygenic × Monogenic Risk Interaction

• Polygenic risk modifies penetrance of rare variants: TTNtv carriers in the highest PRS tertile had 21.5% AF prevalence vs 6.7% in the lowest tertile (Choi et al., UK Biobank n=~44,000)
• Similarly described for HCM P/LP carriers: highest PRS centile = 14× increased risk vs median PRS
• Clinical integration of PRS with rare variants in EOAF counselling remains undefined

Guidelines on Genetic Testing in AF

• 2023 ACC/AHA AF guidelines: First guidelines to recommend genetic testing — Class IIb for AF patients ≤45 years with no obvious risk factors; Class IIb for EP study in those <30 years
• ESC AF guidelines (current): No recommendation for genetic testing in young individuals without comorbidities
• Multi-society consensus document: Genetic testing consideration for familial AF <60 years
• In DCM: genetic testing is a Class IB recommendation in ESC guidelines — comparable diagnostic yield to EOAF (~10% in non-familial DCM)

Gene Selection and Panel Testing Strategy

• Goals: identify P/LP variants known to underlie inherited cardiomyopathies and/or arrhythmia syndromes
• Preferred approach: WES or WGS (enables re-interrogation; PRS calculation from WGS)
• Panel should focus on high-confidence ClinGen-curated genes for cardiomyopathy and channelopathy; genes with unclear roles will inflate VUS rate
• Key high-confidence actionable genes per ACMG: TTN, LMNA, MYBPC3, KCNQ1, DSP, SCN5A, PKP2

When to Consider Genetic Testing

• Favours testing: AF onset <45 years; family history of EOAF or cardiomyopathy in those <65; structural/ECG abnormalities (borderline LVH, LV dysfunction, bundle branch block, AVB, T-wave inversion); clinical features of specific monogenic syndrome (LMNA: AF + conduction disease/VA; KCNQ1: AF + QT abnormality)
• Favours non-genetic cause: Older age; presence of classical AF risk factors (obesity, hypertension, diabetes, sleep apnoea, alcohol, endurance sport, smoking, hyperthyroidism); known trigger (SVT-induced AF)
• Interdisciplinary team required: AF cardiologist, cardiomyopathy cardiologist, cardiovascular geneticist, genetic counsellor

Clinical Implications of Positive Genetic Findings

• Prompt detailed evaluation for early cardiomyopathy signs (ECG, echocardiography, preferably MRI)
• Gene-specific management adjustments:
  • LMNA/FLNC carriers with subclinical cardiomyopathy: increased surveillance, early ICD consideration
  • PKP2 carriers: avoidance of competitive high-level exercise
  • SCN5A LOF: caution with sodium channel blockers
  • KCNQ1/KCNH2 LOF: caution with potassium channel blockers
• Enables cascade screening of family members at risk of HF and SCD
• May represent a first step toward gene- or variant-specific therapies

Variants of Uncertain Significance (VUS)

• ~60–63% of EOAF patients undergoing panel testing will carry ≥1 VUS (Yoneda et al.: 812/1293 = 62.8%)
• VUS frequency in EOAF far exceeds that in idiopathic VF (~30%) or unexplained cardiac arrest (~40%)
• Most VUS are likely benign; clinical significance is not established
• 7.3% of cardiomyopathy variants in ClinVar underwent clinically significant reclassification 2011–2021; reclassification most often involves downgrading of P/LP to VUS
• Mitigation strategies: restrict gene panel to high-confidence genes, patient pre-test education, ACMG/ClinGen-adherent variant curation, avoid reporting VUS in genes with uncertain roles

Non-European Populations

• Genetic studies of AF overwhelmingly derived from European ancestry populations
• Variants with higher minor allele frequency are more likely to be misclassified as P/LP in non-European populations (ClinVar 2011–2021 analysis)
• Data from ethnic minority cohorts (Black and Hispanic AF patients <66 years): 7% P/LP yield (mostly TTNtv)
• All of Us and Million Veterans Program represent initiatives to improve diversity in genomic research

Barriers to Implementation

• Cost of genetic testing and analysis; need for cost-effectiveness studies in common disease (AF)
• Workforce shortages: genetic counsellors and cardiologists with genetic training
• No standardised definition of "early-onset" AF — current evidence supports <45 years as the key cut-off
• Lack of prospective data on genetic testing outcomes, ablation response in variant carriers, and long-term risk in AF–HF overlap

Limitations of the Document

• Review article — no primary data generated; evidence synthesis is subject to selection bias
• Most underlying genetic studies are in European ancestry populations, limiting generalisability
• Genetic yield figures vary widely across studies due to different age cut-offs, gene panels, variant classification criteria, and exclusion criteria
• Temporal relationship between AF onset and ventricular cardiomyopathy remains poorly characterised for most genes
• No prospective randomised data on outcomes of genetic testing in EOAF; management recommendations are largely expert opinion

Key Concepts Mentioned

• concepts/Early-Onset-Atrial-Fibrillation — primary clinical phenotype under review; yield and definition
• concepts/Genetic-Testing-in-AF — framework for testing, gene selection, and clinical integration
• concepts/Cascade-Family-Screening — enabled by identification of P/LP variant in proband
• concepts/Variant-Reclassification — fluid pathogenicity of variants over time; 7.3% cardiomyopathy variants reclassified 2011–2021
• concepts/Atrial-Myopathy-in-HCM — primary atrial myopathy concept, MYL4/RBM20/sarcomere gene mechanisms
• concepts/Cardiogenetic-Centers — interdisciplinary team model for implementation
• concepts/Genetic-Testing-in-Cardiomyopathy — cardiomyopathy genetic testing as the comparator framework

Key Entities Mentioned

• entities/TTN — most common EOAF gene; TTNtv in 4.7–16% of EOAF; AF precedes DCM in ~50%
• entities/LMNA — AF + conduction disease precede ventricular DCM; actionable variant
• entities/PKP2 — ARVC gene enriched in EOAF; exercise restriction implication
• entities/MYBPC3 — truncating variants (HCM) enriched in EOAF
• entities/MYH7 — associated with higher AF in HCM; MYH7 variants in EOAF
• entities/SCN5A — GOF → LQTS-associated EOAF; LOF → Brugada + atrial arrhythmia
• entities/KCNQ1 — GOF and LOF both co-segregate with EOAF; QT abnormalities and SCD risk
• entities/DCM — genetic yield in non-familial DCM (~10%) comparable to EOAF; Class IB ESC recommendation for testing
• entities/ARVC — PKP2 truncating variants enriched in EOAF; exercise restriction
• entities/HCM — MYBPC3/MYH7 variants enriched in EOAF; sarcomere variants → AF and atrial myopathy
• entities/Atrial-Fibrillation — primary disease; Class IIb recommendation for genetic testing ≤45 years (ACC/AHA 2023)
• entities/MYH6 — atrial-predominant myosin; enriched in EOAF

Wiki Pages Updated

• wiki/sources/genetic-eoaf-ehj-2024.md — created (this page)
• wiki/wikiindex.md — updated with new source entry
• wiki/concepts/Early-Onset-Atrial-Fibrillation.md — to be updated
• wiki/concepts/Genetic-Testing-in-AF.md — to be updated
• wiki/entities/LMNA.md — to be updated
• wiki/entities/TTN.md — to be updated
• wiki/entities/ARVC.md — to be updated
• wiki/entities/DCM.md — to be updated