Genetic Evaluation of Early-Onset Atrial Fibrillation: Impact on Patient Management

Authors, Journal, Affiliations, Type, DOI

• Authors: J. Lukas Laws and Mahsima Shabani (equal contribution), with Hollie L. Williams, Zachary T. Yoneda and M. Benjamin Shoemaker (senior author) and ~30 further authors — Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, with Biostatistics, Pharmacology, Paediatrics and Biomedical Informatics
• Journal: European Heart Journal. 2026;47:1554–1572 (Clinical Research, Arrhythmias); published online 30 October 2025; open access
• Type: Prospective single-centre consecutive cohort from a dedicated AF Precision Medicine Clinic, October 2020 – September 2024
• DOI: https://doi.org/10.1093/eurheartj/ehaf829
• Accompanying editorial: MacRae CA. Genetic testing in cardiology: insights into "overlap" from atrial fibrillation. Eur Heart J. doi:10.1093/eurheartj/ehaf988

Overview

The first prospective description of what a dedicated early-onset AF genetics clinic actually finds and what it does. Of 264 patients referred with AF diagnosed before age 60, 242 completed a full cardiomyopathy/arrhythmia panel: 48 (20%) carried a pathogenic or likely pathogenic variant — twice the yield reported from unselected retrospective cohorts. Only 6 of those 48 had a cardiomyopathy or ventricular arrhythmia syndrome diagnosed before referral, so the clinic was making the diagnosis, not confirming it.

The paper's real contribution is measuring consequence. Genetic and phenotypic evaluation changed management in 52% of genotype-positive patients: seven new ICDs, two pacemaker-to-ICD upgrades, guideline-directed medical therapy started or optimised, anticoagulation initiated in seven patients with CHA₂DS₂-VASc-equivalent scores of 1 or less who were newly diagnosed with HCM or ACM, drug-avoidance advice in four channelopathy carriers, and exercise restriction in four ACM carriers. It also supplies the first usable pre-test probability table from a prospective AF population, and one uncomfortable result: conventional AF risk factors do not exclude a genetic cause, and family history of AF does not predict one.

Keywords

Atrial fibrillation · genetic testing · dilated cardiomyopathy · hypertrophic cardiomyopathy · arrhythmogenic cardiomyopathy

Key Takeaways

Clinic framework

• Referral was open to patients diagnosed with AF before age 60, or with a strong family history, supplemented by an automated Best Practice Alert prompting referral of young AF patients through the electronic record.
• Evaluation was uniform: history and examination, AF symptom score, 12-lead ECG, three-generation pedigree, genetic counselling, ambulatory monitoring, and cardiac MRI or echocardiography — with exercise testing, extended monitoring or procainamide challenge added where indicated.
• Testing used commercial cardiomyopathy/arrhythmia panels (Labcorp/Invitae, GeneDx) or the CLIA-approved Vanderbilt laboratory; relatives had targeted familial-variant genotyping only.
• TTN variants required a cardiac exon with a proportion spliced index ≥90% to count as positive — without this filter TTN dominates spuriously.

Yield

• 264 referred, 242 probands completed genetic testing, 48 (20%) positive, including one compound heterozygote.
• Four further variant carriers were identified through targeted cascade screening, giving 52 genotype-positive participants and 246 completed evaluations.
• The 20% is presented as twice the ~10% from unselected retrospective AF cohorts; the two explanations offered are younger age at diagnosis (median 39 years here vs 50 years in the group's earlier retrospective study) and clinician pre-selection of patients with suspicious features. (sources/genetic-eoaf-ehj-2026, rating: high)
• Among the 194 negative probands: 129 (53%) had a VUS, of whom 30 (12% of all negatives) were deemed "suspicious"; 18 (7%) were heterozygous carriers of a recessive syndrome; 47 (20%) had no rare variants at all.
• A gene-elusive AF overlap syndrome was found in 22 patients (9%) — a cardiomyopathy or arrhythmogenic syndrome meeting diagnostic criteria with negative genetic testing. Half of these had neither a suspicious VUS nor a suggestive family history, which is the argument for universal phenotyping rather than phenotyping only genotype-positive patients.

Gene spectrum

• TTN accounted for almost half of all positive results (23 of 48), and 71% of genotype-positive patients carried a cardiomyopathy variant of some kind.
• Ten of the 48 positives fell outside the four AF genetic subgroups: three HFE (C282Y/H63D compound heterozygotes — hereditary haemochromatosis), three CPT2, two TTR p.Val142Ile, one LZTR1 (Noonan syndrome) and one complete GJA5 deletion. Six of those are treatable metabolic diagnoses returned incidentally by a cardiology panel — a benefit of broad testing that is rarely counted in yield discussions.
• The single GJA5 deletion was in a patient with familial AF, and is the only finding on the panel whose primary phenotype is AF itself rather than an overlap syndrome.

Predictors of positive genetic testing

All models adjusted for age at AF diagnosis, sex, and time from diagnosis to testing. (sources/genetic-eoaf-ehj-2026, rating: high)

• T1 mapping outperformed LGE. The authors read this as consistent with T1 being superior for diffuse fibrosis, and argue it supports early detection of adverse remodelling rather than scar.
• Family history of AF did not predict a positive result, nor did AF type (paroxysmal/persistent/permanent) or number of cardioversions — the authors attribute this to AF's polygenic architecture and shared clinical risk factors.
• The aggregate AF risk score did not discriminate. HARMS2-AF showed no difference in aggregated clinical risk between genotype-positive and genotype-negative patients (P=.76), so the clinical risk-factor burden cannot be used to decide who is tested.
• OSA predicted a negative test but did not exclude disease: 14% of patients with OSA still carried a pathogenic variant, which the authors interpret through a "second hit" model in which a rare variant confers susceptibility and a clinical risk factor precipitates AF.
• Tobacco and obesity were not associated with a positive test (tobacco OR 0.9; BMI 30–39 OR 1.0; BMI >40 OR 1.9).
• The authors are explicit that no single predictor is strong enough to decide referral, and that a multivariable model is a future goal.

Penetrance of the ventricular phenotype

Penetrance was assessed in the 52 genotype-positive participants by AF genetic subgroup, with disease penetrance defined as meeting diagnostic criteria for the corresponding cardiomyopathy or arrhythmia syndrome.

• ACM-gene carriers were the most penetrant and the most consequential: 92% of participants with an ACM phenotype had a change in management.
• The TTN penetrance figure of 54% is at a median of about 4 years from AF diagnosis, but the range ran from 1 week to 43 years — and the authors note that TTN-DCM typically declares itself later than HCM, so this figure is a snapshot rather than an endpoint.

Changes to clinical management

• 52% (27 of 52) of genotype-positive participants had a change in management; 11% (7 of 22) of those with a gene-elusive overlap syndrome did too. (sources/genetic-eoaf-ehj-2026, rating: high)
• Seven new ICDs and two upgrades from pacemaker to ICD. The stated indications were: genetic cardiomyopathy with LVEF <45% plus risk factors (1); ACM with syncope and ventricular arrhythmia (1); new HCM diagnoses with individualised primary-prevention risk (2); and a pacing indication in a high-ventricular-arrhythmia-risk genotype, where an ICD with pacing capability is preferred (1, plus the 2 upgrades).
• Anticoagulation beyond the score: seven participants with a CHA₂DS₂-VA of ≤1 were newly diagnosed with HCM or ACM and started on anticoagulation, on the basis that both syndromes warrant it regardless of conventional embolic risk.
• GDMT was started or optimised in genotype-positive patients with any history of LV systolic dysfunction, including TTN carriers whose dysfunction had recovered with rhythm control — the authors' practice being to treat these as cardiomyopathy rather than as arrhythmia-induced dysfunction.
• Channelopathy advice: three SCN5A carriers were told to avoid Class I antiarrhythmics (flecainide, propafenone) and to take fever precautions; one KCNQ1 carrier was told to avoid QT-prolonging and Class III agents (sotalol, dofetilide).
• Exercise restriction to ≤6 METs was advised for four ACM participants with desmosomal variants, while the authors note the general trend toward more permissive advice in HCM and LQTS.
• Management changed in 33% (9 of 27) of those with a DCM phenotype, versus 92% of those with an ACM phenotype and all of those with HCM.

Limitations of the document

• Single centre, newly established clinic, and ~90% White/non-Hispanic. The authors state this themselves; the yield, predictors and penetrance all need replication in other populations and ancestries. Gene-elusive syndromes are known to be commoner in non-European ancestry, and 5 of the 22 here were non-European.
• Ascertainment dominates the headline number. The 20% yield is from patients referred for suspicion of genetic disease, not from unselected early-onset AF — the paper says so, but the figure will be quoted without that caveat.
• Small subgroups. Nine ACM-gene carriers, five HCM, four channelopathy: the penetrance percentages are unstable, and several predictors (sustained ventricular arrhythmia especially) have very wide confidence intervals.
• No outcome data. Management changed, but whether that changed outcomes — stroke, heart failure, arrhythmic death — is explicitly deferred to future follow-up.
• The denominators move. 264 enrolled, 242 tested, 246 evaluated, 52 genotype-positive. The graphical abstract's "246 participants" and the text's 264/242 are reconcilable but require care.
• Internal inconsistencies in the management counts. Guideline-directed therapy is given as 16 of 52 (31%) in the graphical abstract, 18 in the Discussion, and 7 new initiations in the management paragraph. The three may be reconcilable (changes vs initiations) but the paper does not reconcile them.
• Table errors. Table 3 lists two rows numbered 31 (DSP and HFE), and labels the EMD complete deletion as autosomal dominant when EMD is X-linked.
• The Results and Discussion disagree on negative predictors. Results say OSA was the only clinical risk factor significantly predicting a negative test, with tall height and alcohol use disorder not reaching threshold; the Discussion calls all three "the strongest predictors of negative genetic testing."
• No cost-effectiveness analysis, despite proposing a clinic model with pedigree, genetic counselling, MRI, ambulatory monitoring and genetic testing for every patient.

Key Concepts Mentioned

concepts/Early-Onset-Atrial-Fibrillation · concepts/Genetic-Testing-in-AF · concepts/Cascade-Family-Screening · concepts/Arrhythmogenic-Cardiomyopathy · concepts/CHA2DS2-VA · concepts/Late-Gadolinium-Enhancement · concepts/Cardiogenetic-Centers · concepts/Variant-Reclassification

Key Entities Mentioned

entities/TTN · entities/LMNA · entities/SCN5A · entities/PKP2 · entities/FLNC · entities/DSP · entities/EMD · entities/MYH7 · entities/MYH6 · entities/KCNQ1 · entities/ATTR-Amyloidosis · entities/HCM · entities/DCM · entities/Atrial-Fibrillation

Named but unlinked: HFE · CPT2 · LZTR1 · TRPM4 · MYBPC3 · GJA5 · HARMS2-AF

Wiki Pages Updated

• sources/genetic-eoaf-ehj-2026 — created
• concepts/Early-Onset-Atrial-Fibrillation — prospective clinic yield, predictors, penetrance, management impact
• concepts/Genetic-Testing-in-AF — the pre-test probability table and the 52% management-change figure
• entities/TTN — dominant gene in a prospective AF cohort; 54% ventricular penetrance
• entities/ATTR-Amyloidosis — p.Val142Ile found twice in an AF cohort
• entities/LMNA — ACM subgroup penetrance and the ICD triggers it produced
• concepts/Cascade-Family-Screening — targeted cascade testing in an AF cohort
• wiki/wikiindex · wiki/sourceindex