Genetic Testing for Early-Onset Atrial Fibrillation: When Is It Necessary?

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EP LAB DIGEST. 2025;25(3):6.

Bradley P Knight, MD, FACC, FHRS

Dear Readers,

A 32-year-old man presented to clinic with recently diagnosed recurrent paroxysmal atrial fibrillation (AF). He had 4 episodes of AF in the past 4 months and has had to present to the emergency department with each episode despite treatment with moderate doses of metoprolol. He is otherwise healthy with no evidence of structural heart disease on echocardiography. Interestingly, his father has had AF since before age 60 and has undergone a catheter ablation procedure. The patient’s electrocardiogram in clinic (Figure) showed sinus rhythm, but at times he has atrial bigeminy with very early coupled premature atrial contractions (PACs) that are upright in the inferior leads and that usually block in the AV node but occasionally conduct with a right bundle branch block (RBBB) aberrancy.

This young man with paroxysmal AF and very early coupled PACs likely has a pulmonary vein trigger.¹ For many years, we referred to this type of

patient as having idiopathic or lone AF. However, his family history of AF and the fact that he is so young raise the possibility of a genetic cause. Clearly, there is some genetic basis to AF.² For example, having a first-degree relative with AF at a young age increases the odds of developing AF. However, genes identified using genome-wide association suggest that most of the genetic basis is polygenetic basis. There is increasing evidence, however, that these patients may have a single gene defect causing their AF. A study by the group at Vanderbilt led by Yoneda et al³ in 2021 showed that when patients with AF who are under age 65 underwent genetic testing, a pathological mutation or likely pathological mutation was identified in up to 10% of cases. This percentage is inversely associated with the age at onset of AF, with a prevalence of 17% of rare variants in patients younger than 30 years. One might think that the mutations found would be related to channelopathies. Indeed, some patients are found to have a sodium channel defect or other gene defects that are also associated with Brugada or long QT syndrome, but the disease-causing variants were more often observed in genes known to cause dilated, arrhythmogenic, and hypertrophic cardiomyopathies. Genetic truncations in the TTN gene (encoding titin) were most often observed. This then raises the question of why these young patients who have a mutation that causes a cardiomyopathy have AF, even when there is no detectable ventricular involvement. Although AF may just be an early manifestation of ventricular dysfunction (perhaps diastolic), it may be instead that in the early stages, these genes that lead to cardiomyopathies and heart failure cause primary electrophysiological changes that predispose to AF, much like a channelopathy.

The most recent guidelines suggest testing patients with AF who do not have overt heart disease and are under age 45 years but give this only a IIb indication: “Growing evidence suggests that, in addition to risk factors for AF present in older populations, young patients who develop AF may also harbor susceptibility for inherited ion channel and cardiomyopathic disorders, even in those with normal echocardiograms. In addition to the standard workup for newly diagnosed AF, genetic testing for rare pathogenic variation, advanced imaging modalities, and surveillance screening could detect otherwise occult cardiomyopathy.”⁴ As the evidence grows that these patients can be found to have a gene mutation which has a clinically meaningful impact on their prognosis and treatment, it is likely that the guidelines will recommend genetic testing more strongly in very young patients like this. 

Disclosures: Dr Knight has served as a paid consultant to Medtronic and was an investigator in the PULSED AF trial. In addition, he has served as a consultant, speaker, investigator, and/or has received EP fellowship grant support from Abbott, AltaThera, AtriCure, Baylis Medical, Biosense Webster, Biotronik, Boston Scientific, CVRx, Philips, and Sanofi; he has no equity or ownership in any of these companies.

References

1. Yamane T, Shah DC, Peng JT, et al. Morphological characteristics of P waves during selective pulmonary vein pacing. J Am Coll Cardiol. 2001;38(5):1505-1510. doi:10.1016/s0735-1097(01)01578-9

2. Kany S, Jurgens SJ, Rämö JT, et al. Genetic testing in early-onset atrial fibrillation. Eur Heart J. 2024;45(34):3111-3123. doi:10.1093/eurheartj/ehae298

3. 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):1371-1379. doi:10.1001/jamacardio.2021.3370

4. Joglar JA, Chung MK, Armbruster AL, et al. 2023 ACC/AHA/ACCP/HRS guideline for the diagnosis and management of atrial fibrillation: a report of the American College of Cardiology/American Heart Association Joint Committee on clinical practice guidelines. Circulation. 2023;149(1):e1-156. doi:10.1161/CIR.0000000000001193