Early onset atrial fibrillation as a marker of inherited cardiomyopathy: lessons from combined imaging and genetic assessment

Introduction

Early-onset atrial fibrillation (AF) may represent the first expression of an inherited cardiomyopathy or electrical disease. Recent data show a relevant prevalence of pathogenic variants, particularly in genes linked to cardiomyopathy and ion channel function, among young AF patients (1-2). Identifying these variants supports risk stratification, family screening, and personalized management (3). Combining imaging with genetic testing may enhance diagnostic accuracy and improves understanding of AF pathophysiology in this population.

Purpose

To evaluate the diagnostic yield of genetic testing in patients with early-onset atrial fibrillation, integrating cardiac magnetic resonance (CMR) and electrocardiographic (ECG) findings to identify potential underlying cardiomyopathic or arrhythmogenic substrates.

Methods

Patients with AF onset before age 50 were referred for comprehensive evaluation, including family history, ECG with Brugada leads, echocardiography, and CMR when available. Genetic testing was performed using targeted or extended panels for cardiomyopathy and arrhythmia genes. Imaging and genetic data were correlated to determine the prevalence of structural abnormalities and pathogenic or likely pathogenic variants.

Results

A total of 24 patients (19 males) were evaluated, with a mean age at first AF episode of 33.1 ± 10.4 years. CMR was performed in 11 patients (46%) and was abnormal in 6 (55%), mainly due to the presence of late gadolinium enhancement (LGE). ECG anomalies were detected in 11 patients (46%), most frequently QRS fragmentation (n = 4) and T-wave alterations (n = 3). No definite Brugada-type patterns were observed.

Genetic testing was completed in 19 patients (79%) (Figure 1). Of these, 12 (63%) were negative, 2 (10.5%) carried variants of uncertain significance (VUS) in DSP + TRPM4 and KCNA5, 2 (10.5%) harbored likely pathogenic (LP) variants in TTN and SCN5A, and 3 (16%) had pathogenic (P) variants in LMNA (two family members) and MYH7. All six patients with abnormal CMR also had ECG anomalies; among them, two carried P/LP variants (LMNA, SCN5A) and one a VUS (DSP + TRPM4). The patients with KCNA5 (VUS) and TTN (LP) variants had normal imaging and ECG findings. Of the remaining pathogenic variant carriers (LMNA, MYH7), CMR was unavailable, though one exhibited ECG abnormalities. Overall, 3 of 5 patients with LP/P variants showed structural and/or conduction abnormalities (Figure 2).

Conclusion

In this cohort, a notable proportion (26%) carried pathogenic or likely pathogenic variants, primarily in sarcomeric and nuclear envelope genes (TTN, LMNA, MYH7, SCN5A), correlating with imaging and ECG abnormalities. The integration of imaging and genetic analysis proved essential for refining the diagnosis particularly in AF patients with early-onset presentations.Results of genetic testingOverlap of ECG, CMR and Genetic Abnormal