Atrial fibrillation is the most prevalent cardiac arrhythmia and recent studies highlight the complexity of genetics in this context (1). Clinical and genetic features overlap with cardiomyopathy and arrhythmia syndromes and for this reason the most recent 2023 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on management of atrial fibrillation provide a Class IIb recommendation on genetic testing in individuals with atrial fibrillation before the age of 45 years and no obvious risk factors (2).  

Kany et a´s review, “Genetic testing in early-onset atrial fibrillation”,  focuses on the benefits and risks of integrating genetic testing of atrial fibrillation patients in the clinical practice. The importance of this topic has increased given the wider availability of genetic testing including panels, whole exome and genome sequencing. In people with early-onset atrial fibrillation, an enrichment in pathogenic or likely pathogenic rare variants in cardiomyopathy has been observed, mainly truncating variants in MYBPC3, LMNA, TTN and PKP2. Similarly, variants in SCN5A and KCNQ, ion-channel genes associated with QT disorders, have also been related (3). Higher genetic yield has been found associated with earlier age of onset and a cut-off of 45 years gave a yield around 10% that increased to 16% in patients diagnosed before 30 years (4). An increased risk of death in almost 10 years follow-up of variant carriers versus non carriers has also been demonstrated and risk of cardiomyopathy and sudden cardiac death appears to be higher (5). There are some unresolved issues such as the underrepresentation of non-European population in genetics studies, the understanding of the temporal relation between the atrial and ventricular manifestations among clinical relevant variants carriers and the integration of polygenic risk and rare variants (3).  

Genetic panel testing including cardiomyopathies and arrhythmia syndromes genes that are considered high confidence for inherited cardiac disease, particularly genes where rare variants are considered actionable by the ACMG, would be the best approach (6,7).  Pretest genetic counselling that include discussion about the implication of testing results and the possibility of finding variant of unknown significance is necessary.  Around 60% of patients with early-onset atrial fibrillation might carry such variants and this is a challenge for both clinicians and patients (4). Strategies for addressing these variants are needed, including future re-classification based on new evidence.  

Despite the potential benefits of increasing genetic testing for atrial fibrillation, several barriers still need to be resolved. Cost-effectiveness studies would be needed given the high frequency of the disease and the risk of limiting genetic testing to large academic centres. Also, the lack of genetic counsellors and cardiologists with specialized training and knowledge could limit wide-spread implementation (3).  

Current ESC guidelines on AF do not provide a recommendation for genetic testing in young patients without comorbidities. However, it would be reasonable to consider this in patients with a very early-onset of disease, familial aggregation of atrial fibrillation or cardiomyopathy or ECG and structural suggestive abnormalities. A more personalized care could be delivered including cascade screening, information about prognosis and management. A structured pathway on how to include genetic testing in patient care is proposed in this review to facilitate clinical integration of genetic data.