Atrial fibrillation (AF)

Atrial fibrillation is the most common cardiac arrhythmia worldwide. The arrhythmia is characterised by uncoordinated atrial electrical activity, producing a rapid and irregular ventricular response and conferring an elevated risk of thromboembolic stroke and sudden cardiac death. Onset is variable: isolated familial forms often manifest before the age of 60 and may be diagnosed in young adulthood, whereas the prevalence of atrial fibrillation in the general population rises sharply with age and is highest after 65 years of age. A positive family history, early onset, or absence of conventional cardiovascular risk factors (hypertension, valvular disease, coronary artery disease) raises the clinical index of suspicion for an underlying (mono)genic cause. Such underlying causes include isolated familial atrial fibrillation and atrial fibrillation occurring as part of an inherited cardiomyopathy or primary arrhythmia syndrome.

The estimated prevalence is approximately 0.4% in the general population and rises to 6% in adults over 65 years.

The genetic conditions associated with atrial fibrillation follow heterogeneous inheritance patterns. Autosomal dominant inheritance predominates among isolated familial forms and among the inherited cardiomyopathies and channelopathies in which atrial fibrillation is a frequent complication.

Atrial fibrillation is most often a multifactorial condition. In the majority of patients, it develops in the context of acquired cardiovascular, metabolic, or lifestyle-related risk factors, including increasing age, hypertension, structural or valvular heart disease, coronary artery disease, heart failure, obesity, diabetes mellitus, sleep apnoea, alcohol consumption, and systemic inflammatory or endocrine disorders.

Genetic factors may nevertheless contribute to atrial fibrillation susceptibility. In most cases, this contribution is complex and polygenic rather than attributable to a single disease-causing variant. Rare monogenic forms are uncommon but clinically relevant, particularly in patients with early-onset atrial fibrillation, a positive family history, and an absence of conventional risk factors. Current evidence suggests that around 15% of patients with atrial fibrillation report a positive family history, indicating a relevant genetic contribution.

Monogenic atrial fibrillation may occur as apparently isolated familial atrial fibrillation or as part of an inherited cardiac disorder, especially cardiomyopathies and primary arrhythmia syndromes (cardiac channelopathies). Genes implicated in such presentations include, among others, cardiac ion-channel genes such as KCNQ1 and SCN5A, as well as cardiomyopathy-associated genes such as TTN and LMNA. In these cases, atrial fibrillation may represent an early manifestation of an underlying inherited cardiac condition rather than an isolated arrhythmia.

• Genetic testing is not indicated for all patients with atrial fibrillation. Its clinical value is greatest in selected patients in whom the presentation raises suspicion of an inherited cardiac disorder. This includes atrial fibrillation with early onset, atrial fibrillation occurring in the absence of established acquired risk factors, familial clustering of atrial fibrillation or history of sudden cardiac death. Contemporary European and international cardiology expert recommendations support genetic testing in selected patients with atrial fibrillation as a Class IIb (“may be considered”) diagnostic option.
• In this setting, molecular genetic testing aims not merely to “explain” atrial fibrillation but to identify a possible underlying inherited cardiomyopathy or primary arrhythmia syndrome with implications for prognosis, surveillance, and family assessment. Detection of a pathogenic or likely pathogenic germline variant can support a more precise clinical diagnosis, guide targeted cardiac evaluation such as imaging or rhythm monitoring, and inform individualised management by the treating physicians. Recent studies suggest that genetic findings in early-onset atrial fibrillation may alter clinical management in a relevant subset of genotype-positive patients.
• Identification of the familial pathogenic variant also enables predictive testing of at-risk relatives. This can help distinguish relatives who require cardiological surveillance from those who are unlikely to be at increased familial risk due to the identified variant.

• Wilde AAM, Semsarian C, Márquez MF, Shamloo AS, Ackerman MJ, Ashley EA, et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus statement on the state of genetic testing for cardiac diseases. Europace. 2022;24(8):1307-1367. doi:10.1093/europace/euac030. PMID: . PMCID: PMC9435643.
• Laws JL, Shabani M, Williams HL, Grauherr DD, Kilbourne WM, Crawford DM, et al. Genetic evaluation of early-onset atrial fibrillation: impact on patient management. Eur Heart J. 2026;47(13):1554-1572. doi:10.1093/eurheartj/ehaf829. PMID: .
• Zeppenfeld K, Tfelt-Hansen J, de Riva M, Winkel BG, Behr ER, Blom NA, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43(40):3997-4126. doi:10.1093/eurheartj/ehac262. PMID: .
• Arbelo E, Protonotarios A, Gimeno JR, Arbustini E, Barriales-Villa R, Basso C, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503-3626. doi:10.1093/eurheartj/ehad194. PMID: .