Genetic testing in early-onset atrial fibrillation

Abstract

Atrial fibrillation (AF) is a globally prevalent cardiac arrhythmia with significant genetic underpinnings, as highlighted by recent large-scale genetic studies. A prominent clinical and genetic overlap exists between AF, heritable ventricular cardiomyopathies, and arrhythmia syndromes, underlining the potential of AF as an early indicator of severe ventricular disease in younger individuals. Indeed, several recent studies have demonstrated meaningful yields of rare pathogenic variants among early-onset AF patients (∼4%-11%), most notably for cardiomyopathy genes in which rare variants are considered clinically actionable. Genetic testing thus presents a promising opportunity to identify monogenetic defects linked to AF and inherited cardiac conditions, such as cardiomyopathy, and may contribute to prognosis and management in early-onset AF patients. A first step towards recognizing this monogenic contribution was taken with the Class IIb recommendation for genetic testing in AF patients aged 45 years or younger by the 2023 American College of Cardiology/American Heart Association guidelines for AF. By identifying pathogenic genetic variants known to underlie inherited cardiomyopathies and arrhythmia syndromes, a personalized care pathway can be developed, encompassing more tailored screening, cascade testing, and potentially genotype-informed prognosis and preventive measures. However, this can only be ensured by frameworks that are developed and supported by all stakeholders. Ambiguity in test results such as variants of uncertain significance remain a major challenge and as many as ∼60% of people with early-onset AF might carry such variants. Patient education (including pretest counselling), training of genetic teams, selection of high-confidence genes, and careful reporting are strategies to mitigate this. Further challenges to implementation include financial barriers, insurability issues, workforce limitations, and the need for standardized definitions in a fast-moving field. Moreover, the prevailing genetic evidence largely rests on European descent populations, underscoring the need for diverse research cohorts and international collaboration. Embracing these challenges and the potential of genetic testing may improve AF care. However, further research-mechanistic, translational, and clinical-is urgently needed.

Keywords: Atrial fibrillation; Cardiomyopathy; Cascade testing; Genetic testing; Rare variants.

Graphical Abstract

In people with early-onset atrial fibrillation (AF), an enrichment in pathogenic or likely pathogenic variants in cardiomyopathy and or/arrhythmia syndrome-associated genes is observed (see Figure 2 for more details). The diagnostic yield of capturing people with variants in these genes is higher with younger age, family history, structural or electrocardiogram (ECG) abnormalities (see Figure 1 for more details). Uncovering these high-risk individuals for heart failure enables personalized management that will need to comprehensively assess potential risks and benefits of genetic testing results. Some benefits include genotype-informed clinical assessment such as reinterpretation of borderline left ventricular hypertrophy in the setting of hypertrophic cardiomyopathy variants as well as genetic counselling and cascade testing of family members. Potential risks include the high likelihood of variants of uncertain significance that may lead to anxiety without informing healthcare decisions. Resource constraints in clinical settings might lead to further inequity for people without access to academic centres with the necessary infrastructure to offer such genetic testing services or genetic counselling (see Figure 3 for more details).

Figure 1

Overview of when to consider genetic testing and expected diagnostic yield in rare variant testing in early-onset atrial fibrillation across lifetime. This figure uses medical images from Servier Medical Art under the Creative Commons 3.0 license. VUS, variants of unknown significance

Figure 2

Overview of genes where rare coding variants have been implicated in early-onset atrial fibrillation (turquoise), genes with high confidence for cardiomyopathy or arrhythmia syndromes, and genes in the American College of Medical Genetics and Genomics actionable subset overlapping with the latter (red), or overlapping with the former and latter

Figure 3

Overview of potential benefits, barriers, and risks associated with increases in genetic testing for atrial fibrillation. CV, cardiovascular; VUS, variants of unknown significance