Prevalence of deleterious cardiomyopathy variants in early-onset atrial fibrillation.

Background: Atrial fibrillation (AF) is a common cardiac arrhythmia associated with an increased risk of stroke, heart failure, and death. Recent studies suggests that individuals with early onset of AF could be at increased risk of developing heart failure and dilated cardiomyopathy. This study aimed to identifying genetic variants in a broad panel of cardiomyopathy genes among early-onset AF individuals. Methods: We conducted targeted genetic sequencing of 29 cardiomyopathy-associated genes in 478 individuals with AF onset below 45 years of age from a Danish cohort. Additionally, we analyzed whole exome sequencing data in 374,289 individuals from the UK Biobank, including 29,108 individuals with AF. The cohort was stratified by age at AF diagnosis, and individuals with pre-existing cardiomyopathy were excluded. We focused on rare, truncating variants predicted to lead to loss of function, and potentially deleterious missense variants in the UK Biobank. Results: In the Danish cohort, 42 (8.8%) individuals with early-onset AF had truncating genetic variants in known cardiomyopathy genes. The UK Biobank analysis showed an inverse dose-response-like relationship between age of AF onset and prevalence of truncating variants, ranging from 3.8% in the AF onset <45 years group to 1.4% in the group without AF diagnosis. The prevalence of rare missense variants showed a similar pattern. Conclusions: We identified a high prevalence of deleterious variants in cardiomyopathy-associated genes among individuals with early-onset AF. This supports recent guideline suggestions and indicates that genetic testing and surveillance for cardiomyopathy could be relevant in selected individuals with an early AF diagnosis.