Abstract Body (Do not enter title and authors here): Background: The genetic basis of atrial fibrillation (AF) remains incompletely understood. While next-generation sequencing (NGS) can detect various rare variants, the identification of pathogenic variants associated with AF remains challenging. Additionally, the indications for genetic testing in early-onset AF vary considerably across different guidelines and have not been clearly established.
Research Questions: This study aimed to assess the prevalence of pathogenic variants in AF candidate genes in patients with early-onset AF and to identify clinical factors associated with a positive genetic test result.
Methods: Using NGS, we investigated 180 arrhythmia and cardiomyopathy related genes including 15 known AF-associated genes for 123 probands with early-onset AF who had AF diagnosed before 60 years of age. Variants were filtered and classified according to the ACMG/AMP guidelines. Functional study of variants of uncertain significance in ion channel genes was performed using the patch-clamp technique. Logistic regression analysis was conducted to predict positive results of genetic testing.
Results: Among the cohort (n=123), the average age of AF onset was 43±9 years, 104 (85%) individuals were male and 42 had a family history of AF. Twenty (16%) presented with heart failure, 17 (14%) with cardiomyopathy, and 23 (19%) with bradyarrhythmias. Electrocardiographic abnormalities, including QTc ≥ 440 ms, QRS ≥ 120 ms, or ST-T abnormalities, were observed in 25 (21%). Echocardiographic abnormalities such as left ventricular wall thickness ≥ 13 mm, left ventricular end-diastolic diameter ≥ 55 mm, or left ventricular ejection fraction < 50% were identified in 34 (29%). Sixteen pathogenic or likely pathogenic variants with known AF-associated genes were identified from 18 probands; 6 variants in TTN, 4 in SCN5A, 2 in MYH7, 1 in KCNA5, 1 in KCNQ1, 1 in LMNA, and 1 in MYBPC3. Patch-clamp study revealed a loss-of-function abnormality in KCNA5:c.1105-1112del and a gain of function abnormality in SCN5A:p.Ile450Thr. Multivariable logistic regression showed that electrocardiographic abnormalities, QTc ≥ 440 ms and ST-T abnormalities were significantly associated with positive results of genetic testing.
Conclusion: Among 123 early-onset AF patients, we identified 16 pathogenic or likely pathogenic variants of known AF-associated genes in 18 probands (14.6%). Genetic testing might be considered for early-onset AF patients exhibiting electrocardiographic abnormalities.