Whole exome sequencing in young atrial fibrillation patients

Abstract

Abstract Background Up to 10% of atrial fibrillation (Afib) patients develop the condition in the young age and in the absence of any related risk factors. Recent publications emphasized the importance of genetic testing in this population. However, the yield of the investigation is highly variable and ranges from 1 to 24% precents. Purpose The purpose of this study is to evaluate the prevalence of causative genetic variants in young Afib patients without risk factors and evaluate any structural changes of the heart. Methods We performed whole exome sequencing in 54 young (age of Afib onset less than 65 years) Afib patients without any Afib related risk factors (original cohort). Using ACMG guidelines we performed analysis of 349 previously described cardiomyopathy and arrhythmia associated genes. If a pathogenic (P) or likely pathogenic (LP) variant was found, a cardiac magnetic resonance imaging (CMR) was performed to exclude any structural abnormalities of the heart. We also extracted 107 young Afib patients without any risk factors from UK Biobank (UK Biobank cohort) and performed analysis of the same genes in the subgroup. Results The prevalence of P and LP variants was 24% (13 cases) in the original cohort and 8% (9 cases) in the UK Biobank cohort (p=0.006). We observed variants in cardiac structural and developmental genes only in both cohorts (Table 1 and 2). In the original cohort there were nine (17%) patients with P and LP variant in TTN gene. Moreover, five patients were positive for the same TTN variant NM_001267550.2:c.13696C>T p.(Gln4566Ter). In six (46%) original cohort patients we observed structural changes of the heart on CMR – in five patients there was dilation of one or both ventricles and in one there was increased T1 mapping intensity of septal wall segments. Conclusions 1. There is a high prevalence of pathogenic and likely pathogenic causative genetic variants in young atrial fibrillation patients without any risk factors. 2. All variants are localized in cardiac structural or developmental genes only. 3. There is a high grade of structural changes of the heart observed on cardiac magnetic resonance imaging in patients with monogenic atrial fibrillation.Table 1.WES data in original cohortTable 2.WES data in UK Biobank cohort