Enrichment of loss-of-function and copy number variants in ventricular cardiomyopathy genes in ‘lone’ atrial fibrillation

Abstract

Aims Atrial fibrillation (AF) is a complex heritable disease whose genetic underpinnings remain largely unexplained, though recent work has suggested that the arrhythmia may develop secondary to an underlying atrial cardiomyopathy. We sought to evaluate for enrichment of loss-of-function (LOF) and copy number variants (CNVs) in genes implicated in ventricular cardiomyopathy in ‘lone’ AF. Methods and results Whole-exome sequencing was performed in 255 early onset ‘lone’ AF cases, defined as arrhythmia onset prior to 60 years of age in the absence of known clinical risk factors. Subsequent evaluations were restricted to 195 cases of European genetic ancestry, as defined by principal component analysis, and focused on a pre-defined set of 43 genes previously implicated in ventricular cardiomyopathy. Bioinformatic analysis identified 6 LOF variants (3.1%), including 3 within the TTN gene, among cases in comparison with 4 of 503 (0.80%) controls [odds ratio: 3.96; 95% confidence interval (CI): 1.11–14.2; P = 0.033]. Further, two AF cases possessed a novel heterozygous 8521 base pair TTN deletion, confirmed with Sanger sequencing and breakpoint validation, which was absent from 4958 controls (P = 0.0014). Subsequent cascade screening in two families revealed evidence of co-segregation of a LOF variant with ‘lone’ AF. Conclusion ‘Lone’ AF cases are enriched in rare LOF variants from cardiomyopathy genes, findings primarily driven by TTN, and a novel TTN deletion, providing additional evidence to implicate atrial cardiomyopathy as an AF genetic sub-phenotype. Our results also highlight that AF may develop in the context of these variants in the absence of a discernable ventricular cardiomyopathy.

Patient and cell-type specific hiPSC-modeling of a truncating titin variant associated with atrial fibrillation

“…Participants were recruited through the PERSONALIZE AF biobank (H15-02970) in Vancouver, Canada. [10][11][12] All individuals provided written informed consent.…”

Genetically Based Atrial Fibrillation: Current Considerations for Diagnosis and Management

“…Of interest, in this analysis, TTNtv carriers did not have echocardiographic evidence of left ventricular (LV) structural dysfunction and had normal left atrial (LA) and LV dimensions at time of diagnosis or at follow-up multiple years later. 61 LOF variants in TTN are more common among patients with early-onset AF compared to healthy controls 62 , with a higher proportion of variants seen in younger patients at time of AF diagnosis. 63 Additionally, when compared to all patients with AF, early-onset AFTTNtv carriers are at increased risk of reduction in left ventricular ejection fraction and left atrial late gadolinium enhancement on cardiac magnetic resonance imaging, a marker of atrial fibrosis.…”

Genetically based atrial fibrillation: Current considerations for diagnosis and management

“…Of interest, in this analysis, TTNtv carriers did not have echocardiographic evidence of LV structural dysfunction and had normal left atrial (LA) and LV dimensions at the time of diagnosis or at follow‐up multiple years later 62 . LOF variants in TTN are more common among patients with early‐onset AF compared with healthy controls, 63 with a higher proportion of variants seen in younger patients at the time of AF diagnosis 64 . Additionally, when compared with all patients with AF, early‐onset AF TTNtv carriers are at increased risk of reduction in LV ejection fraction and LA late gadolinium enhancement on cardiac magnetic resonance imaging, a marker of atrial fibrosis 65 …”