RARE LOSS-OF-FUNCTION VARIANT ANALYSIS IN LONE ATRIAL FIBRILLATION

Abstract

Atrial fibrillation (AF) is a complex heritable disorder that substantially increases the risk for stroke, sudden death and all-cause mortality. Lone AF is a subset defined by early diagnosis (less than 60 years) and with no evidence of cardiopulmonary disease. Genome-wide association studies have associated loci near genes for structural integrity and function of muscles with AF susceptibility. In addition, some studies have identified rare loss-of-function (LoF) variants in dilated cardiomyopathy (DCM) genes in lone AF. The increased burden of these variants in lone AF patients may indicate a shared predisposition between AF and DCM. We performed a retrospective study on 252 adult patients and a control group of 503 healthy European subjects. Exome sequencing and microarray assays were performed at the McGill Genome Center while exome data from the controls was retrieved from 1KG Consortium. Principal component analysis was performed to define a group with common ancestry using SVS software. Variants within candidate DCM genes were filtered by minor allele frequency of ≤0.1%, a Combined Annotation Dependent Depletion (CADD) Phred score of >20 and a LoF variant type (frameshift, splice acceptor, splice donor and stop gain). These factors were retrieved from public annotation databases and applied using VarSeq software for variant analysis. All variants were confirmed with Sanger sequencing. Cascade screening was attempted on all cases positive for variants. The AF cohort, an ethnically homogenous composite of 181 lone AF cases, had 6 heterozygous LoF variants, including 4 novel variants, in 6 individuals, while the controls had 4 in 503 individuals. Half of variants in the cases were in the TTN gene (3/6). The prevalence of rare LoF variants in the lone AF cohort was 3.3% while in the control cohort 0.79%, the odds ratio of rare LoF variants found in lone AF patients compared to controls is 4.28 (95%CI: 1.19-15.33, P-value: 2.5E-02). Cascade screening in one family demonstrated co-segregation of one of the rare TTN variants and AF. Patients with lone AF carry a significant burden of heterozygous LoF variants in DCM genes. Our results are in agreement with a previous study identifying TTN variants in lone AF patients. Further, we identified novel variants in different DCM genes and confirmed the co-segregation of a TTN variant and AF in one family. Our findings may indicate a common genetic predisposition between lone AF and DCM, which may help elucidate novel pathophysiologic mechanisms, and improve diagnosis and treatment.