부산대학교 도서관

Background: Atrial fibrillation (AF) is a common cardiac arrhythmia with a substantial genetic component. Rare variation in TTN and other sarcomeric genes have been associated with AF, in particular in early-onset disease.Aim: To describe the burden of rare, functional variants in a Norwegian early-onset AF population and to perform functional characterization in a Ttn truncating variant (Ttntv) mouse model.Methods: We performed whole-genome sequencing in 90 individuals with onset of AF before age 50 years and calculated the burden of rare, functional variation for all genes. Variant frequencies and gene burden from gnomAD 3.1.2 NFE were used as controls. The burden was defined as the sum of allele counts for rare (MAF<1%) and damaging variants (high and moderate impact) for each gene, and differences in burden was assessed using Fisher’s exact test. Functional characterization, including echocardiography, electron microscopy and mRNA expression analyses, was performed in atria from haploinsufficient Ttntv mice.Results: We identified an increased burden of rare, functional variation in 57 genes, including the sarcomeric genes TTN, MYH6 and OBSL1, but also in the cell adhesion gene DCHS2, in individuals with early-onset AF. Ttntv mice had normal cardiac function assessed by echocardiography, but electron microscopy revealed structural remodeling of the atria, with a patchy pattern of unorganized sarcomeres with focal fibrosis and lipid droplet accumulation. Molecular profiling of atria using RNA sequencing showed differential expression of genes related to cellular stress, sarcomeric structure and fibrosis, including increased levels of Anp, Malat1 and Kcna1. Dchs2 displayed decreased expression in Ttntv atria.Conclusion: We identified an increased burden of rare, functional variation in genes associated with sarcomeric function in early-onset AF. Atrial myopathy with sarcomeric lesions, focal fibrosis, lipid droplet accumulation and altered gene expression of Anp, Malat1 and Kcna1 was found in atria of mice with Ttntv, suggesting a causal, pathophysiological relationship between TTN variants and AF. Interestingly, DCHS2 displayed both increased burden of rare variation in early-onset AF and decreased expression in Ttntv mouse atria.