1211Genetic background of sudden cardiac death caused by idiopathic myocardial fibrosis

Abstract

Background: In our previous studies we have identified idiopathic myocardial fibrosis (IMF) in autopsy as the most common cause of sudden cardiac death (SCD) among young SCD victims. Reports from UK also show unexplained myocardial fibrosis as prominent cause of SCD among young athletes. We have previously detected a lamin A/C mutation in one young IMF SCD subject but largely the cause of IMF is unknown. Objective: Assess the genetic etiology of sudden cardiac death caused by idiopathic myocardial fibrosis. Methods: We have collected autopsy findings and tissue samples (formalin fixed, paraffin embedded samples) from 4,031 SCD victims since 1998 in Northern Finland as a part of the Fingesture study. Idiopathic myocardial fibrosis was the cause of SCD in 145 subjects. Most were previously asymptomatic. We performed next generation sequencing (Illumina OS-Seq) of 174 myocardial structure related genes in 48 IMF SCD victims (median age 52, 32 males). We selected the youngest SCD victims with the best quality DNA for the analysis. All variants with under 1% prevalence in ExAC exome database were included in further analysis. The pathogenic capabilities of the variant were studied in current literature and with Sift and PolyPhen software. Results: We detected probably pathogenic mutations (literary and database search) in nine subjects and possibly pathogenic mutations according to software and database search in 12 additional subjects. From the probably pathogenic mutations two mutations were in genes associated with arrhythmogenic right ventricular dysplasia (ARVD) (DSP, PKP2). Additionally, ARVD related genes were found also in possibly pathogenic mutations list (DSP). One probably pathogenic mutation was detected in lamin A/C gene. The most interesting finding was in gene CTF1. Three unrelated SCD subjects had the same mutation in this gene. The mutation has been previously associated with dilated cardiomyopathy in one case report. Conclusion: Surprisingly high number of IMF SCD victims have myocardial structure encoding gene mutations. Mutations in ARVD related genes are evident even without classical autopsy findings of ARVD. Mutation in CTF1 suggest to a founder mutation in this population of SCD victims from North Finland.