Real-World Genetic Characteristics of Candidates for Implantable Cardioverter-Defibrillators with Dilated Cardiomyopathy

Background The real-world prevalence of sudden cardiac death (SCD)–related gene mutations and their relationship with implantable cardioverter-defibrillator (ICD) implantation in dilated cardiomyopathy (DCM) has not been clearly investigated. Methods This study included patients with sporadic DCM with persistent left ventricular ejection fraction (LVEF) ≤ 35% even after 3 months of guideline-directed medical treatment or those with an ICD for secondary prevention and LVEF < 50%. Genetic tests targeting 444 pan-cardiomyopathy genes (including 36 core DCM genes) were performed, along with the collection of clinical and electrophysiological information. Results A total of 105 patients were enrolled (median age, 65.0 [57.5–75.0] years), and 33 (31%) were women. The average LVEF was 27.4 ± 5.9%, and 46 patients (44%) had ICD or cardiac resynchronization therapy with ICD (34 for primary prevention and 12 for secondary prevention purpose) at the time of enrollment. Fourteen patients (13%) had pathogenic (P) or likely pathogenic (LP) variants (comprising 6 TTN , 4 DSP , 2 TNNT2 , 1 RBM20, 1 DSG and 1 MYBPC3 , one patients had both DSP and RBM20 ), and 59 patients (56%) had P/LP/variant of uncertain significance (VUS) in the 36 core DCM genes. Twenty-eight patients (27%) harbored SCD-related gene variants (14 DSP , 11 FLNC , 9 RBM20 and 2 TMEM43 ). The prevalence of SCD gene variants tended to be higher in the secondary prevention and non-ICD groups (33.3% for secondary purposes, 11.8% for primary purposes, and 33.8% for non-ICD; p = 0.058). Conclusions In patients with advanced heart failure and DCM, P/LP-validated DCM variants were not common in sporadic cases. However, when extended to VUS, approximately half of the patients had core DCM-related variants. The prevalence of SCD variants was not lower in the non-ICD group, thus suggesting a potential risk of fatal arrhythmia. (Trial registration: CRIS KCT0004913) ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial CRIS KCT0004913 ### Funding Statement This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2019R1F1A1045911) and Research Fund of Korean Society of Circulation, (202003-04). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol was approved by Gangnam Severance and four other centers (IRB 17 No 3-2019-0372, CR319168, 2020AN0454, KHUH2020-03-071 and GNAH2020-01-005) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets used and/or analyzed in the current study are available from the corresponding author upon reasonable request. * DCM : dilated cardiomyopathy GDMT : guideline-directed medical treatment SCD : sudden cardiac death NYHA : New York Heart Association CRT : cardiac resynchronization therapy P : pathogenic LP : likely pathogenic MAF : minor allele frequency CRTD : CRT with defibrillator BBB : bundle branch block VUS : variant of uncertain significance ARVC : arrhythmogenic right ventricular cardiomyopathy