Introduction Several gene defects are associated with idiopathic ventricular fibrillation (IVF) and sudden cardiac death (SCD). The recent development of NGS-based mutation screening provides a unique opportunity to estimate extensively the spectrum and prevalence of rare variants in genes associated with cardiac diseases. Methods Cohort 1 was composed of 75 patients resuscitated from cardiac arrest due to IVF. All patients have undergone a complete clinical cardiac examination including 12 lead-ECG, cardiac echography, coronography and exercise test. Cohort 2 was composed of 99 victims of SCD related to ventricular fibrillation younger than 45 years old and without explanation for the SCD at the time of the reanimation. Genetic screening was based on the use of the HaloPlex(tm) Target Enrichment System (Agilent Technologies) prior to HiSeq sequencing (Illumina). The custom kit designed for this study covers 163 genes previously reported as involved in cardiac arrhythmias, conduction defect and cardiomyopathies. Results In cohort 1, the mean age was 36±10 years with a male predominance (52 males, 69%). In cohort 2, the mean age was 37±7 years with a male predominance (76 males, 79%). In cohort 1, we identified 50 putative mutations in 35 patients (47%). In cohort 2, we identified 30 putative mutations in 24 patients (24%). Conclusion Our study identified mutations in almost 50 % of IVF patients after a complete cardiac evaluation. These results suggest that molecular analysis must be part of the work up in this kind of patients. In young patients affected by unexplained sudden death, the molecular analyses are less contributive probably because of a more important percentage of patients affected by ischemic cardiomyopathies.