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BackgroundSudden unexplained death may be the first manifestation of an unknown inherited cardiac disease. Current genetic technologies may enable the unraveling of an etiology and the identification of relatives at risk. The aim of our study was to define the etiology of natural deaths, younger than 50 years of age, and to investigate whether genetic defects associated with cardiac diseases could provide a potential etiology for the unexplained cases.Methods and FindingsOur cohort included a total of 789 consecutive cases (77.19% males) <50 years old (average 38.6±12.2 years old) who died suddenly from non-violent causes. A comprehensive autopsy was performed according to current forensic guidelines. During autopsy a cause of death was identified in most cases (81.1%), mainly due to cardiac alterations (56.87%). In unexplained cases, genetic analysis of the main genes associated with sudden cardiac death was performed using Next Generation Sequencing technology. Genetic analysis was performed in suspected inherited diseases (cardiomyopathy) and in unexplained death, with identification of potentially pathogenic variants in nearly 50% and 40% of samples, respectively.ConclusionsCardiac disease is the most important cause of sudden death, especially after the age of 40. Close to 10% of cases may remain unexplained after a complete autopsy investigation. Molecular autopsy may provide an explanation for a significant part of these unexplained cases. Identification of genetic variations enables genetic counseling and undertaking of preventive measures in relatives at risk.

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twitter: @dr_pavia // @fernidom Tweet: "Natural history study of PRKAG2 syndrome reveals high rates of AF, conduction disease, advanced HF and life-threatening arrhythmias." ABSTRACT Background: PRKAG2 gene variants cause a syndrome characterised by cardiomyopathy, conduction disease and ventricular preexcitation. Only a small number of cases have been reported to date, and the natural history of the disease is poorly understood. Objectives: To describe phenotype and natural history of PRKAG2 variants in a large multicenter European cohort. Methods: We retrospectively studied clinical, electrocardiographic and echocardiographic data from 90 individuals with PRKAG2 variants (53% males, median 33 years (IQR: 15-50) recruited from 27 centers. Results: At first evaluation, 93% of patients were in NYHA functional class I or II. Maximum left ventricular (LV) wall thickness was 18±8 mm and LV ejection fraction was 61±12%. LV hypertrophy (LVH) was present in 60 (67%) subjects at baseline. Thirty patients (33%) had ventricular preexcitation or had undergone an accessory pathway ablation; 17 (19%) had a pacemaker (median age at implantation 36 years (IQR: 27-46)) and 16 (18%) had atrial fibrillation (AF) (median age 43 years (IQR: 31-54)). After a median follow-up of 6 years (IQR:2.3-13.9), 71% of individuals had LVH, 29% had AF, 21% a de novo pacemaker (median age at implantation 37 years (IQR: 29-48)), 14% required admission for heart failure (HF), 8% experienced sudden cardiac death or equivalent, 4% required a heart transplant and 13% died. Conclusions: PRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of AF, conduction disease, advanced HF and life-threatening arrhythmias. Classical features of preexcitation and severe LVH are not uniformly present and diagnosis should be considered in patients with LVH who develop AF or require a PPM at a young age.