Sudden 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. Our 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. Cardiac 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.

Brugada syndrome is a rare inherited arrhythmogenic disease leading to ventricular fibrillation and high risk of sudden death. In 1998, this syndrome was linked with a genetic variant with an autosomal dominant pattern of inheritance. To date, rare variants identified in more than 40 genes have been potentially associated with this disease. Variants in regulatory regions, combinations of common variants and other genetic alterations are also proposed as potential origins of Brugada syndrome, suggesting a polygenic or oligogenic inheritance pattern. However, most of these genetic alterations remain of questionable causality; indeed, rare pathogenic variants in the SCN5A gene are the only established cause of Brugada syndrome. Comprehensive analysis of all reported genetic alterations identified the origin of disease in no more than 40% of diagnosed cases. Therefore, identifying the cause of this rare arrhythmogenic disease in the many families without a genetic diagnosis is a major current challenge in Brugada syndrome. Additional challenges are interpretation/classification of variants and translation of genetic data into clinical practice. Further studies focused on unraveling the pathophysiological mechanisms underlying the disease are needed. Here we provide an update on the genetic basis of Brugada syndrome.

The reason behind a sudden death of a young individual remains unknown in up to 50% of postmortem cases. Pathogenic mutations in genes encoding heart proteins are known to cause sudden cardiac death. The aim of our study was to ascertain whether genetic alterations could provide an explanation for sudden cardiac death in a juvenile cohort with no-conclusive cause of death after comprehensive autopsy. Twenty-nine cases <15 years showing no-conclusive cause of death after a complete autopsy were studied. Genetic analysis of 7 main genes associated with sudden cardiac death was performed using Sanger technology in low quality DNA cases, while in good quality cases the analysis of 55 genes associated with sudden cardiac death was performed using Next Generation Sequencing technology. Thirty-five genetic variants were identified in 12 cases (41.37%). Ten genetic/variants in genes encoding cardiac ion channels were identified in 8 cases (27.58%). We also identified 9 cases (31.03%) carrying 25 genetic variants in genes encoding structural cardiac proteins. Nine cases carried more than one genetic variation, 5 of them combining structural and non-structural genes. Our study supports the inclusion of molecular autopsy in forensic routine protocols when no conclusive cause of death is identified. Around 40% of sudden cardiac death young cases carry a genetic variant that could provide an explanation for the cause of death. Because relatives could be at risk of sudden cardiac death, our data reinforce their need of clinical assessment and, if indicated, of genetic analysis.

Background: During the severe acute respiratory syndrome Coronavirus 2 pandemic, there has been an increase in hyperinflammatory presentation in previously healthy children with a variety of cardiac manifestations. Our objective is to describe the cardiac manifestations found in an international cohort of 55 pediatric cases with multi‐system inflammatory syndrome during the severe acute respiratory syndrome Coronavirus 2 pandemic. Methods and Results: We reviewed data on previously healthy pediatric patients (≤18 years) with structurally normal hearts who presented at hospitals in the United States, United Kingdom, Spain, and Pakistan with multi‐system inflammatory syndrome in children and had consultation with a pediatric cardiologist. Data collected included demographics, clinical presentation, laboratory values, electrocardiographic abnormalities, echocardiographic findings, and initial therapies. A total of 55 patients presented with multi‐system inflammatory syndrome in children. Thirty‐five patients (64%) had evidence of decreased left ventricular function, 17 (31%) had valvulitis, 12 (22%) with pericardial effusion, and 11 (20%) with coronary abnormalities. Twenty‐seven (49%) required intensive care unit admission and 24 (44%) had evidence of shock. Eleven patients (20%) fulfilled complete Kawasaki disease criteria and had lower NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), D‐dimer, and ferritin levels compared with those who did not fulfill criteria. Electrophysiologic abnormalities occurred in 6 patients and included complete atrioventricular block, transient atrioventricular block, and ventricular tachycardia. Conclusions: To our knowledge, we describe the first international cohort of pediatric patients with multi‐system inflammatory syndrome in children during the severe acute respiratory syndrome Coronavirus 2 pandemic with a range of cardiac manifestations. This article brings awareness and alertness to the global medical community to recognize these children during the pandemic and understand the need for early cardiology evaluation and follow‐up.