Sudden death is a rare event in the pediatric population but with a social shock due to its presentation as the first symptom in previously healthy children. Comprehensive autopsy in pediatric cases identify an inconclusive cause in 40–50% of cases. In such cases, a diagnosis of sudden arrhythmic death syndrome is suggested as the main potential cause of death. Molecular autopsy identifies nearly 30% of cases under 16 years of age carrying a pathogenic/potentially pathogenic alteration in genes associated with any inherited arrhythmogenic disease. In the last few years, despite the increasing rate of post-mortem genetic diagnosis, many families still remain without a conclusive genetic cause of the unexpected death. Current challenges in genetic diagnosis are the establishment of a correct genotype–phenotype association between genes and inherited arrhythmogenic disease, as well as the classification of variants of uncertain significance. In this review, we provide an update on the state of the art in the genetic diagnosis of inherited arrhythmogenic disease in the pediatric population. We focus on emerging publications on gene curation for genotype–phenotype associations, cases of genetic overlap and advances in the classification of variants of uncertain significance. Our goal is to facilitate the translation of genetic diagnosis to the clinical area, helping risk stratification, treatment and the genetic counselling of families.

Brugada syndrome (BrS) is classified as an inherited cardiac channelopathy attributed to dysfunctional ion channels and/or associated proteins in cardiomyocytes rather than to structural heart alterations. However, hearts of some BrS patients exhibit slight histologic abnormalities, suggesting that BrS could be a phenotypic variant of arrhythmogenic cardiomyopathy. We performed a systematic review of the literature following Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA) criteria. Our comprehensive analysis of structural findings did not reveal enough definitive evidence for reclassification of BrS as a cardiomyopathy. The collection and comprehensive analysis of new cases with a definitive BrS diagnosis are needed to clarify whether some of these structural features may have key roles in the pathophysiological pathways associated with malignant arrhythmogenic episodes.

The titin gene (TTN) is associated with several diseases, including inherited arrhythmias. Most of these diagnoses are attributed to rare TTN variants encoding truncated forms, but missense variants represent a diagnostic challenge for clinical genetics. The proper interpretation of genetic data is critical for translation into the clinical setting. Notably, many TTN variants were classified before 2015, when the American College of Medical Genetics and Genomics (ACMG) published recommendations to accurately classify genetic variants. Our aim was to perform an exhaustive reanalysis of rare missense TTN variants that were classified before 2015, and that have ambiguous roles in inherited arrhythmogenic syndromes. Rare missense TTN variants classified before 2015 were updated following the ACMG recommendations and according to all the currently available data. Our cohort included 193 individuals definitively diagnosed with an inherited arrhythmogenic syndrome before 2015. Our analysis resulted in the reclassification of 36.8% of the missense variants from unknown to benign/likely benign. Of all the remaining variants, currently classified as of unknown significance, 38.3% showed a potential, but not confirmed, deleterious role. Most of these rare missense TTN variants with a suspected deleterious role were identified in patients diagnosed with hypertrophic cardiomyopathy. More than 35% of the rare missense TTN variants previously classified as ambiguous were reclassified as not deleterious, mainly because of improved population frequencies. Despite being inconclusive, almost 40% of the variants showed a potentially deleterious role in inherited arrhythmogenic syndromes. Our results highlight the importance of the periodical reclassification of rare missense TTN variants to improve genetic diagnoses and help increase the accuracy of personalized medicine.

Background/Objectives: Inherited arrhythmogenic syndromes comprise a heterogenic group of genetic entities that lead to malignant arrhythmias and sudden cardiac death. Genetic testing has become crucial to understand the disease etiology and allow for the early identification of relatives at risk; however, it requires an accurate interpretation of the data to achieve a clinically actionable outcome. This is particularly challenging for the large number of rare variants obtained by current high-throughput techniques, which are mostly classified as of unknown significance. Methods: In this work, we present a new algorithm for the genetic interpretation of the remaining rare variants in order to shed light on their potential clinical implications and reduce the burden of unknown significance. Results: Our study illustrates the potential utility of our individualized comprehensive stepwise analyses focused on the rare variants associated with IAS, which are currently classified as ambiguous, to further determine their trends towards pathogenicity or benign traits. Conclusions: We advocate for personalized disease-focused population frequency data and family segregation analyses for all rare variants that remain ambiguous to further clarify their role. The current ambiguity should not influence medical decisions, but a potential deleterious role would suggest a closer clinical follow-up and frequent genetic data review for a more personalized clinical approach.

A conclusive and early diagnosis of cardiomyopathy is essential for implementing preventive therapeutic measures and, therefore, reducing the risk of malignant arrhythmias and even sudden cardiac death. Occasionally, this lethal event can be the first manifestation of cardiomyopathy, with or without a clear structural defect. In cases of sudden death, especially in young patients, the autopsy may be ambiguous and therefore lack a definitive diagnosis of cardiomyopathy, although it can sometimes identify signs that lead us to suspect it. This is one of the current challenges of forensic science, where occult cardiomyopathies often remain unidentified without additional testing that is not routinely included in current forensic protocols. In this protocol, it is crucial to perform a molecular autopsy but also to include additional data, especially family history, that will help conclude or at least suspect this entity. Obtaining this diagnosis or suspicion of concealed cardiomyopathy not only provides an answer to the unexpected death but also helps the relatives determine the cause of death. In addition, physicians should initiate a family assessment to identify other family members who may be at risk early and adopt personalized preventive measures.

We report a pediatric patient with persistent left superior vena cava and a D-transposition of great arteries, which is an uncommon relation. It is crucial to know the anatomy of the persistent left superior vena cava and the dilated coronary sinus to plan the mapping techniques in cases of posterior accessory pathways.