Abstract
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.
Highlights
While sudden cardiac death (SCD) is a rare event in pediatrics, it has a significant social impact, since it often presents as the first symptom in previously healthy children.The reported incidence rate of SCD in children and young adults is estimated to be between1.3 and 1.7 per 100,000 persons-year [1,2], with twice as many cases in males than females.SCD is almost 10 times higher in young adults aged 31–35 years, while very low in children aged 6–10 years of age [3]
Four major inherited arrhythmia syndromes (IASs) can be typically observed in pediatrics: long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) [24]
Inheritance pattern, except for the Jervell and Lange–Nielsen syndromes (JLNS) [31] and the recently characterized triadin knock out syndrome (LQT17) [32], which are inherited in an autosomal recessive (AR) manner
Summary
While sudden cardiac death (SCD) is a rare event in pediatrics, it has a significant social impact, since it often presents as the first symptom in previously healthy children. Of cases in the population under 16 years old This outcome suggests a diagnosis of sudden arrhythmic death syndrome (SADS), the leading cause of SCD in children [8]. Studying a larger number of genes represents new challenges, such as limitations in establishing valid associations between genes and phenotypes To address this problem, in 2013 the National Institute of Health (NIH) encouraged the development of ClinGen (Clinical Genome Resource https://clinicalgenome.org/ accessed on 3 December 2021), an international consortium of geneticists, genomic scientists and experts in the clinical field, which has established an evidence-based gene curation approach to establish gene–. The American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines are the current gold standard for classifying genetic variants. We provide a state of the art overview of the genetic diagnosis of IASs in the pediatric population and its translation into clinical practice, based on international expert guidelines, recent advances in evidence-based genetic curation, and IAS-focused variant classification. Our goal is to facilitate translation of the genetic diagnosis to the clinical area, helping in risk stratification, treatment and the genetic counseling of families
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