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 between 1.3 and 1.7 per 100,000 persons-year ^[1][2][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]. In addition to age and sex, other demographic factors such as ethnicity, exercise habits and geographic location impact on the incidence and survival rate of SCD, but the causes remain to be established ^[4][5][4,5]. During the first year of life, unexpected deaths remain unexplained after a comprehensive autopsy accounts for the highest infant mortality rate and is usually labelled as sudden infant death syndrome (SIDS) [6].

The most prevalent etiologies identified by medico-legal autopsy in children and young adults are cardiomyopathies, accounting for about 30% of SCD [7]. Nevertheless, a negative autopsy result is the most common finding in pediatrics, accounting for 40–50% 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]. In SADS, the regular heart rhythm is abruptly replaced by a lethal ventricular arrhythmia, in the context of a structurally normal heart [9], the so-called inherited arrhythmia syndromes (IASs) or cardiac channelopathies.

Thanks to recent technological advances in the field of genetics, a considerable number of potentially IASs-causing genes have been identified although not comprehensively characterized. Current panels used in genetic testing of IASs range from the most common genes recommended by the clinical guidelines to the less common genes described in a few families, in large part not definitively associated with any IASs. Those that can be tested in a fast and cost-effective approach in clinical practice remain a current matter of argument. Therefore, 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–disease associations. Recently, evaluations of IAS-associated genes according to ClinGen’s approach have been published ^{[10][11][12][13]}[10,11,12,13]. A further major challenge is due to the large number of variants of uncertain significance (VUS) yielded in next-generation sequencing (NGS) studies. The American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines are the current gold standard for classifying genetic variants. However, these guidelines were designed mainly for the classification of genetic variants in recessive or dominant pathologies with complete penetrance. IASs are characterized as diseases with an autosomal dominant inheritance pattern (AD), incomplete penetrance and variable expressivity, thus some criteria of the ACMG/AMP guidelines present limitations for their classification. Together with its strict criteria, this leads to high rates of VUS in the genetic diagnosis of IASs ^{[14][15][16][17]}[14,15,16,17], making it necessary to work with adjusted ACMG/AMP criteria for each pathology and gene. Some researchers in the field of primary arrhythmias have aimed to perform a quantitative implementation of the ACMG/AMP guidelines for IAS’s genetic testing, with success in reducing the VUS rate [18].

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. We will emphasize genotype–phenotype and variant–phenotype correlation. 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.

Cardiac channelopathies are caused by defects in the genes encoding sodium (Na⁺), potassium (K⁺) and calcium (Ca²⁺) ion channels or their associated proteins. Defects in these proteins impair the generation and transmission of the action potential (AP) predisposing the patient to fatal arrhythmias [19]. The arrhythmias are usually of the type ventricular tachycardia (VT) or rapid ventricular fibrillation (VF), and generally polymorphic [20]. Despite the fact that each channelopathy usually has a characteristic electrocardiogram (ECG) profile, an associated clinical phenotype and specific genes involved, these factors can often be shared by two or more syndromes, leading to difficulties in establishing a differential diagnosis. In addition, some of these syndromes are not associated with baseline ECG abnormalities, which make them difficult to diagnose, with the added distress that SCD or resuscitated cardiac arrest is the initial symptom in most cases [21]. Therefore, an accurate genetic diagnosis can help to predict the prognosis and management of patients and their families. IASs are predominantly monogenic syndromes with an AD inheritance pattern, characterized by incomplete penetrance and variable expressivity [22]. Phenotypes with an autosomal recessive (AR) and X-linked inheritance pattern occur, but they are a minority [23]. Four major 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].

LQTS is the most common of the IASs and the main contributor for SCD in young people under 20 years of age. LQTS affects approximately 1 per 2000–2500 persons-year [25] with a slight predominance of females [26]. Moreover, it is the major arrhythmogenic syndrome, responsible for infants’ deaths, especially in the first days of life [27]. It is characterized by QT interval prolongation and T-wave abnormalities in ECG, polymorphic ventricular tachycardia (PVT) in torsade de pointes (TdP), VF and syncope or SCD [28]. LQTS can be hereditary, congenital or acquired, usually associated with drugs and electrolyte imbalance (hypokalemia) (http://www.torsades.org accessed on 3 December 2021).

BrS in children and young adults is rare, and its incidence rate and clinical implications remain unclear. In the general population, its prevalence is estimated to be between 1 in 2000–5000 person-years [150]. The syndrome has a higher prevalence in Southeast Asian countries [151], and is more frequent among males than females [152]. It is characterized by a right bundle branch block, a very sharp T wave and spontaneous or drug-induced ST-segment elevation (J point) in the right precordial leads (V1–V3), known as ‘type-1’ BrS ECG pattern [64]. Clinical manifestations may appear between the ages of 2 months and 77 years old, but the mean age of presentation is 40 years old [153]. Symptoms present at rest, during sleep or febrile episodes, including nocturnal agonal respirations, palpitations, seizures, and polymorphic ventricular tachycardia (PVT) or VF. Most individuals remain asymptomatic, although SCD occurs in 17–42% of the cases and can be the initial presentation [154].

SQTS is an extremely rare inherited disease associated with SCD. To date, less than 200 cases have been reported worldwide [93]. The estimated prevalence varies between 0.18–2.9%, with a higher incidence in males than females [25]. The incidence rate can even be lower (0.02–0.10%) if more restrictive values are considered for its diagnosis ^[185][186][185,186]. While prevalence of the syndrome in children and adolescents is low (about 0.05%), early detection is important, as it is potentially lethal for all age groups. It is characterized by a short QT interval on the ECG (<330 ms), with an asymmetric and peaked T wave. Symptoms occur mostly in men between the ages of 14 and 40 and may be favored by hormonal causes [187]. Cardiac events usually occur in adrenergic situations (noise or exercise), although it can also occur at rest. Clinical presentation includes ventricular repolarization abnormalities (AF and VT) and syncope. The probability of presenting SCD as the first symptom increases with age, reaching 41% at the age of 40 [188]. Currently, approximately 40% of cases remain asymptomatic [189].

The prevalence of CPVT is estimated to be 1 per 10,000 population. However, the real prevalence is uncertain, as it might be underestimated due to its high lethality at a young age and difficulty in diagnosis ^[25][200][25,200]. CPVT is characterized by a bidirectional polymorphic VT, triggered by an adrenergic stimulus mainly during exertion, extreme stress or emotion that can lead to syncope and SCD. Syncopal episodes are increasingly reported during “awake rest” possibly due to anxiety, stress, or other psychological stimuli unrelated to exertion [201]. The age of onset can range from infancy to the age of 30, although it is more common in children aged 7–10 years old [202]. By the age of 10, about 35% of patients are symptomatic, increasing to 72% by the age of 21 [203]. A younger age of debut is often accompanied by more severe phenotypes and increased risk of SCD [42].

Several causative genes for IASs are common to two or more syndromes (LQTS, SQTS, BrS, and CPVT) (Figure 1) and have been found to overlap with other cardiac and extracardiac clinical phenotypes (Table 1). This genetic overlap could be explained since pathogenic variants can alter different properties of the channels or proteins, affecting ion exchange, interaction with auxiliary proteins, as well as gene expression. The final phenotype would depend not only on which property is affected, but also how it is affected. Notably, some genes that cause LQTS are the same genes that also cause SQTS (KCNQ1, KCNH2, KCNJ2, CACNA1C, CACNB2, and CACNA2D1), CPVT (CALM1, CALM2, CALM3, TRDN, KCNJ2, SCN5A, ANK2 and TECRL) or BrS (SCN5A) ^[42][89][42,89]. However, the pathogenic variants usually cause an opposite effect on the channel.

Some pathogenic variants have been found to lead to complex overlapping forms of two or more syndromes. Several publications support the fact that pathogenic variants in KCNQ1, ANK2, KCNE1, KCNE2, KCNH2, KCNJ2 and SCN5A can lead to a complex overlapping phenotype of LQTS, CPVT and ventricular ectopy ^[42][48][92][42,48,92]. Hirose et al., recently described in a cohort of children (<16 years old) the association of loss-of-function pathogenic variants in RYR2 with various types of arrhythmia, including LQTS, VF and scTdP, depending on the alteration of channel activity ^[83][84][83,84]. The pathogenic variants p.I4855M and deletion of exon 3 in the RYR2 gene have been associated with the rare syndrome of left ventricular non-compaction (LVNC) overlap and CPVT, presenting a high lethality [85]. Pathogenic variants in the TRPM4 gene, both gain and loss of function, have been identified in patients with different forms of cardiac disorder including conduction defects, BrS and LQTS [77]. The PKP2 gene, the main gene mutated in arrhythmogenic cardiomyopathy (ACM), has been recently associated with BrS and CPVT. The p.S183N pathogenic variant has been reported in both a patient with BrS and a patient with a definite diagnosis of ACM [221]. However, further studies are needed to establish the pathophysiological mechanisms of these correlations.