Family cardiopathies with severe familial phenotype in pediatric age, what does genetics explain?

Abstract Introduction Familial cardiopathies (FC) are predominantly inherited in an autosomal dominant manner. However, multiple cases with ≥1 pathogenic or likely pathogenic (P/LP) variants in associated genes have been reported, particularly in children presenting with severe phenotypes. Objective To characterize the genetic features of severe FC cases in the pediatric population. Methods A single-center, retrospective descriptive study of severe FC in pediatric patients. Probands with severe FC, aged ≤18 years, and undergoing genetic analysis of 116 FC-associated genes were included. Severe FC was defined as FC with early onset and/or the occurrence of ≥1 cardiac event (CE). Patients with syndromic and/or autosomal recessive FC were excluded. CEs were defined as cardiogenic syncope, ventricular tachycardia/fibrillation (VT/VF), appropriate ICD shocks, sudden cardiac death (SCD), and sudden cardiac arrest (SCA). Demographic, clinical, and genetic data were extracted from electronic medical records. Results Between 2014 and 2024, 381 children were evaluated for FC onset, of whom 85 (22.3%; 41% female; mean age at onset 9±6.1 years) presented with severe FC. Diagnoses included 54 cardiomyopathies [63.5%; 29 hypertrophic cardiomyopathy (HCM), 10 dilated cardiomyopathy (DCM), 9 arrhythmogenic cardiomyopathy (ACM), 4 noncompaction cardiomyopathy (NCCM), and 2 restrictive cardiomyopathy (RCM)] and 31 channelopathies [36.5%; 14 Brugada syndrome (BrS), 10 long QT syndrome (LQTS), and 7 catecholaminergic polymorphic ventricular tachycardia (CPVT)]. Genetic testing yielded positive results in 73 cases (86%; 46 cardiomyopathies and 27 channelopathies). A single associated variant was identified in 34 cases [46.6%; 30 P/LP -5 de novo- and 4 variants of uncertain significance (VUS)], while >1 associated variant was detected in 39 cases (53%; 29 P/LP -2 de novo- and 10 VUS). Among these, 7 cases had a second P/LP variant, and 22 had an additional VUS. Conclusions Pediatric FC predominantly exhibit a single causal genetic variant. However, severe FC frequently involves additional variants (digenic or composite), which may act as modulators of worse outcomes. Comprehensive genetic analysis is recommended in cases of severe FC in children to identify these contributory factors.