Genetic loci responsible for atrioventricular block in children

Abstract

Atrioventricular block (AVB) represents a prevalent form of bradyarrhythmia in the pediatric population, broadly classified into congenital and acquired subtypes. Historically, the underlying mechanisms of AVB were predominantly attributed to structural cardiac anomalies, maternal autoantibody-mediated inflammatory processes, and pharmacological agents; however, the contribution of genetic factors remained largely underexplored. With the advent and progressive refinement of genetic sequencing technologies, a growing repertoire of arrhythmia-associated genes has been systematically identified. In this review, we comprehensively examine the genetic determinants implicated in pediatric AVB, encompassing genes encoding cardiac ion channels, including SCN5A, KCNQ1/KCNJ2 (KCN family), KCNH2 (HERG), TRPM4, and HCN4, as well as genes governing cardiac structural integrity (GJA5/GJA1, ZO-1, NKX2-5, TBX3/TBX5, HAND1/HAND2, and ID family members), metabolic regulation (PRKAG2, PPARA, and LAMP2), and immune-mediated pathways (TRIM21/TROVE2 and HLA class II loci). The genetic architecture underlying pediatric AVB demonstrates considerable complexity, characterized by notable genotypic heterogeneity and “multi-phenotypic” expressivity, wherein distinct mutations within a single gene may manifest across a spectrum of clinical phenotypes. Collectively, these findings establish a molecular framework for elucidating the pathogenesis of AVB, while simultaneously offering valuable insights to inform clinical diagnosis, facilitate precision-based intervention strategies, and guide the development of targeted therapeutic modalities.