Trio-based whole genome sequencing identifies coding and regulatory de novo variants in sporadic young-onset atrioventricular block

Background/Introduction In the absence of immune-mediated or structural heart disease, the aetiology of sporadic young-onset atrioventricular block (AVB) often remains unexplained. Although genetic causes have been described in channelopathies, cardiomyopathies and syndromic disorders, the basis of isolated sporadic cases is poorly understood. As AVB typically increases with age, early-onset disease may indicate a genetic predisposition. Previous studies have largely focused on coding regions of known disease genes, leaving the contribution of regulatory non-coding variation unexplored. We therefore performed trio-based whole-genome sequencing (WGS) to identify candidate coding and regulatory de novo variants in sporadic young-onset AVB. Methods We performed WGS in eight trios comprising female probands diagnosed before 20 years of age and their unaffected parents. All probands had non-immune AVB without structural heart disease and no pathogenic variants in known AVB genes on prior panel testing. Trio analysis was used to identify heterozygous de novo variants filtered by population allele frequency. Coding and splice-site variants were analysed alongside non-coding variants. Non-coding prioritisation was restricted to variants within cardiac open chromatin regions defined using integrated public single-cell ATAC-seq data from the human atrioventricular node and bulk ATAC-seq datasets from healthy human cardiac tissue to identify putative regulatory elements1,2. Results The median age at diagnosis among probands was 4.0 years (IQR 1.5–10.0), and five underwent pacemaker implantation at a median age of 9.0 years (IQR 5.0–12.0). We identified 11 de novo rare coding variants and 14 de novo rare non-coding variants within cardiac open chromatin regions. One potentially deleterious coding variant was identified in SOS2, a gene reported in congenital heart disease. Additional coding variants involved genes with cardiac phenotypes in experimental models. Notably, one non-coding variant was located upstream of LBH, a gene expressed in the atrioventricular canal during cardiac development and implicated in endocardial cushion formation. Several candidate genes showed supporting RNA and/or protein expression in cardiac tissue. No recurrent variants or genes were identified across probands. Conclusions To our knowledge, this preliminary study provides the first evidence implicating both coding and regulatory de novo variation in sporadic isolated young-onset AVB. These findings suggest a genetically heterogeneous architecture and support a potential contribution of regulatory mechanisms to disease pathogenesis. Although replication and functional validation are required, the results highlight the value of WGS and regulatory genome interrogation for uncovering novel genetic contributors to early-onset cardiac conduction disease.