Young-onset atrioventricular block (AVB) is a rare but clinically important condition that may require lifelong pacing. When immune-mediated and structural causes are excluded, the underlying cause often remains unknown. Although monogenic causes have been described in various cardiac and syndromic disorders, the genetic basis of isolated sporadic AVB is poorly defined. We therefore performed trio-based whole-genome sequencing (WGS) to identify candidate coding and regulatory de novo variants in sporadic young-onset AVB.

We performed WGS in eight trios comprising 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. Coding and splice-site variants were analyzed alongside non-coding variants, the latter restricted to cardiac open chromatin regions defined using integrated ATAC-seq datasets from healthy human cardiac tissues.

All probands were females and the median age at diagnosis was 4.0 years (IQR 1.5–10.0). We identified 11 rare de novo coding variants and 14 rare de novo non-coding variants within cardiac open chromatin regions. One potentially deleterious coding variant was identified in SOS2 , a gene reported in congenital heart disease. The other two coding variants involved genes with cardiac phenotypes in animal models. One non-coding variant was located upstream of a gene expressed in the atrioventricular canal during cardiac development. Several candidate genes showed supporting RNA and/or protein expression in cardiac tissue. No recurrent variants or genes were identified.

These preliminary findings suggest that sporadic young-onset AVB has a genetically heterogeneous basis and that both coding and regulatory de novo variants may contribute to disease pathogenesis. Although replication and functional validation are needed, WGS including regulatory genome analysis may improve the investigation of otherwise unexplained early-onset conduction disease.