Neuro-Genomic Mapping of Cardiac Neurons with Systemic Analysis Reveals Cognitive and Neurodevelopmental Impacts in Congenital Heart Disease

Congenital heart disease (CHD) is associated with neurodevelopmental and cognitive impairments, but the underlying molecular mechanisms remain unclear. This study investigated cardiac neuronal genomics in CHD using single-nucleus RNA-sequencing data (GSE203274) from 157,273 cardiac nuclei of healthy donors and patients with hypoplastic left heart syndrome (HLHS), Tetralogy of Fallot (TOF), dilated (DCM), and hypertrophic (HCM) cardiomyopathies. The Uniform Manifold Approximation and Projection (UMAP) clustering identified major cardiac cell types, revealing neuron-specific transcriptional programmes. Neuronal populations showed enriched expression of neurodevelopmental disorder-linked genes (<i>NRXN3</i>, <i>CADM2</i>, <i>ZNF536</i>) and synaptic signalling pathways. CHD cardiac neurons exhibited upregulated markers of cognitive dysfunction (<i>APP</i>, <i>SNCA</i>, <i>BDNF</i>) and neurodevelopment regulators (<i>DNMT1</i>, <i>HCFC1</i>) across subtypes. Cardiomyocyte troponin elevation correlated with neuronal exosome receptor expression (<i>TLR2</i>, <i>LRP1</i>), suggesting intercellular communication. Gene ontology analysis highlighted overlaps between cardiovascular disease pathways and neurodevelopmental disorder signatures in CHD neurons. These findings provide the first neuro-genomic map of cardiac neurons in CHD, linking cardiac pathology to neural outcomes through transcriptional dysregulation. Further, the systemic analysis of clinical findings in CHD further supports the risk of neurodevelopmental impacts. In summary, this study identifies transcriptional dysregulation within cardiac neurons in CHD and, together with a systemic analysis of clinical data, provides molecular evidence linking cardiac pathology to neurodevelopmental and cognitive impairments.