Genetic Insights into the Comorbidity of Congenital Heart Disease and Neurodevelopmental Disorders: Focus on Copy Number Variations

Congenital heart disease (CHD) and neurodevelopmental disorders (NDDs) frequently co-occur, indicating that cardiac and neural phenotypes can arise from shared developmental disturbances rather than exclusively from the physiological consequences of heart disease. Copy number variations (CNVs) provide a major genomic basis for this overlap, but their effects extend beyond changes in protein-coding gene dosage. This review synthesizes evidence from recurrent CNV syndromes, genomic cohorts, developmental studies, and experimental models to define how CNVs jointly influence heart and brain development. We examine four interconnected mechanisms: dosage alteration of pleiotropic and multiple genes, disruption of non-coding regulatory elements, remodeling of non-coding RNA networks, and reorganization of three-dimensional chromatin architecture. We further describe how developmental timing, cell-type-specific regulatory context, additional genomic variants, cardiac physiology, and clinical exposures shape incomplete penetrance and variable expressivity. Together, these findings support a layered model in which a primary CNV establishes cross-organ susceptibility, whereas genetic and developmental modifiers determine whether CHD, NDD, or both become clinically manifest. Clinically, CNV diagnosis can inform neurodevelopmental surveillance, multisystem management, and genetic counseling. Genotype-first longitudinal cohorts, developmental multi-omics, parallel cardiac and neural models, and prospective clinical studies will advance individualized risk prediction and intervention.