Cardiac Organoids for Modeling Congenital Heart Disease: From Genetic Discovery to Therapeutic Screening.

PURPOSE OF REVIEW: Congenital heart disease (CHD) is the most common birth defect and a leading cause of infant mortality. This review highlights recent advances in human stem cell-derived cardiac organoids and their applications to understand CHD etiology, with a focus on functional genomics and therapeutic discovery. RECENT FINDINGS: Advances in cardiac organoid engineering have enabled increasingly complex models with enhanced vascularization, diverse cellular lineages, and chamber-specific features that more faithfully mimic the developing heart. Single-cell transcriptomic and epigenomic profiling of organoid differentiation has revealed gene regulatory programs governing cardiogenesis. Machine learning models trained on these datasets provide powerful frameworks for predicting genetic variant effects associated with CHD. Cardiac organoids provide scalable, human-specific platforms for investigating CHD etiology across multiple cell types and disease-relevant developmental stages. Combined with single-cell profiling and machine learning, cardiac organoids offer new opportunities for CHD mechanistic discovery, improved genetic risk prediction, and personalized therapeutic development.