Elucidating Gene Functions in Congenital Heart Disease

Purpose of Review Congenital heart defects (CHDs) arise from disruption of precisely orchestrated developmental programs that coordinate cardiac lineage specification, morphogenesis, maturation, and tissue remodeling. This review highlights recent advances in experimental systems used to connect CHD-associated genes and variants to developmental mechanisms. Recent Findings In vivo mouse and vertebrate studies have refined models of early cardiogenic mesoderm formation, heart-field allocation, valve development, outflow tract morphogenesis, epicardial-myocardial interactions, and ventricular compaction. Parallel work on postnatal cardiac maturation highlights how RNA processing, metabolic remodeling, immune signaling, and non-myocyte populations influence cardiomyocyte maturation and regenerative competence, with implications for long-term outcomes in CHD survivors. Human pluripotent stem cell models provide complementary platforms for investigating gene functions: two-dimensional differentiation enables scalable, temporally controlled analysis of lineage commitment and cell-autonomous phenotypes, whereas organoids and other three-dimensional models introduce spatial organization, multicellular interactions, and tissue-level readouts. Genome editing, CRISPR screening, base and prime editing, regulatory-element assays, and inducible protein-depletion systems now allow increasingly precise and high-throughput characterization of coding and noncoding variants. Summary Together, these advances are enabling a transition in CHD research from descriptive genomics to integrated, multi-model approaches that connect genetic variation to gene function, developmental mechanisms, and disease phenotypes.