Understanding normal cardiac morphogenesis and its disruptions: a journey through pathways

Congenital heart diseases (CHDs) encompass a broad spectrum of structural anomalies with substantial clinical and genetic heterogeneity. They are the most common birth defects in humans, and a leading cause of paediatric morbidity and mortality. Yet, its genetic substrate remains difficult to interpret at the bedside: despite advances in cytogenetics and next-generation sequencing, a definitive or candidate genetic cause is identified in fewer than half of cases, and even when a variant is recovered, mapping it onto the developmental program that produces a specific malformation is rarely straightforward for the practising clinician. This narrative review revisits normal cardiogenesis as a single, coordinated developmental program, integrating embryological events with progenitor populations, transcription factor networks, and signalling pathways. We then highlight how perturbation of these developmental modules may result in syndromic and non-syndromic CHD. By aligning embryological events with their regulatory logic, the review offers a developmental framework intended to help clinicians situate molecular findings within the biology of heart formation, sharpen genotype-phenotype interpretation, support more precise diagnostic and prognostic reasoning, and inform emerging regenerative strategies for the malformed and injured heart.