Understanding normal cardiac morphogenesis and its disruptions: a journey through pathways
TL;DR
A narrative review revisits normal cardiogenesis as a single, coordinated developmental program, integrating embryological events with progenitor populations, transcription factor networks, and signalling pathways, and highlights how perturbation of these developmental modules may result in syndromic and non-syndromic CHD.
Abstract
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.