From outflow tract development to ventriculo-arterial discordance - Developmental and genetic mechanisms of d-TGA and ccTGA.

Discordant ventriculo-arterial (VA) connection characterizes dextro-transposition of the great arteries (d-TGA) and congenitally corrected transposition of the great arteries (ccTGA). These distinct defects involve overlapping developmental processes related to cardiac looping, left-right patterning, and outflow tract (OFT) morphogenesis. Recent genetic studies in sporadic and familial cases support second-heart field and neural crest involvement and an oligogenic architecture shaped by gene-environment interactions. Consistent with this framework, environmental perturbations, including retinoic acid imbalance and maternal diabetes, can also disrupt OFT development and contribute to VA discordance. Phenotypic variability and in some instances the association of ccTGA or d-TGA with laterality defects/heterotaxy syndrome suggest dose-sensitive left-right signaling and stochastic influences on cardiac asymmetry. This review provides a comprehensive and up-to-date synthesis of developmental and genetic mechanisms underlying VA discordance and highlights prenatal environmental and placental influences, neurodevelopmental risks, and emerging therapeutic approaches.