ZIC3 is an X-linked C2H2 zinc finger transcription factor essential for early vertebrate development, functioning primarily as a transcriptional activator that binds to the GLI-consensus sequence 5'-GGGTGGTC-3' 1. ZIC3 plays critical roles in establishing the embryonic left-right axis and axial midline development 2. Mechanistically, ZIC3 recruits SWI/SNF chrX remodeling complexes to primed-specific enhancers to maintain and facilitate progression to primed pluripotency 3. Additionally, ZIC3 is involved in early stages of cardiac and neural development, including blood-brain barrier maturation 4. Clinically, ZIC3 mutations cause X-linked heterotaxy syndrome, characterized by disrupted laterality of internal organs and severe congenital heart defects 51. Heterotaxy arises from defects in early left-right axis formation, potentially involving abnormal nodal and ciliary functions 5. ZIC3 mutations have also been associated with additional malformations including lumbosacral and anal anomalies, neural tube defects, and VACTERL-associated hydrocephalus 2. ZIC3 represents one of at least 33 genes implicated in human situs defects 6. Loss of ZIC3 function results in decreased transcriptional activity and aberrant cellular localization, demonstrating the functional impact of pathogenic variants 1.