GDF1 (growth differentiation factor 1) is a TGF-β superfamily signaling molecule that mediates critical developmental processes during early embryogenesis. GDF1 functions as the mammalian ortholog of Xenopus Vg1 1 and signals through type I receptor ALK4, type II receptors ActRIIA/ActRIIB, and co-receptor Cripto to activate Smad-dependent pathways 1. During embryonic development, GDF1 cooperates functionally with GDF3 to regulate anterior visceral endoderm and mesoderm formation, with compound knockouts showing more severe defects than single mutants 1. GDF1 plays a crucial role in left-right axis patterning and laterality determination 1. Pathogenic variants in GDF1 are a major genetic cause of congenital heart disease (CHD), particularly in laterality disorders and right atrial isomerism 23. Recessive GDF1 mutations account for approximately 5% of severe CHD in Ashkenazi Jewish populations 4 and contribute significantly to recessive CHD burden, with founder variants representing 74% of recessive genotypes among Ashkenazi Jewish CHD probands 5. GDF1 mutations are associated with conotruncal heart malformations, tetralogy of Fallot, and complex CHD phenotypes 6. These findings establish GDF1 as a critical developmental regulator with substantial clinical significance for CHD diagnosis and genetic counseling, particularly in consanguineous populations.