Among the many dozens of genes highly conserved through evolution and identified as key effectors of animal cardiogenesis, only a handful of them, including a disproportional number of transcription factors (GATA4, NKX2.5, ZIC3, TBX1,TBX20 and CHD7[55]–[60]), but also intracellular effectors (TAB2[61], MID1[62]) and ligands (BMP4[56]) or membrane-bound proteins (STRA6[63], [64], NOTCH1[65], and CFC1[66]), have so far been directly linked to congenital heart malformations of the OFT in humans. This evidence concerns the gene ZIC3 and congenital heart malformation.