The third signaling pathway of HSCR pathogenesis includes class 3 semaphorins (SEMA3s), involving SEMA3D (4, 8, 9) SEMA3D has been implicated in the development of HSCR and contributes to risk through both common and rare variants in European ancestries (4, 8, 9), as evidenced by (1) the detection of both common and rare SEMA3D variants in HSCR patients; (2) the expression of SEMA3D in the human, mouse, and zebrafish intestines and, particularly, the enteric nervous system (ENS); and (3) the joint effect of Ret and Sema3d loss of function in an aganglionosis animal model. This evidence concerns the gene RET and Hirschsprung disease.