Hirschsprung's disease (HSCR, aganglionic megacolon) is a frequent congenital 
malformation regarded as a multigenic neurocristopathy. Three susceptibility 
genes have been recently identified in HSCR, namely the RET proto-oncogene, the 
endothelin B receptor (EDNRB) gene, and the endothelin 3 (EDN3) gene. RET gene 
mutations were found in significant proportions of familial (50%) and sporadic 
(15-20%) HSCR, while homozygosity for EDNRB or EDN3 mutations accounted for the 
rare HSCR-Waardenburg syndrome (WS) association. More recently, heterozygous 
EDNRB and EDN3 missense mutations have been reported in isolated HSCR patients. 
Some of these results were obtained after the identification of mouse genes 
whose natural or site-directed mutations resulted in megacolon and coat color 
spotting. There is also conclusive evidence for the involvement of other 
independent loci in HSCR. In particular, the recent identification of 
neurotrophic factors acting as RET ligands (GDNF and Neurturin) provide 
additional candidate genes for HSCR. The dissection of the genetic etiology of 
HSCR disease may then provide a unique opportunity to distinguish between a 
polygenic and a genetically heterogeneous disease, thereby helping to understand 
other complex disorders and congenital malformations hitherto considered as 
multifactorial in origin. Finally, the study of the molecular bases of HSCR is 
also a step towards the understanding of developmental genetics of the enteric 
nervous system giving support to the role of the tyrosine kinase and 
endothelin-signaling pathways in the development of neural crest-derived enteric 
neurons in human.