Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome)

Hirschsprung disease (HSCR) and Waardenburg syndrome (WS) are congenital malformations regarded as neurocristopathies since both disorders involve neural crest-derived cells1–3. The WS-HSCR association (Shah-Waardenburg syndrome)4 is a rare autosomal recessive condition that occasionally has been ascribed to mutations of the endothelin-receptor B (EDNRB) gene5,6. WS-HSCR mimicks the megacolon and white coat-spotting observed in Ednrb mouse mutants7. Since mouse mutants for the EDNRB ligand, endothelin-3 (EDN3), displayed a similar phenotype8, the EDA/3 gene was regarded as an alternative candidate gene in WS-HSCR. Here, we report a homozygous substitution/deletion mutation of the EDA/3 gene in a WS-HSCR patient. EDA/3 thus becomes the third known gene (after RET and EDNRB) predisposing to HSCR, supporting the view that the endothelin-signaling pathways play a major role in the development of neural crests.