Hypomorphic or null mutations in EDNRB, EDN3 (encoding the prepropeptide for ET-3), or the ligand-processing protease endothelin-converting enzyme (ECE) can cause HSCR, usually in the context of Waardenburg syndrome type 4 (WS4), a disorder that includes pigmentation defects, sensorineural deafness, dysmorphic facial features, and aganglionic megacolon in humans. The gene discussed is EDNRB; the disease is Waardenburg-Shah syndrome.