Hirschsprung disease (HSCR) is thought to result as a consequence of multiple 
gene interactions that modulate the ability of enteric neural crest cells to 
populate the developing gut. However, it remains unknown whether the single 
complete deletion of important HSCR-associated genes is sufficient to result in 
HSCR disease. In this study, we found that the null mutation of the Ednrb gene, 
thought indispensable for enteric neuron development, is insufficient to result 
in HSCR disease when bred onto a different genetic background in rats carrying 
Ednrb(sl) mutations. Moreover, we found that this mutation results in serious 
congenital sensorineural deafness, and these strains may be used as ideal models 
of Waardenburg Syndrome Type 4 (WS4). Furthermore, we evaluated how the same 
changed genetic background modifies three features of WS4 syndrome, 
aganglionosis, hearing loss, and pigment disorder in these congenic strains. We 
found that the same genetic background markedly changed the aganglionosis, but 
resulted in only slight changes to hearing loss and pigment disorder. This 
provided the important evidence, in support of previous studies, that different 
lineages of neural crest-derived cells migrating along with various pathways are 
regulated by different signal molecules. This study will help us to better 
understand complicated diseases such as HSCR and WS4 syndrome.