Hirschsprung disease (HSCR) is a frequent neurocristopathy characterized by the 
absence of submucosal and myenteric plexuses in a variable length of the 
gastrointestinal tract. Pedigrees and segregation analyses suggested the 
involvement of one or several dominant genes with low penetrance in HSCR. 
Considering that RET and glial cell line-derived neurotrophic factor (GDNF) 
mutations have been reported in the disease, we regarded the other RET ligand, 
neurturin (NTN), as an attractive candidate gene, especially as it shares large 
homologies with GDNF. Here, we report on the finding of a heterozygous missense 
NTN mutation in a large non-consanguineous family including four children 
affected with a severe aganglionosis phenotype extending up to the small 
intestine. Interestingly, it appears that the NTN mutation reported here is not 
sufficient to cause HSCR, and this multiplex family also segregates a RET 
mutation. This cascade of independent and additive genetic events fits well with 
the multigenic pattern of inheritance expected in HSCR, and further support the 
role of RET ligands in development of the enteric nervous system.