PURPOSE: The RET proto-oncogene is considered to be the major susceptibility 
gene involved in Hirschsprung disease. Traditional RET germline mutations 
account for a small subset of Hirschsprung disease patients, but several studies 
have shown that there is a specific haplotype of RET associated with the 
sporadic forms of Hirschsprung disease. We have investigated for RET germline 
mutations and analyzed the RET haplotypic distribution in carriers versus 
noncarriers of RET germline mutations.
METHODS: We have screened the coding region of RET in 106 Spanish Hirschsprung 
disease patients using dHPLC technology. Statistical comparisons of the 
distribution of RET haplotypes between sporadic patients with and without a RET 
germline mutation were performed.
RESULTS: Nine novel germline mutations and one previously described were 
identified. A significant over-transmission of the "Hirschsprung disease 
haplotype" was detected when comparing transmitted versus nontransmitted alleles 
in the group of Hirschsprung disease triads without mutation. However, no 
distortion of the transmission of alleles was found in the group of mutated 
families.
CONCLUSIONS: These results would be concordant with a complex additive model of 
inheritance. The whole findings seem to suggest that low-penetrance mutations 
would be necessary but not sufficient and the additional presence of the 
"Hirschsprung disease haplotype" could contribute to the manifestation of the 
disease.