A complex additive model of inheritance for Hirschsprung disease is supported by both RET mutations and predisposing RET haplotypes.

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.