BACKGROUND: In Hirschsprung's disease (HSCR), a hypomorphic allele of a major 
gene, RET, accounts for most isolated (non-syndromic) cases, along with other 
autosomal susceptibility loci under a multiplicative model. However, some 
syndromic forms of HSCR are monogenic entities, for which the disease causing 
gene is known.
OBJECTIVE: To determine whether RET could be considered a modifier gene for the 
enteric phenotype on the background of a monogenic trait.
METHODS: The syndromic HSCR entities studied were congenital central 
hypoventilation (CCHS) and Mowat-Wilson syndrome (MWS), caused by PHOX2B and 
ZFHX1B gene mutations, respectively. The RET locus was genotyped in 143 CCHS 
patients, among whom 44 had HSCR, and in 30 MWS patients, among whom 20 had 
HSCR. The distribution of alleles, genotypes, and haplotypes was compared within 
the different groups. To test the interaction in vivo, heterozygous mice were 
bred for a null allele of Phox2b and Ret genes.
RESULTS: RET was shown to act as a modifier gene for the HSCR phenotype in 
patients with CCHS but not with MWS. The intestine of double heterozygote mice 
was indistinguishable from their littermates. A loss of over 50% of each gene 
function seemed necessary in the mouse model for an enteric phenotype to occur.
CONCLUSIONS: In CCHS patients, the weak predisposing haplotype of the RET gene 
can be regarded as a quantitative trait, being a risk factor for the HSCR 
phenotype, while in MWS, for which the HSCR penetrance is high, the role of the 
RET predisposing haplotype is not significant. It seems likely that there are 
both RET dependent and RET independent HSCR cases.