Complex diseases are common genetic disorders showing familial aggregation but 
no typical Mendelian inheritance. Hirschsprung disease (HSCR), a developmental 
disorder characterized by the absence of enteric neurons in distal segments of 
the gut, shows a complex pattern of inheritance, with the RET protooncogene 
acting as a major gene and additional susceptibility loci playing minor roles. 
In the last years, we have identified a "protective" RET haplotype, which is 
underrepresented in HSCR patients with respect to controls. Here, we demonstrate 
that the protective effect of this haplotype is due to a variant located in the 
3' untranslated region (UTR) of the RET gene, which slows down the physiological 
mRNA decay of the gene transcripts. Such a functional effect of this common RET 
variant explains the under-representation of the whole haplotype and its role as 
a modifying factor in HSCR pathogenesis.