A common variant located in the 3′UTR of the RET gene is associated with protection from Hirschsprung disease

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 underrepresentation of the whole haplotype and its role as a modifying factor in HSCR pathogenesis. Hum Mutat 28(2), 168–176, 2007. © 2006 Wiley‐Liss, Inc.