Specific polymorphisms in the RET proto-oncogene are over-represented in patients with Hirschsprung disease and may represent loci modifying phenotypic expression

Hirschsprung disease (HSCR) is a common genetic disorder presenting with fu nctional intestinal obstruction secondary to enteric aganglionosis. HSCR ca n be familial or sporadic. Although five putative susceptibility genes have been identified, only germline mutations in the RET proto-oncogene account for a significant minority (up to 50%) of familial HSCR; 3% of sporadic HS CR in a population based series carry RET mutations. From 1998 to February 1999, we prospectively ascertained 64 cases of sporadic HSCR fi om the west ern Andalusia region. To determine if polymorphic sequence variants within RET could act as low penetrance predisposing alleles, we examined allelic f requencies at seven polymorphic loci in this population based series. Wheth er allele frequencies differed from those in the control population were de termined by either chi-squared analysis or Fisher's exact test. For two seq uence variants, A45A (c 135G-->A) (exon 2) and L769L (c 2307T-->G) (exon 13 ), the rarer polymorphic allele was over-represented among HSCR cases versu s controls (p<0.0006). In contrast, two other polymorphisms, G691S (c 2071C -->A) (exon 11) and S904S (c 2712C-->G) (exon 15), were under-represented i n the HSCR patients compared to controls (p=0.02). Polymorphisms in the RET proto-oncogene appear to predispose to HSCR in a complex, low penetrance f ashion and may also modify phenotypic expression.