PT - JOURNAL ARTICLE AU - Salud Borrego AU - María Eugenia Sáez AU - Agustín Ruiz AU - Oliver Gimm AU - Manuel López-Alonso AU - Guillermo Antiñolo AU - Charis Eng TI - Specific polymorphisms in the <em>RET</em>proto-oncogene are over-represented in patients with Hirschsprung disease and may represent loci modifying phenotypic expression AID - 10.1136/jmg.36.10.771 DP - 1999 Oct 01 TA - Journal of Medical Genetics PG - 771--774 VI - 36 IP - 10 4099 - http://jmg.bmj.com/content/36/10/771.short 4100 - http://jmg.bmj.com/content/36/10/771.full SO - J Med Genet1999 Oct 01; 36 AB - Hirschsprung disease (HSCR) is a common genetic disorder presenting with functional intestinal obstruction secondary to enteric aganglionosis. HSCR can 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 HSCR in a population based series carry RETmutations. From 1998 to February 1999, we prospectively ascertained 64 cases of sporadic HSCR from the western Andalusia region. To determine if polymorphic sequence variants within RETcould act as low penetrance predisposing alleles, we examined allelic frequencies at seven polymorphic loci in this population based series. Whether allele frequencies differed from those in the control population were determined by either chi-squared analysis or Fisher’s exact test. For two sequence variants, A45A (c 135G→A) (exon 2) and L769L (c 2307T→G) (exon 13), the rarer polymorphic allele was over-represented among HSCR cases versus controls (p&lt;0.0006). In contrast, two other polymorphisms, G691S (c 2071C→A) (exon 11) and S904S (c 2712C→G) (exon 15), were under-represented in the HSCR patients compared to controls (p=0.02). Polymorphisms in theRET proto-oncogene appear to predispose to HSCR in a complex, low penetrance fashion and may also modify phenotypic expression.