Specific polymorphisms in the RETproto-oncogene are over-represented in patients with Hirschsprung disease and may represent loci modifying phenotypic expression
- Salud Borregoa,
- María Eugenia Sáeza,
- Agustín Ruiza,
- Oliver Gimmc,
- Manuel López-Alonsob,
- Guillermo Antiñoloa,
- Charis Engc,d
- aUnidad de Genética Médica y Diagnóstico Prenatal, Hospitales Universitarios Virgen del Rocío, Avenida Manuel Siurot s/n, 41013 Sevilla, Spain, bCirugía Infantil, Hospitales Universitarios Virgen del Rocío, Sevilla, Spain, cClinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center, 420 W 12th Avenue, Suite 690, Columbus, OH 43210, USA, dCRC Human Cancer Genetics Research Group, University of Cambridge, Cambridge, UK
- Dr Borrego.
- Revised 19 July 1999
- Accepted 22 July 1999
Abstract
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<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.
