Localizing a putative mutation as the major contributor to the development of sporadic Hirschsprung disease to the RET genomic sequence between the promoter region and exon 2

Eur J Hum Genet. 2004 Aug;12(8):604-12. doi: 10.1038/sj.ejhg.5201199.


Hirschsprung disease (HSCR), a congenital disorder characterized by intestinal obstruction due to absence of enteric ganglia along variable lengths of the intestinal tract, occurs both in familial and sporadic cases. RET mutations have been found in approximately 50% of the families, but explains only a minority of sporadic cases. This study aims at investigating a possible role of RET in sporadic HSCR patients. Haplotypes of 13 DNA markers, within and flanking RET, have been determined for 117 sporadic HSCR patients and their parents. Strong association was observed for six markers in the 5' region of RET. The largest distortions in allele transmission were found at the same markers. One single haplotype composed of these six markers was present in 55.6% of patients versus 16.2% of controls. Odds ratios (ORs) revealed a highly increased risk of homozygotes for this haplotype to develop HSCR (OR>20). These results allowed us to conclude that RET plays a crucial role in HSCR even when no RET mutations are found. An unknown functional disease variant(s) with a dosage-dependent effect in HSCR is likely located between the promoter region and exon 2 of RET.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Child
  • DNA Primers
  • Exons / genetics
  • Gene Components
  • Gene Frequency
  • Genetic Predisposition to Disease / genetics
  • Haplotypes / genetics
  • Hirschsprung Disease / genetics*
  • Humans
  • Linkage Disequilibrium
  • Microsatellite Repeats / genetics
  • Mutation / genetics*
  • Netherlands
  • Oncogene Proteins / genetics*
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases / genetics*


  • DNA Primers
  • Oncogene Proteins
  • Proto-Oncogene Proteins c-ret
  • RET protein, human
  • Receptor Protein-Tyrosine Kinases