Contribution of RET, NTRK3 and EDN3 to the expression of Hirschsprung disease in a multiplex family

J Med Genet. 2009 Dec;46(12):862-4. doi: 10.1136/jmg.2009.067819. Epub 2009 Jun 25.

Abstract

Background: Hirschsprung disease (HSCR) is a developmental disorder caused by a defect in the neural crest neuroblast migration process. It is considered to be a paradigm of complex disorders, with many loci contributing to manifestation of the disease. Although HSCR commonly appears as a sporadic trait, approximately 20% of HSCR cases are familial, with complex patterns of inheritance.

Method: A multiplex HSCR family with an additive model of inheritance, in which the contribution of three genes (RET, NTRK3, EDN3) leads to the HSCR phenotype is reported.

Results and discussion: The findings suggest that both RET and NTRK3 mutations acting together are necessary and sufficient for the appearance of the disease, and that the EDN3 mutation is acting as a phenotype-modifier factor in the context of this family, as two different HSCR phenotypes are seen among the affected members: a short segment form, and a total colonic aganglionosis. The results therefore support the complex additive model of inheritance previously proposed for Hirschsprung disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA / chemistry
  • DNA / genetics
  • Endothelin-3 / genetics*
  • Hirschsprung Disease / genetics*
  • Humans
  • Male
  • Mutation / genetics
  • Pedigree
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins c-ret / genetics*
  • Receptor, trkC / genetics*

Substances

  • Endothelin-3
  • DNA
  • Proto-Oncogene Proteins c-ret
  • RET protein, human
  • Receptor, trkC