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

Abstract

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. 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. 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.