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, ∼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.
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Funding This study was funded by Fondo de Investigación Sanitaria, Spain (PI070080, and PI071315 for the E-Rare project), Consejeria de Innovación Ciencia y Empresa de la Junta de Andalucia (CTS 2570) and Consejeria de Salud de la Junta de Andalucia (PI0249-2008). The CIBER de Enfermedades Raras is an initiative of the ISCIII. ASM is predoctoral fellow funded by Instituto de Salud Carlos III, Spain.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.