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Contribution of RET, NTRK3 and EDN3 to the expression of Hirschsprung disease in a multiplex family
  1. A Sánchez-Mejías1,2,
  2. R M Fernández1,2,
  3. M López-Alonso2,3,
  4. G Antiñolo1,2,
  5. S Borrego1,2
  1. 1
    Unidad de Gestión Clínica de Genética, Reproducción y Medicina Fetal, Hospital Universitario Virgen del Rocío, Seville, Spain
  2. 2
    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Seville, Spain
  3. 3
    Unidad de Gestión Clínica de Cirugía Infantil, Hospital Universitario Virgen del Rocío, Seville, Spain
  1. Correspondence to Dr S Borrego, Unidad de Gestión Clínica de Genética, Reproducción y Medicina Fetal, Hospital Universitario Virgen del Rocío, Avda Manuel Siurot s/n, 41013 Seville, Spain; salud.borrego.sspa{at}


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.