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Contribution of RET, NTRK3 and EDN3 to the expression of Hirschsprung disease in a multiplex family
  1. Avencia Sánchez-Mejías (avencia.sanchez.exts{at}juntadeandalucia.es)
  1. Hospital Universitario Virgen del Rocío, Seville, Spain
    1. Raquel Maria Fernández (raquel.fernandez.exts{at}juntadeandalucia.es)
    1. Hospital Universitario Virgen del Rocío, Seville, Spain
      1. Manuel López-Alonso
      1. Hospital Universitario Virgen del Rocío, Seville, Spain
        1. Guillermo Antiñolo
        1. Hospital Universitario Virgen del Rocío, Seville, Spain
          1. Salud Borrego (salud.borrego.sspa{at}juntadeandalucia.es)
          1. Hospital Universitario Virgen del Rocío, Seville, Spain

            Abstract

            Hirschsprung disease (HSCR) is a developmental disorder due to a defect of neural crest neuroblasts migration process. It is considered as the paradigm of complex disorders, with many loci contributing to the manifestation of the disease. Although HSCR commonly appears as a sporadic trait, approximately 20% of HSCR cases are familial, with complex patterns of inheritance. Here we report a multiplex HSCR family with an additive model of inherence, in which the contribution of 3 genes (RET, NTRK3, EDN3) leads to HSCR phenotype. Our findings suggest that both RET and NTRK3 mutations acting together would be necessary and sufficient for the appearance of the disease, while the EDN3 mutation would act as a phenotype modifier factor in the context of this family as 2 different HSCR phenotypes are seen among the affected members: a short segment form, and a total colonic aganglionosis. The present results therefore support the complex additive model of inheritance previously proposed for Hirschsprung disease.

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