title: Mutations in Hirschsprung disease: when does a mutation contribute to the phenotype.
abstract: Hirschsprung disease is a congenital disorder clinically characterized by the absence of colonic ganglia and genetically by extensive heterogeneity. Genes involved include RET, GDNF, EDNRB and EDN3. Mutations of these genes may give dominant, recessive, or polygenic patterns of inheritance. In particular in the case of missense mutations, it is therefore far from easy to assess whether a given mutation will contribute to the phenotype. We discuss criteria for such an assessment and pay special attention to functional assays. The interpretation of mutations as contributing to a disease phenotype or as merely representing a rare polymorphism has direct clinical consequences. Hirschsprung disease with major and modifying sequence variants in a variety of genes might well serve as a model for the many complex disorders for which the search for genes involved has only just been initiated.
authors.affiliation: Department of Medical Genetics, University of Groningen, The Netherlands.
authors.forename: R M
authors.initials: RM
authors.lastname: Hofstra
authors.forename: J
authors.initials: J
authors.lastname: Osinga
authors.forename: C H
authors.initials: CH
authors.lastname: Buys
mesh_terms: D019334:Endothelin-3 / Q000235:genetics; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D009154:Mutation; D010641:Phenotype; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D017466:Receptors, Endothelin / Q000235:genetics
chemical_list: D019334:Endothelin-3; D017466:Receptors, Endothelin; D020794:Receptor Protein-Tyrosine Kinases