Hirschsprung's disease is characterized by the absence of ganglion cells in the myenteric and submucosal plexuses of the gastrointestinal tract. Genetic dissection was successful as nine genes and four loci for Hirschsprung's disease susceptibility were identified. Different approaches were used to find these loci such as classical linkage in large families, identity by descent mapping in an inbred kindred, candidate gene approaches based on naturally occurring mutant mice models, and finally the use of model-free linkage and association analyzes. In this study, we review the identification of genes and loci involved in the non-syndromic common form and syndromic Mendelian forms of Hirschsprung's disease. The majority of the identified genes are related to Mendelian syndromic forms of Hirschsprung's disease. The non-Mendelian inheritance of sporadic non-syndromic Hirschsprung's disease proved to be complex; involvement of multiple loci was demonstrated in a multiplicative model. We discuss the practical implications of the elucidation of genes associated with Hirschsprung's disease susceptibility for genetic counseling. Finally, we speculate on possible strategies to identify new genes for Hirschsprung's disease.

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doi.org/10.1111/j.1399-0004.2004.00319.x, hdl.handle.net/1765/61963
Clinical Genetics: an international journal of genetics and molecular medicine
Department of Pediatric Surgery

Brooks, A.S, Oostra, B.A, & Hofstra, R.M.W. (2005). Studying the genetics of Hirschsprung's disease: Unraveling an oligogenic disorder. Clinical Genetics: an international journal of genetics and molecular medicine, 67(1), 6–14. doi:10.1111/j.1399-0004.2004.00319.x