Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a common 
hereditary disorder causing intestinal obstruction, thereby showing considerable 
phenotypic variation in conjunction with complex inheritance. Moreover, 
phenotypic assessment of the disease has been complicated since a subset of the 
observed mutations is also associated with several additional syndromic 
anomalies. Coding sequence mutations in e.g. RET, GDNF, EDNRB, EDN3, and SOX10 
lead to long-segment (L-HSCR) as well as syndromic HSCR but fail to explain the 
transmission of the much more common short-segment form (S-HSCR). Furthermore, 
mutations in the RET gene are responsible for approximately half of the familial 
and some sporadic cases, strongly suggesting, on the one hand, the importance of 
non-coding variations and, on the other hand, that additional genes involved in 
the development of the enteric nervous system still await their discovery. For 
almost all of the identified HSCR genes incomplete penetrance of the HSCR 
phenotype has been reported, probably due to modifier loci. Therefore, HSCR has 
become a model for a complex oligo-/polygenic disorder in which the relationship 
between different genes creating a non-mendelian inheritance pattern still 
remains to be elucidated.