Hirschsprung disease (HSCR, aganglionic megacolon) represents the main genetic 
cause of functional intestinal obstruction with an incidence of 1/5000 live 
births. This developmental disorder is a neurocristopathy and is characterised 
by the absence of the enteric ganglia along a variable length of the intestine. 
In the last decades, the development of surgical approaches has importantly 
decreased mortality and morbidity which allowed the emergence of familial cases. 
Isolated HSCR appears to be a non-Mendelian malformation with low, sex-dependent 
penetrance, and variable expression according to the length of the aganglionic 
segment. While all Mendelian modes of inheritance have been described in 
syndromic HSCR, isolated HSCR stands as a model for genetic disorders with 
complex patterns of inheritance. The tyrosine kinase receptor RET is the major 
gene with both rare coding sequence mutations and/or a frequent variant located 
in an enhancer element predisposing to the disease. Hitherto, 10 genes and five 
loci have been found to be involved in HSCR development.