Genetics of Hirschsprung disease:Rare variants, in vivo analysis and expression profiling

Hirschsprung disease (HSCR) is characterized by the absence of neurons in the distal region of the colon. Due to the lack of neuronal innervation, the muscles in the colon are unable to relax, causing life-threatening obstipation. HSCR is a heritable disease. Over 15 genes have been associated with the disease, but mutations in these genes are found in only a quarter of all patients. We aimed to identify new disease genes for HSCR by focusing on de novo mutations. De novo mutations are new genetic variations that are found in a child, but not in the parents. We investigated whether genes carrying de novo mutations in HSCR patients are involved in the development of the nervous system in the gut. To this end we inactivated these genes one by one in a zebrafish model in which the cells of the nervous system are fluorescently labeled. This led to the identification of four new genes for HSCR. We employed the same zebrafish model to show that overexpression of a particular gene on chromosome 21 possibly explains the high prevalence of HSCR among patients with Down syndrome. Additionally, we studied which genes are important for the development of the nervous system in the gastrointestinal tract of the mouse. We identified several genes that are critical for this developmental process, and these genes are excellent candidate genes for HSCR