Hirschsprung disease is an inherited intestinal disorder occurring in 1 in 5000 individuals.
People with the disease lack intestinal nerve cells, resulting in an enlarged colon.
Affected individuals have a characteristic distended abdomen, as well as constipation, vomiting, and enterocolitis.
By combing through the genomes of families with multiple cases of Hirschsprung, Aravinda Chakravarti, Stanislas Lyonnet, and colleagues were able to detect three regions of the genome in which mutations are both necessary and sufficient to cause the disease.
The findings offer a complete explanation for both inherited and sporadic cases of the disease.
In one of these regions, the researchers identified mutations in a gene called RET, which had been previously implicated in the disease.
The other two regions harbor genes that are yet to be identified.
| Mutations in 3 genes are sufficient to cause Hirschsprung disease.
Over the past twenty years, molecular geneticists have been successfully identifying the genes that underlie "simple" genetic disorders.
In these disorders, a mutation in one gene is usually sufficient to result in the manifestation of each of the diseases.
However, the majority of genetic disorders are far from simple, and for these it has remained unclear how many genes may be involved.
The task of identifying these genes and learning how they interact has represented a daunting task for geneticists.
The finding, that mutations in what would seem to be 3 genes are sufficient to cause this complex disorder, offers hope that genetic dissection of other complex diseases may be feasible using already established tools.
Eberhard Passarge, who has been investigating Hirschsprung disease for over 30 years, will publish a News & Views article at the same time as the report by Chakravarti and colleagues.