Kapur's main approach to understanding this problem is to study transgenic mice. These mice are bred to carry spontaneous or genetically-engineered mutations that cause Hirschsprung disease. At the same time, they are also given a gene that researchers suspect may correct the mutation. On a certain level, such results represent a treatment for Hirschsprung disease, but one far from clinical application. Incomplete penetrance is the phrase used to describe why a given mutation in a given gene does not always result in disease.
Researchers suspect one of two reasons for the phenomenon.
Either there are other genes involved that suppress or promote the primary genetic mutation, or there are environmental factors, maternal exposures, for instance, that influence the migrating neurons in a way that allows the primary mutation to manifest as a birth defect. Out of the seven genes with known mutations that cause Hirschsprung disease, five of the genes are expressed in the neural crest cells themselves, while the other two genes are expressed in adjacent cells during embryonic development. Not every individual with a mutation in one of these genes develops the disease. The severity of the disease also varies among individuals. Curiously, Kapur said, there is a four to one predominance of Hirschsprung disease in males, which has prompted researchers to search for a gene on the X or Y chromosomes that may function as a modifier by helping express the primary mutation.