Johns Hopkins Study

Dr. Aravinda Chakravarti’s laboratory at Johns Hopkins University has been investigating the genetics of Hirschsprung disease (HSCR) for fifteen years, and has played an important role in identifying several genes involved in the development of the condition.  However, there is more work to be done in clarifying the genetic basis of HSCR.  The purpose of our study is: to continue the search for genes involved in Hirschsprung disease; to further characterize the known genes and study the interactions between them; and to identify additional "modifying" genes that influence whether a particular individual develops HSCR.  Our study will hopefully lead to a better understanding of the genetics of HSCR and, further down the road, improved diagnosis, treatment, and genetic counseling.

Current efforts in our laboratory include:

1.)   We continue to look for additional genes that could be involved in HSCR.

2.)   More in-depth analysis of the RET gene. We are collaborating with the National Institutes of Health to probe even further into the sequence of the major gene implicated in Hirschsprung disease.  We will attempt to classify the different sorts of changes in the sequence that are detected, and whether a given gene change is harmful or just a benign variation.  This will help with development and interpretation of a more sensitive genetic test for Hirschsprung disease.

3.)   Mouse studies.  We are using a mouse model of Hirschsprung disease to identify regions on human chromosomes that could modify the risk of Hirschsprung disease in a person who has a disease-causing mutation in the RET gene. 

Why are researchers so interested in Hirschsprung disease?

Hirschsprung disease is a great model of a “complex” genetic disease.  Unlike other conditions where there is a clear pattern of inheritance, the majority of cases of Hirschsprung disease are the first in a family. Additionally, in families that do have multiple affected individuals, it can be seen to skip generations. 

The charactertics of Hirschsprung disease that make it complex and interesting to researchers are:

• Multigenic—At least 8 different genes have been implicated in Hirschsprung disease in different patients. (Sometimes also called “oligogenic” meaning “a few genes”.)
  
• Reduced penetrance—Inheriting a disease-causing mutation does not guarantee that a person will develop HSCR.  It is still unknown what influences the expression of a harmful gene change.  However, penetrance is estimated at 65% for males and 45% for females.
  
• Variable expressivity—Different family members with HSCR may have different lengths of their colon affected by HSCR.
  
• Non-coding mutation—Genes are made up of “coding” and “non-coding” sequence.  The RET gene was found to have a gene change in a non-coding part of the sequence which may account for more of the susceptibility to HSCR than those mutations in the “coding” region.  If so, this would be an important finding in the field of genetics.

“Currently HSCR is probably the best example of an oligogenic disease…”  Strachan and Read, Human Molecular Genetics, 2^nd ed.