So-called orphan diseases are rare and frequently deadly because often there are mutations in essential-to-survival genes, researchers from Cincinnati Children's Hospital Medical Center explain in The American Journal of Human Genetics.

In the USA, an orphan disease is one that affects fewer than 200,000 of its citizens.

The researchers in this study say their findings differ vastly from what we know about mutations that have occurred in non-essential genes being drivers of common diseases that have higher prevalence rates.

This study used computer technology to link diseases and conditions with causative genes, shared molecular pathways and interacting proteins. The researchers produced a global network map including 1,772 orphan diseases caused by gene mutations.

Senior investigator, Anil Jegga, Ph.D., from the Division of Biomedical Informatics, said:

"The map gives scientists a precise starting point to launch innovative research into developing new therapies or repositioning existing drugs for diseases that lack effective treatments."

Approximately 25 million Americans are affected by at least one of 8,000 different orphan diseases. Some diseases, such as cystic fibrosis and several forms of childhood cancers start early in life and are influenced by genetics and the immune system.

Dr. Jegga said:

"Only about 300 of these 8,000 diseases have effective drug therapy, so collectively orphan diseases pose a formidable challenge for public health authorities. Previous studies on disease networks have not separated out these rare diseases, many of which are fatal while others induce chronic and debilitating illnesses."

Study first co-author, Minlu Zhang and Cheng Zhu, from the Department of Computer Science at the University of Cincinnati, explains that by analyzing networks that offer a natural representation of orphan diseases, scientists get a systems-level view of the complex associations that bring about these diseases.

The scientists discovered that orphan disease genes encode hub proteins - these have multiple protein-to-protein interactions which are crucial for the proper function of a cell.

According to previous studies, non-essential genes which cause common illnesses and conditions do not encode hub proteins. If 43% of orphan disease causing gene homologs in mice are deleted, the animal dies soon or before its time, indicating the role of the genes in essential survival and related biological processes.

2,124 mutant genes are linked to 1772 orphan diseases in this study, the scientists explained. 69% of the diseases have one causative gene, while the rest are caused by at least two genes. Of all the disease-causing genes they identified, 1,393 (over half) are linked to just one disease, the remaining 731 genes are implicated in at least two diseases.

The authors give the example of the gene LMNA - its mutations are implicated in 17 different orphan diseases. Nonsyndromic genetic deafness has 43 causative genes (the highest number).

Dr. Jegga said:

"Our findings indicate that the wiring of the gene-based and function-based networks of orphan diseases is different. By considering the shared functions among causal genes, molecular targets for the treatment of orphan diseases can be revealed. These maps of molecular targets can then be used to create novel hypotheses and guide treatment strategies for orphan diseases."

Between 1973 and 1983 just ten new medications for orphan diseases were approved by the FDA (Food and Drug Administration). In 1983 the US Orphan Drug Act was born. Since then, over 300 rare disease drugs have been approved.

The American Journal of Human Genetics

Written by Christian Nordqvist