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Rare Disease Research at NHGRI: Not So Rare

March 7, 2017

Every year in late February, there is a date designated as Rare Disease Day. The goal of this annual event is to raise awareness about rare diseases and the lives they impact. Just last week, NIH held its annual symposium for Rare Disease Day; the archived webcast is accessible here. A rare disease is defined as a disorder or condition affecting fewer than 200,000 people in the United States. However, as it is often said, rare diseases considered together are not so rare! Over 7,000 rare diseases have been identified, with upwards of 25 million people affected by rare diseases in the United States alone- similar to the number of people affected by diabetes. 

Rare Disease Day

The small affected population size per disease creates challenges for studying these disorders in several ways. First, it can be difficult to identify patients affected with a particular rare disease, stymying efforts to carry out sufficiently large scientific studies, including clinical trials of treatment response. Even when patients are identified, their locations are often highly dispersed, incurring major costs for their travel to sites conducting appropriate studies. In addition, there is often a lack of adequate incentives for pharmaceutical companies to develop treatments for conditions affecting very small numbers of people, especially with the typical large cost of drug development. Currently, it is estimated that there is a treatment for less than 5% of rare diseases.

One of the features of the NIH Intramural Research Program is that it provides a highly productive environment for studying rare diseases, and this has, in turn, attracted a remarkable set of rare disease experts. For example, NIH intramural researchers are currently studying over 500 rare diseases (involving nearly 2,250 patients) at the NIH Clinical Center.

Within the NHGRI Intramural Research Program, investigators are collectively conducting research on over 45 rare diseases. With the available dedicated clinical resources, physician-scientists can become experts about a particular rare disease within just a few years. Different approaches are used to address different areas of studying rare diseases. The Undiagnosed Diseases Program, headed by NHGRI Clinical Director Dr. William Gahl, combines genome sequencing with the expertise of a network of medical specialists to diagnose the most challenging and rare genetic diseases. This program began in-house at NHGRI and NIH, and was later expanded into a national effort, the NIH Undiagnosed Diseases Network. This Network is now routinely making major discoveries about new rare diseases through the intense study of individual patients and families.

Other approaches are also used by NHGRI researchers to study rare diseases. The Institute houses experts in all aspects of clinical research, including the natural history of rare diseases. Elucidating natural histories can be critical to the design of successful clinical trials. Dr. Wendy Introne, a rare disease researcher at NHGRI, conducts clinical research on alkaptonuria, a metabolic disorder occurring in ~1 in 500,000, and Chediak-Higashi disease, a multi-system disease occurring in ~1 in 1,000,000. She began her research on alkaptonuria by defining the natural history of the disorder, with an eye towards investigating a possible therapy.

Graphic Stethoscope ACTG

Dr. Introne credits the unique environment at NIH and its capacity to bring patients from all over the world for comprehensive and state-of-the-art clinical evaluations in a time-efficient manner. "For studying rare diseases, it is critical to gather as large a cohort as possible to fully understand the spectrum of disease and clinical, molecular, and cell biological variability. The NIH is the master of translational medicine."

By studying rare diseases, discoveries and insights are made about common diseases. For example, Dr. Introne's studies of the pathophysiology of alkaptonuria have shown that these patients suffer from both arthritis that resembles osteoarthritis and aortic stenosis that resembles more generalized heart-valve disease, such as that seen in the general population. The earlier onset and faster progression of these conditions in alkaptonuria patients distinguish this rare disease from its more common counterparts, but understanding the mechanisms of rare diseases can inform studies of the biological pathways involved in more common disorders.

All major aspects of studying rare diseases can be found within the NHGRI Intramural Research Program. Appropriately, some of the Institute's research in rare diseases were showcased in a recent Reddit "Ask Me Anything" with experts from the Undiagnosed Diseases Network, including NHGRI's Dr. William Gahl and Dr. Cyndi Tifft, who discussed everything from diagnosing medical mysteries to getting support when dealing with a loved one with a rare disease. To learn more about rare diseases, visit the NHGRI- and NCATS-funded resource, the Genetic and Rare Diseases Information Center (GARD) at

Posted: April 4, 2017

See Also:

March Genomics LandscapePDF file