Genome Advance of the Month

Undiagnosed Diseases Program (UDP) Discovers a New Disease

February 2011
By Jonathan Gitlin, Ph.D.
Science Policy Analyst

From left to right: Researcher Manfred Boehm, M.D.; patients with ACDC Paula Allen and Louise Benge; UDP Director William Gahl, M.D., Ph.D.; and Researcher Cynthia St. Hilaire, Ph.D.
Researcher Manfred Boehm, M.D.; patients with ACDC Paula Allen and Louise Benge; UDP Director William Gahl, M.D., Ph.D.; and Researcher Cynthia St. Hilaire, Ph.D.
An awful lot of cool science happens here at the National Institutes of Health (NIH), but it's not every month that someone discovers a new disease.

In February, the team at the NIH Clinical Center, who run the Undiagnosed Diseases Program (UDP) — a joint initiative between the National Human Genome Research Institute (NHGRI), the National Institutes of Health NIH Clinical Center, and the NIH Office of Rare Diseases Research — reported its first new diagnosis in the New England Journal of Medicine.

The Undiagnosed Diseases Program has two goals: To provide answers to patients with mysterious conditions that have long eluded diagnosis, and to advance medical knowledge about rare and common diseases. Patients are referred to UDP by their stumped clinicians, and if accepted, travel to Bethesda, Md. where the full might of NIH's talent can be brought to bear on their illness.

Conceived by William A. Gahl, M.D., Ph.D., NHGRI's clinical director and an expert in rare diseases, and launched in 2008, UDP is only possible because it can leverage the resources of NIH's Clinical Center and its diverse collection of medical experts. Some 1,500 different studies are underway at the Clinical Center, mainly clinical trials in phase I and phase II. This may be stating the obvious, but it's a lot easier to treat someone if you know what's wrong with them. For a rare number of individuals with severe health problems, actually getting such a diagnosis can prove almost impossible. UDP exists for just such individuals.

The case leading to the discovery of a new disease involves nine patients from three unrelated families. All suffered from calcium deposits building up in the arteries of their legs and in the joints of their hands and feet, resulting in pain and cramping, poor circulation, and reduced mobility. In the case of one patient, the condition was so advanced, and blood flow so reduced, that a foot amputation was necessary.

The UDP used a range of techniques to get to the bottom of the cause of this disease. X-rays and MRIs were used to get a good idea of the extent and progression of the calcification. Skin biopsies were taken and used to grow cells called fibroblasts in laboratories that could then be examined using sophisticated molecular biology approaches, and blood samples were used to obtain genetic and genomic data that could pin down the gene or genes responsible.

These analyses identified the culprit as mutations in a gene called NT5E. The gene makes a protein called CD73 that sticks out from a cell's membrane and is involved in metabolizing ATP (the chemical that cells use as an energy source). Although each family had a different mutation in NT5E, in each case the result was an inactive version of CD73. Much of this work involved Manfred Boehm, M.D., and Cynthia St. Hilaire, two researchers from the National Heart, Lung and Blood Institute, who collaborated with the UDP team.

Finding the genetic mutation may lead to a treatment. While this is the first time the molecular cause of adult arterial calcification has been pinpointed, there is another rare condition that affects infants (often fatally) where the causative gene is also known. In this case the culprit is a gene called ENPP1. Since both ENPP1 and NT5E are part of the same extracellular metabolic pathway, and since drugs called bisphosphonates have been shown to treat ENPP1 deficiency, there is the possibility that they may also be effective for NT5E deficient patients. Several other possible treatments are also being considered, initially by testing them in the cells growing in the lab that were taken from these patients.

As for the other patients studied by UDP experts, around 75 percent will get a diagnosis in the end, whether that be a disease already known but which is presenting in an unusual manner, or, as in this case, one that is new to medicine. So there you have it, a great example of how the nation's investment in scientific research can be brought to bear on some of medicine's most puzzling mysteries, and without a single reference to the hit TV show House MD.

February saw several other research findings NHGRI thought interesting enough to highlight. They are as follows:

Five new organisms have joined the "we've had our genome sequenced" club. Sadly none are as loveable as last month's new member, the orangutan. They are:

One of the less well-understood aspects of human genetic variation is copy number variations, or CNVs. CNVs are involved with a range of diseases, particularly those that affect brain function. As part of NHGRI's 1000 Genomes Project, researchers have been able to create a high-resolution map of CNVs, greatly adding to our knowledge of this aspect of genome biology.

There have been a number of genomic advances in the field of prostate cancer, including one that may be adapted for use as a prognostic test to guide doctors in their treatment of patients. Meanwhile, a collaboration between the Mayo Clinic and the Translational Genomics Research Institute used whole genome sequencing to compare the DNA [] of a patient's pancreatic tumor with his normal DNA, and used that information to guide his treatment.

One interesting article was published on shared genome-wide associations study (GWAS)-identified variants for Crohn's disease and celiac disease. The study design was a twist on a typical GWAS, as they combined GWAS data from two different but related outcomes and discovered/replicated several variants identified with both outcomes. It's a good example of how to leverage existing data to make new discoveries.

Preconception genetic testing for severe recessive genetic diseases such as Tay-Sachs and cystic fibrosis has resulted in a remarkable decline in the incidences of these diseases. It has been impractical until now to test for the entire range of severe inherited diseases, but a paper in Science Translational Medicine details a new method of carrier screening using next-generation sequencing technology.

Finally, this one isn't a research paper as such, but Stanford School of Medicine tried applying whole genome sequencing as a kind of molecular autopsy to determine the cause of a young man's death: Stanford's 'molecular autopsies' hope to help grieving families []

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Last Reviewed: May 23, 2012