Despite today’s advanced state of medical diagnosis and treatment, there are people with challenging medical mysteries who, even after referrals to multiple specialists and seemingly endless testing, have no answers for the cause of their sometimes-debilitating symptoms.

To help address this reality, the National Institutes of Health established the Undiagnosed Diseases Network (UDN) in 2014 to help find answers for patients and their families affected by mysterious conditions. The UDN also exists to use the insights gained from studying rare diseases to potentially improve and advance treatments for more common illnesses. Barnes-Jewish Hospital and St. Louis Children’s Hospital, in partnership with Washington University School of Medicine, are part of the UDN, increasing the number of clinical sites in the United States participating in the network from seven to 12. In addition, the School of Medicine serves as a Model Organisms Screening Center for the UDN.

“Between 2015 and 2018, the Undiagnosed Diseases Network was successful in providing a diagnosis for approximately 35% of the people undergoing evaluation,” says F. Sessions Cole, MD, who leads the UDN clinical site at Barnes-Jewish and St. Louis Children’s hospitals. Cole, a Washington University neonatologist, recently stepped down from his role as director of the Division of Newborn Medicine, which he held from 1986. “At a minimum, these people now have names for their disorders and for the genes that cause them. This knowledge allows us to look for alternative treatments as well as predict the recurrence risk for the affected family.”

People interested in being evaluated through the UDN must meet certain criteria, including having a condition that remains undiagnosed despite a thorough evaluation. A UDN participant must also provide a recommendation letter from a health care provider. Once an application is reviewed and approved, the participant is assigned to one of the 12 clinical sites for evaluation. During Phase I of the UDN (2015 to 2017), 382 of 1,519 applicants nationally were accepted for evaluation, and 132 (35%) of those evaluated were successfully diagnosed.

“Patients referred to our clinical site are treated as individual research projects. We have a core team of physicians and medical professionals who review medical records and develop a plan outlining the subspecialists they should see and any additional imaging or diagnostic procedures we feel are needed,” explains Cole. “The UDN requires that our evaluation be completed within a five-day period.” At the end of the evaluation period, Cole says, “we provide patients and their referring physicians with a summary of our conclusions and any suggestions for changes in treatment. Sometimes our recommendation is for additional testing.”

In most cases, the evaluation team uses gene-code deciphering, also called whole genome sequencing, and advanced computational methods to discover the gene-code variant that is causing the person’s health problems. When this discovery process identifies a variant for which no prior human disease association exists, its function may be tested in a model organism—a worm, perhaps, or zebra fish—by the Model Organisms Screening Center to confirm its role in the diagnosis. That process can take six months to a year. The hoped-for end result is a gene-code diagnosis.

THE VAST MAJORITY OF THESE UNDIAGNOSED DISEASES ARE LINKED TO GENETICS.

“The vast majority of these undiagnosed diseases are linked to genetics,” Cole notes. “In Phase I of the UDN’s program, specialists paid careful attention to environmental factors that might cause health problems or trigger a specific gene-code variant to cause disease. We will continue to examine environmental factors as we move into Phase II.”

In addition to helping unravel medical mysteries, the UDN’s genome-sequencing work can aid in advancing treatment for more common illnesses. To illustrate this point, Cole uses the example of cystic fibrosis. “Cystic fibrosis is a relatively rare condition that causes the production of abnormally thick mucus in the lungs and can often result in respiratory infection and steadily deteriorating lung function,” he says. “Researchers discovered that drugs developed for the specific gene-code problems that cause cystic fibrosis also have a favorable impact on more common lung diseases, including chronic obstructive pulmonary disease.”

Cole says that participation in the Undiagnosed Diseases Network will allow the involved institutions to make significant advances in personalized medicine: diagnosis and treatment tailored to a patient’s genetic makeup. “The partnerships formed through the UDN will help accelerate the rate of medical discoveries for people with undiagnosed illnesses and for people with more common diseases who can benefit from newly identified treatments.”

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To learn more about the Undiagnosed Diseases Network, including the process for submitting an application to be evaluated, visit https://www.undiagnosed.wustl.edu or https://www.undiagnosed.hms.harvard.edu.

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