Focus on the Undiagnosed Diseases Network

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Accelerating discovery and innovation in the way we diagnose and treat patients with previously undiagnosed diseases. 

The Undiagnosed Diseases Network (UDN) is a research program that combines basic and clinical research services to understand health conditions for individuals and their families who have sought a clinical diagnosis without success. The program is supported by 17 Institutes and Centers at the National Institute of Health and is led by the National Institute of Neurological Disorders and Stroke (NINDS).  Launched by the NIH Office of the Director’s Common Fund in 2013, it has facilitated difficult diagnoses for more than 650 people in the past decade – providing answers to patients who have long searched for the cause of their symptoms. Team science and collaboration among UDN investigators has led to the discovery of hundreds of novel disease-associated genes and genomic variants, including the identification of new diseases and syndromes. Together, the UDN has built an international reputation for advancing disease research while establishing exemplary clinical practices for undiagnosed diseases. 

What are Undiagnosed Diseases?

Undiagnosed diseases are defined as long-standing symptoms or elusive medical conditions that have not been diagnosed despite extensive clinical evaluation. Undiagnosed diseases are often due to rare conditions and can include: 1) previously described diseases that are not recognized due to very low incidence or prevalence; 2) yet-to-be-described disorders that have not been previously documented; and 3) rare variations of more common diseases. These conditions and the lack of a diagnosis present difficult problems for patients, their families, and physicians resulting in a high emotional, physical, and financial burden to patients who may spend many years seeking a diagnosis and path to treatment.

History of the UDN

The National Human Genome Research Institute and the NIH Clinical Center established the intramural Undiagnosed Diseases Program (UDP) in 2008 to make progress in uncovering, understanding, and treating rare disorders. Based on the success of the UDP, the NIH Common Fund established the Undiagnosed Diseases Network (UDN) in FY 2013 (phase I) to achieve this type of cross-disciplinary approach to disease diagnosis in academic medical centers around the United States. The NIH Common Fund expanded the network in 2018 (phase II) to increase the availability of diagnostic services, foster opportunities for collaboration between laboratory and clinical investigators, provide resulting data and protocols to the broader community, and assess development of a sustainable national resource after Common Fund support ends. The UDN transitioned from Common Fund in 2023.

The Next Phase

NIH is using a NIH-wide approach to support the UDN beyond 2023. The National Institute of Neurological Disorders and Stroke (NINDS) will oversee the Network in Phase III, which will launch in July 2023, with help from 17 different NIH Institutes and Centers along with the NIH Office of the Director. With help from patients, family members, patient advocacy groups, a Data Management and Coordinating Center (DMCC), several Clinical Sites, and other stakeholders, the NIH envisions the UDN evolving into a larger, diverse, and self-sustained network that fosters scientific discovery and provides expert diagnostic services for undiagnosed patients across the nation.

The overarching goals of the UDN in Phase III include:

Phase III UDN Priorities

• Scale clinical capacity to engage more patients across the US by incorporating community and third-party payer support for patient services while NIH funds continue to support the research efforts. 
• Expand access to the UDN for individuals and groups who historically have not benefited from modern diagnostic investigations due to racial, ethnic, socioeconomic, geographic or other systemic reasons.
• Continue to incorporate input from patients, caregivers and family members into the practice of the UDN.
• Continue the fruitful genetic investigations, but expand to including other potential causal factors such as environmental insults, infectious, oncologic, immunologic, or complex multi-organ disorders.
• Continue to develop health economics approaches to support the sustainability of the UDN approach to investigate persons with undiagnosed medical conditions.
• Incorporate implementation science methods to facilitate the translation of UDN lessons- learned into the mainstream of medical care. 

Phase III UDN

In FY2023, NINDS and 17 other NIH Institutes joined together to launch the Phase III Network as a Trans-NIH Initiative. NIH has awarded a cooperative agreement to establish a new UDN Data Management and Coordinating Center (DMCC), which will provide infrastructure and research support for a new network of clinical sites. The DMCC will also support Research Cores (genomic sequencing, model organisms screening center, metabolomic and proteomic analysis, etc.) based on the needs of the Network cases, via subawards. To ease the transition from Phase II to Phase III and ensure that applicants continue to have the opportunity to receive a diagnosis, eligible Phase II extramural clinical sites were also awarded an additional year of support under the Limited Competition for the Continuation of Clinical Sites for the Undiagnosed Diseases Network Notice of Funding Opportunity (NOFO). The intramural Undiagnosed Disease Program, housed within the NIH Clinical Center and currently supported as a UDN clinical site, will continue to receive support and oversight from multiple NIH Institutes and Centers.

More About Phase III UDN

Starting in 2023, additional, new Clinical sites with the appropriate infrastructure, expertise, and resources needed to conduct the clinical evaluation and DNA sequencing of participants enrolled at their sites can apply for designation as a Diagnostic Center of Excellence via an X01 Resource Access Program or through future NIH NOFOs. The Diagnostic Centers of Excellence will have access to the rich research capacity, data infrastructure and the DMCC subaward resources to enable diagnoses for the most difficult cases. Thus, these clinical sites will be poised to expand geographic coverage and reach individuals in the U.S. specifically from populations defined by the NIH to experience health disparities.

Phase III Awardees

Explore our awardees for the Data Management Coordinating Center for Diagnostic Centers of Excellence RFA (RFA-NS-22-051) and the Limited Competition for the continuation of UDN Clinical Sites RFA (RFA-NS-23-004).

Current Trans-NIH UDN Working Group Members

Contact

For questions about UDN, please contact Argenia Doss or Laura Mamounas.

For more information about the UDN or application process, individuals can contact the UDN Coordinating Center by:

• Telephone
  • Toll-free from USA, Canada, Mexico: 1-844-RING UDN (746-4836)
  • From all other countries: 1-617-432-2344
• Email: UDN@hms.harvard.edu