Background: Patients with rare disorders or previously undocumented conditions with a genetic basis often go undiagnosed for many years despite extensive evaluations under skilled physicians in their communities and tertiary care centers. These patients are often high- volume consumers of healthcare and a frequent source of hospital admissions and readmissions. Without a clear diagnosis they often lack a cohesive care plan. Our protocol seeks to elucidate the genetic and molecular basis for their clinical conditions to shed light on previously unrecognized genetic pathways and open potential new avenues for therapy.

Methods: Candidates apply through the NIH Undiagnosed Diseases Network (UDN) web portal and are assigned to one of 7 clinical sites. Patients who have had a complete standard of care evaluation in the community or tertiary care centers but still have no formal diagnosis and/or have symptoms that are likely attributable to a new disease are discussed and accepted in a committee setting. Accepted patients, and along with available family members when appropriate, are consented for testing. Patients assigned to and accepted by the NIH site are admitted to the NIH Clinical Center for a comprehensive evaluation aimed at complete phenotyping. Additional testing such as imaging, blood work and biopsies are performed as clinically indicated. All new test results are evaluated in the context of prior testing and evaluations in multidisciplinary conferences, including pathology and radiology. Some patients have clinical syndromes that may qualify them for other investigational NIH protocols involving collaboration with our program. Exome or genome sequencing, ideally including the nuclear family, is obtained in unsolved cases. All identified genetic variants are reviewed in a multidisciplinary committee. Previously unreported candidate gene variants classified as having a high likelihood for causing the presenting phenotype are then considered for functional studies to corroborate the findings. Functional studies may include referral to a model organism core where an animal model with a specific genetic variation may be developed for phenotyping. Close collaborations among laboratory scientists, bioinformaticians and clinicians increase the likelihood that diagnoses are identified.

Results: Since inception in September 2015, 1902 UDN applications were reviewed, and 795 were accepted for evaluations. A genetic diagnosis matching the clinical phenotype was identified in 113 cases so far. Of the cases reviewed but not accepted, we recommended specific testing in 152 and specific expert care in 136.

Conclusions: Our multidisciplinary approach and unique access to research expertise and resources at the NIH involving a wide variety of disciplines aids our effort to provide accurate diagnosis of undiagnosed patients. Providing an accurate diagnosis down to the genetic and molecular basis opens new therapeutic opportunities not previously considered and expands our understanding of disease mechanisms applicable to more common diseases. Undiagnosed patients found in the hospital setting can benefit from referral to the Undiagnosed Diseases Program where they may be able to obtain an accurate diagnosis which can then qualify them for services, targeted therapy and improved their quality of life.