Clinical and Genetic Evaluation of Individuals With Undiagnosed Disorders Through the Undiagnosed Diseases Network

Without an explanation for severe and sometimes life-threatening symptoms, patients and their
families are left in a state of unknown. Many individuals find themselves being passed from
physician to physician, undergoing countless and often repetitive tests in the hopes of
finding answers and insight about what the future may hold. This long and arduous journey to
find a diagnosis does not end for many patients- the Office of Rare Diseases Research (ORDR)
notes that 6% of individuals seeking their assistance have an undiagnosed disorder. In 2008,
the National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) was established
with the goal of providing care and answers for these individuals with mysterious conditions
who have long eluded diagnosis. The NIH UDP is a joint venture of the NIH ORDR, the National
Human Genome Research Institute Intramural Research Program (NHGRI-IRP), and the NIH Clinical
Research Center (CRC). The goals of the NIH UDP are to: (1) provide answers for patients with
undiagnosed diseases; (2) generate new knowledge about disease mechanisms; (3) assess the
application of new approaches to phenotyping and the use of genomic technologies; and (4)
identify potential therapeutic targets, if possible. To date, the UDP has evaluated 3300
medical records and admitted 750 individuals with rare and undiagnosed conditions to the NIH
Clinical Center. The NIH UDP has identified more than

70 rare disease diagnoses and several new conditions. The success of the NIH UDP prompted the
NIH Common Fund to support the establishment of a network of medical research centers, the
Undiagnosed Diseases Network (UDN), for fiscal years 2013-2022. The clinical sites will
perform extensive phenotyping, genetic analyses, and functional studies of potential
disease-causing variants. The testing performed on patients involves medically indicated
studies intended to help reach a diagnosis, as well as research investigations that include a
skin biopsy, blood draws, and DNA analysis. In addition, the UDN will further the goals of
the UDP by permitting the sharing of personally identifiable phenotypic and genotypic
information within the network. By sharing participant information and encouraging
collaboration, the UDN hopes to improve the understanding of rare conditions and advance the
diagnostic process and care for individuals with undiagnosed diseases.

- INCLUSION CRITERIA:

- The applicant has a condition that remains undiagnosed despite thorough evaluation by
a healthcare provider and has at least one objective finding.

- The applicant (or legal guardian) agrees to the storage and sharing of information and
biomaterials in an identified fashion amongst the UDN centers, and in a de-identified
fashion to research sites beyond the network.

- Applicants unable to consent can be enrolled

- For the metabolomics analysis site-specific research project, the individual must be a
patient in the inherited metabolic disease clinic at Boston Children s Hospital or the
Oregon Health & Science University and have a confirmed diagnosis of an inherited
metabolic disorder based on DNA, enzyme analysis, or other standard practice.

EXCLUSION CRITERIA:

- The applicant has a diagnosis that explains the objective findings.

- Review of the records suggests a diagnosis and further evaluation by the UDN is deemed
unnecessary.

- The UDN is unlikely to improve on the comprehensive workup the applicant already
received

- The applicant is too seriously ill to travel safely to the UDN site and
telemedicine/distance consult is not possible or appropriate.

- For the metabolomics analysis site-specific research project, individuals who are
pregnant, have intercurrent illness, or are using drugs and/or supplements deemed
likely to alter the usual metabolic state will be excluded. Individuals unable to
provide informed consent or assent will also be excluded