The NIH Common Fund's Undiagnosed Diseases Network (UDN) was established to accelerate the diagnosis and clinical management of rare or previously unrecognized diseases, and to advance research in disease mechanisms. The UDN is composed of multiple clinical sites around the United States and multiple research cores, including DNA sequencing, model organisms and metabolomics. As the Metabolomics Core for Phase I of the UDN, our role was to provide comprehensive untargeted measurements to identify qualitative and quantitative changes of metabolites (metabolomics) and lipids (lipidomics) in biofluids from probands to assist in the evaluation and/or identification of the causes of rare and undiagnosed diseases. In contrast to identifying inborn errors of metabolism, the metabolic changes associated with rare diseases may be more subtle, consisting of complex patterns of minor changes of a large number of analytes rather than a few significant outliers. In addition, due to the rare nature of these disorders, the number of individuals with a given phenotype is usually limited to one or just a few, precluding the use of the balanced study designs typically used in metabolomics. In this presentation, we will discuss our experiences in applying metabolomics and lipidomics measurements in the study of individuals with rare disease and the associated unique challenges.
Thomas (Tom) Metz
Metabolomics Team Lead, Biomedical Scientist
Pacific Northwest National Laboratory
thomas.metz@pnnl.gov
509-371-6581
David Koeller
Professor of Molecular and Medical Genetics, School of Medicine
Oregon Health & Science University
503-494-8307
Kyle J, K Stratton, E Zink, YM Kim, K Bloodsworth, M Monroe, KM Waters, BJM Webb-Robertson, D Koeller, and TO Metz. 2021. "A resource of lipidomics and metabolomics data from individuals with undiagnosed diseases." Scientific Data 8: 114. PMCID: PMC8060404
Webb-Robertson BJM, KG Stratton, JE Kyle, YM Kim, LM Bramer, KM Waters, DM Koeller, and TO Metz. 2020. "Statistically-driven metabolite and lipid profiling of patients from the undiagnosed diseases network." Analytical Chemistry 92 (2): 1796-1803. PMCID: PMC7183858
Blanco-Sánchez B, A Clément, SJ Stednitz, J Kyle, JL Peirce, M McFadden, J Wegner, JB Phillips, E Macnamara, Y Huang, DR Adams, C Toro, WA Gahl, MCV Malicdan, CJ Tifft, EM Zink, KJ Bloodsworth, KG Stratton, DM Koeller, TO Metz, P Washbourne, and M Westerfield. 2020. "yippee like 3 (ypel3) is a novel gene required for myelinating and perineurial glia development." PLoS Genetics 16 (6):e1008841. PMCID: PMC7319359
K Splinter, et al. 2018. "Undiagnosed Diseases Network. Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease." N Engl J Med. 2018 Oct 10. PMID: 30304647
M Oláhová, et al. 2018. "Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder." Am J. Human Genetics. 2018;102(3):494-504. https://doi.org/10.1016/j.ajhg.2018.01.020
