Undiagnosed diseases take a disproportionate toll on the health care system and on affected patients and families. Our renewal application builds on our success in helping to form and grow the current Undiagnosed Diseases Network (UDN). Our proposal strengthens a collaborative network of researchers and healthcare providers, all with a stake in improving healthcare and outcomes for persons affected by various rare genetic disorders. Our approach synergizes basic and clinical research and patient care with the use of cutting-edge phenotyping technologies, an array of world class experts, and the translation of genome sequencing to the bedside. This results in a greatly improved diagnostic process for rare genetic diseases and facilitates novel discovery in clinical practice. Investigating rare diseases involving multiple systems and incorporating comprehensive genomic data into clinical care creates considerable challenges, from the interpretation of vast amounts of genetic variants to their relevance to the symptoms, to the communication issues linked to their disclosure, and to their impact on clinical management. Our proposal describes our current UDN Clinical Site and modifications necessary to transition to a sustainable clinic model that functions within the UCLA Health System and as a component of an ongoing international network to tackle the incorporation of cutting edge molecular diagnostics into the clinical workflow, analyze patients? symptoms in a standardized and reproducible fashion, and perform research investigations to elucidate the mechanisms of undiagnosed diseases. We will reach these overarching goals by implementing the following specific aims:
Aim 1 : Sustain a UDN clinic model that functions locally and network-wide;
Aim 2 : Investigate the clinical phenotypes of new and rare disorders;
Aim 3 : Investigate the underlying mechanisms of new and rare disorders;
Aim 4 : Build a network-wide sustainable infrastructure for translational research on new and rare disorders. Substantial David Geffen School of Medicine resources are available to facilitate the transition and maintenance of the sustainable clinic model that serves an essential need with the UCLA Health System, the School of Medicine, and the Institute for Precision Health. The UCLA approach is an efficient model for accelerating translational and clinical research while improving care delivery and augmenting the educational mission of UCLA. Our project integrates the resources of (1) the infrastructure of the UCLA Clinical and Translational Science Institute, (2) an experienced team of clinicians from all specialty fields, (3) expertise in the combined interrogation of DNA and RNA sequencing data for novel gene discovery; (4) expertise in the investigation of environmental effects on clinical symptoms; (5) expertise in outcomes of genetic counseling and testing, (6) access to a large, ethnically varied population and (7) a sustainable approach that includes training clinicians, genetic counselors, and basic scientists in the multidisciplinary approach to solve undiagnosed diseases.

Public Health Relevance

Patients with undiagnosed diseases, that is, with long-standing symptoms that have not been diagnosed despite extensive clinical investigation, suffer from a costly, time-consuming and psychologically taxing approach to their diagnosis, with uncertain outcomes and a high financial burden on the health care system. The sequencing of the entire human genome is revolutionizing the way medicine is practiced, as large amounts of genomic information can be integrated in clinical practice. This proposal tackles the challenge of undiagnosed diseases by creating a sustainable clinical model that integrates state-of-the-art clinical and laboratory investigations with interpretable genomic information across a network to result in improved diagnosis and management of disease.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HG007703-06
Application #
9789903
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Doss, Argenia Lanisha Necole
Project Start
2014-07-01
Project End
2022-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Genetics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Marcogliese, Paul C; Shashi, Vandana; Spillmann, Rebecca C et al. (2018) IRF2BPL Is Associated with Neurological Phenotypes. Am J Hum Genet 103:245-260
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Pena, Loren D M; Jiang, Yong-Hui; Schoch, Kelly et al. (2018) Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases. Genet Med 20:464-469
Shashi, Vandana; Pena, Loren D M; Kim, Katherine et al. (2017) De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype. Am J Hum Genet 100:179
Chao, Hsiao-Tuan; Davids, Mariska; Burke, Elizabeth et al. (2017) A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3. Am J Hum Genet 100:128-137
Ramoni, Rachel B; Mulvihill, John J; Adams, David R et al. (2017) The Undiagnosed Diseases Network: Accelerating Discovery about Health and Disease. Am J Hum Genet 100:185-192
Zastrow, Diane B; Zornio, Patricia A; Dries, Annika et al. (2017) Exome sequencing identifies de novo pathogenic variants in FBN1 and TRPS1 in a patient with a complex connective tissue phenotype. Cold Spring Harb Mol Case Stud 3:a001388
Bashamboo, Anu; Donohoue, Patricia A; Vilain, Eric et al. (2016) A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development. Hum Mol Genet 25:5286
Gahl, William A; Wise, Anastasia L; Ashley, Euan A (2015) The Undiagnosed Diseases Network of the National Institutes of Health: A National Extension. JAMA 314:1797-8

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