The NIH Undiagnosed Diseases Network (UDN) evaluates participants with disorders that have defied diagnosis, applying personalized clinical and genomic evaluations and innovative research. The clinical sites of the UDN are essential to advancing the UDN mission; this study assesses their contributions relative to standard clinical practices.
We analyzed retrospective data from four UDN clinical sites, from July 2015 to September 2019, for diagnoses, new disease gene discoveries and the underlying investigative methods.
Of 791 evaluated individuals, 231 received 240 diagnoses and 17 new disease–gene associations were recognized. Straightforward diagnoses on UDN exome and genome sequencing occurred in 35% (84/240). We considered these tractable in standard clinical practice, although genome sequencing is not yet widely available clinically. The majority (156/240, 65%) required additional UDN-driven investigations, including 90 diagnoses that occurred after prior nondiagnostic exome sequencing and 45 diagnoses (19%) that were nongenetic. The UDN-driven investigations included complementary/supplementary phenotyping, innovative analyses of genomic variants, and collaborative science for functional assays and animal modeling.
Investigations driven by the clinical sites identified diagnostic and research paradigms that surpass standard diagnostic processes. The new diagnoses, disease gene discoveries, and delineation of novel disorders represent a model for genomic medicine and science.
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Gahl WA, Wise AL, Ashley EA. The Undiagnosed Diseases Network of the National Institutes of Health: a national extension. JAMA. 2015;314:1797–1798.
Undiagnosed Diseases Network. 2017. https://undiagnosed.hms.harvard.edu/. Accessed 2020.
Splinter K, Adams DR, Bacino CA, et al. Effect of genetic diagnosis on patients with previously undiagnosed disease. N Engl J Med. 2018;379:2131–2139.
Gahl WA, Tifft CJ. The NIH Undiagnosed Diseases Program: lessons learned. JAMA. 2011;305:1904–1905.
Global Genes. Rare disease statistics. 2015. https://ir.alexion.com/static-files/e07be2fa-fb02-43d7-ad00-844e3c66e86f. Accessed 2020.
Nguengang Wakap S, Lambert DM, Olry A, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet. 2020;28:165–173.
Need AC, Shashi V, Hitomi Y, et al. Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet. 2012;49:353–361.
Lee H, Deignan JL, Dorrani N, et al. Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA. 2014;312:1880–1887.
Yang Y, Muzny DM, Xia F, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 2014;312:1870–1879.
Baldridge D, Heeley J, Vineyard M, et al. The Exome Clinic and the role of medical genetics expertise in the interpretation of exome sequencing results. Genet Med. 2017;19:1040–1048.
Bowdin S, Gilbert A, Bedoukian E, et al. Recommendations for the integration of genomics into clinical practice. Genet Med. 2016;18:1075–1084.
Lazaridis KN, McAllister TM, Babovic-Vuksanovic D, et al. Implementing individualized medicine into the medical practice. Am J Med Genet C Semin Med Genet. 2014;166c:15–23.
Lazaridis KN, Schahl KA, Cousin MA, et al. Outcome of whole exome sequencing for diagnostic odyssey cases of an individualized medicine Clinic: the Mayo Clinic experience. Mayo Clin Proc. 2016;91:297–307.
Shashi V. The utility of the traditional medical genetics diagnostic evaluation in the context of next-generation sequencing for undiagnosed genetic disorders. J Intellect Disabil Res. 2014;16:176–182.
Williams MS, Buchanan AH, Davis FD, et al. Patient-centered precision health in a learning health care system: Geisinger’s genomic medicine experience. Health Aff (Millwood). 2018;37:757–764.
Bertier G, Senecal K, Borry P, Vears DF. Unsolved challenges in pediatric whole-exome sequencing: A literature analysis. Crit Rev Clin Lab Sci. 2017;54:134–142.
Brittain HK, Scott R, Thomas E. The rise of the genome and personalised medicine. Clin Med (Lond). 2017;17:545–551.
Volk A, Conboy E, Wical B, et al. Whole-exome sequencing in the clinic: lessons from six consecutive cases from the clinician’s perspective. Mol Syndromol. 2015;6:23–31.
Thevenon J, Duffourd Y, Masurel-Paulet A, et al. Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole-exome sequencing as a first-line diagnostic test. Clin Genet. 2016;89:700–707.
Sobreira N, Schiettecatte F, Valle D, Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat. 2015;36:928–930.
Shashi V, McConkie-Rosell A, Schoch K. et al. Practical considerations in the clinical application of whole-exome sequencing. Clin Genet. 2015;89:173–181.
Wenger AM, Guturu H, Bernstein JA, Bejerano G. Systematic reanalysis of clinical exome data yields additional diagnoses: implications for providers. Genet Med. 2017;19:209–214.
Eldomery MK, Coban-Akdemir Z, Harel T, et al. Lessons learned from additional research analyses of unsolved clinical exome cases. Genome Med. 2017;9:26.
Hiatt SM, Amaral MD, Bowling KM, et al. Systematic reanalysis of genomic data improves quality of variant interpretation. Clin Genet. 2018;94:174–178.
Liu P, Meng L, Normand EA, et al. Reanalysis of clinical exome sequencing data. N Engl J Med. 2019;380:2478–2480.
Ewans LJ, Schofield D, Shrestha R, et al. Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders. Genet Med. 2018;20:1564–1574.
Wright CF, McRae JF, Clayton S, et al. Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1,133 families with developmental disorders. Genet Med. 2018;20:1216–1223.
Shashi V, Schoch K, Spillmann R, et al. A comprehensive iterative approach is highly effective in diagnosing individuals who are exome negative. Genet Med. 2019;21:161–172.
Fennell AP, Hunter MF, Corboy GP. The changing face of clinical genetics service delivery in the era of genomics: a framework for monitoring service delivery and data from a comprehensive metropolitan general genetics service. Genet Med. 2020;22:210–218.
Williams JL, Faucett WA, Smith-Packard B, et al. An assessment of time involved in pre-test case review and counseling for a whole genome sequencing clinical research program. J Genet Couns. 2014;23:516–521.
Sukenik-Halevy R, Ludman MD, Ben-Shachar S, Raas-Rothschild A. The time-consuming demands of the practice of medical genetics in the era of advanced genomic testing. Genet Med. 2016;18:372–377.
Maiese DR, Keehn A, Lyon M, et al. Current conditions in medical genetics practice. Genet Med. 2019;21:1874–1877.
Attard CA, Carmany EP, Trepanier AM. Genetic counselor workflow study: the times are they a-changin’? J Genet Couns. 2019;28:130–140.
Undiagnosed Diseases Network. 2014. https://gateway.undiagnosed.hms.harvard.edu/assets/start.html. Accessed 2020.
Zastrow DB, Kohler JN, Bonner D, et al. A toolkit for genetics providers in follow-up of patients with nondiagnostic exome sequencing. J Genet Couns. 2019;28:213–228.
MyGene2. 2020. http://www.mygene2.org.
Shashi V, Geist J, Lee Y, et al. Heterozygous variants in MYBPC1 are associated with an expanded neuromuscular phenotype beyond arthrogryposis. Hum Mutat. 2019;40:1115–1126.
Reuter CM, Kohler JN, Bonner D, et al. Yield of whole exome sequencing in undiagnosed patients facing insurance coverage barriers to genetic testing. J Genet Couns. 2019;28:1107–1118.
Köhler S, Doelken SC, Mungall CJ, et al. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data. Nucleic Acids Res. 2014;42:D966–D974.
Schoch K, Tan QK, Stong N, et al. Alternative transcripts in variant interpretation: the potential for missed diagnoses and misdiagnoses. Genet Med. 2020;22:1269–1275.
We thank all of the individuals and their families for their participation in this study. Research reported in this paper was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under award number(s) U01HG007672 (Duke University), U01HG007708 (Stanford Medicine), U01HG007674 (Vanderbilt University Medical Center), and U01HG007530 (Coordinating Center at Harvard Medical School). The NIH clinical site (UDP) was supported by the National Human Genome Research Institute (NHGRI) Intramural Research Program under award number HG000215-17. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
P.L. is an employee of Baylor College of Medicine and derives support through a professional services agreement with Baylor Genetics, which performs clinical genetic testing services. M.T.W. is a stockholder of Personalis Inc. D.B.G. is a founder of and holds equity in Q State Biosciences and Praxis Therapeutics, holds equity in Apostle Inc., and serves as a consultant to AstraZeneca, Gilead Sciences, and GoldFinch Bio, outside the submitted work. The other authors declare no conflicts of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Schoch, K., Esteves, C., Bican, A. et al. Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science. Genet Med (2020). https://doi.org/10.1038/s41436-020-00984-z
- exome sequencing
- genome sequencing
- ultrarare diseases
- undiagnosed diseases