Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science



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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Details of the 240 diagnoses.


  1. 1.

    Gahl WA, Wise AL, Ashley EA. The Undiagnosed Diseases Network of the National Institutes of Health: a national extension. JAMA. 2015;314:1797–1798.

    CAS  Article  Google Scholar 

  2. 2.

    Undiagnosed Diseases Network. 2017. Accessed 2020.

  3. 3.

    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.

    CAS  Article  Google Scholar 

  4. 4.

    Gahl WA, Tifft CJ. The NIH Undiagnosed Diseases Program: lessons learned. JAMA. 2011;305:1904–1905.

    CAS  Article  Google Scholar 

  5. 5.

    Global Genes. Rare disease statistics. 2015. Accessed 2020.

  6. 6.

    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.

    Article  Google Scholar 

  7. 7.

    Need AC, Shashi V, Hitomi Y, et al. Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet. 2012;49:353–361.

    CAS  Article  Google Scholar 

  8. 8.

    Lee H, Deignan JL, Dorrani N, et al. Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA. 2014;312:1880–1887.

    Article  Google Scholar 

  9. 9.

    Yang Y, Muzny DM, Xia F, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 2014;312:1870–1879.

    CAS  Article  Google Scholar 

  10. 10.

    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.

    CAS  Article  Google Scholar 

  11. 11.

    Bowdin S, Gilbert A, Bedoukian E, et al. Recommendations for the integration of genomics into clinical practice. Genet Med. 2016;18:1075–1084.

    CAS  Article  Google Scholar 

  12. 12.

    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.

    Article  Google Scholar 

  13. 13.

    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.

    Article  Google Scholar 

  14. 14.

    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.

    CAS  Google Scholar 

  15. 15.

    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.

    Article  Google Scholar 

  16. 16.

    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.

    CAS  Article  Google Scholar 

  17. 17.

    Brittain HK, Scott R, Thomas E. The rise of the genome and personalised medicine. Clin Med (Lond). 2017;17:545–551.

    Article  Google Scholar 

  18. 18.

    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.

    CAS  Article  Google Scholar 

  19. 19.

    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.

    CAS  Article  Google Scholar 

  20. 20.

    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.

    Article  Google Scholar 

  21. 21.

    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.

    Article  Google Scholar 

  22. 22.

    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.

    Article  Google Scholar 

  23. 23.

    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.

    Article  Google Scholar 

  24. 24.

    Hiatt SM, Amaral MD, Bowling KM, et al. Systematic reanalysis of genomic data improves quality of variant interpretation. Clin Genet. 2018;94:174–178.

    CAS  Article  Google Scholar 

  25. 25.

    Liu P, Meng L, Normand EA, et al. Reanalysis of clinical exome sequencing data. N Engl J Med. 2019;380:2478–2480.

    Article  Google Scholar 

  26. 26.

    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.

    Article  Google Scholar 

  27. 27.

    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.

    Article  Google Scholar 

  28. 28.

    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.

    CAS  Article  Google Scholar 

  29. 29.

    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.

    Article  Google Scholar 

  30. 30.

    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.

    Article  Google Scholar 

  31. 31.

    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.

    Article  Google Scholar 

  32. 32.

    Maiese DR, Keehn A, Lyon M, et al. Current conditions in medical genetics practice. Genet Med. 2019;21:1874–1877.

    Article  Google Scholar 

  33. 33.

    Attard CA, Carmany EP, Trepanier AM. Genetic counselor workflow study: the times are they a-changin’? J Genet Couns. 2019;28:130–140.

    Article  Google Scholar 

  34. 34.

    Undiagnosed Diseases Network. 2014. Accessed 2020.

  35. 35.

    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.

    Article  Google Scholar 

  36. 36.

    MyGene2. 2020.

  37. 37.

    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.

    CAS  Article  Google Scholar 

  38. 38.

    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.

    Article  Google Scholar 

  39. 39.

    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.

    Article  Google Scholar 

  40. 40.

    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.

    Article  Google Scholar 

Download references


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.

Author information




Corresponding author

Correspondence to Vandana Shashi MD.

Ethics declarations


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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

Key words

  • exome sequencing
  • genome sequencing
  • phenotyping
  • ultrarare diseases
  • undiagnosed diseases