The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases
Open accessAbstract
Purpose This report describes the National Institutes of Health Undiagnosed Diseases Program, details the Program's application of genomic technology to establish diagnoses, and details the Program's success rate during its first 2 years.Methods Each accepted study participant was extensively phenotyped. A subset of participants and selected family members (29 patients and 78 unaffected family members) was subjected to an integrated set of genomic analyses including high-density single-nucleotide polymorphism arrays and whole exome or genome analysis.Results Of 1,191 medical records reviewed, 326 patients were accepted and 160 were admitted directly to the National Institutes of Health Clinical Center on the Undiagnosed Diseases Program service. Of those, 47% were children, 55% were females, and 53% had neurologic disorders. Diagnoses were reached on 39 participants (24%) on clinical, biochemical, pathologic, or molecular grounds; 21 diagnoses involved rare or ultra-rare diseases. Three disorders were diagnosed based on single-nucleotide polymorphism array analysis and three others using whole exome sequencing and filtering of variants. Two new disorders were discovered. Analysis of the single-nucleotide polymorphism array study cohort revealed that large stretches of homozygosity were more common in affected participants relative to controls.Conclusion The National Institutes of Health Undiagnosed Diseases Program addresses an unmet need, i.e., the diagnosis of patients with complex, multisystem disorders. It may serve as a model for the clinical application of emerging genomic technologies and is providing insights into the characteristics of diseases that remain undiagnosed after extensive clinical workup.
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Cites
dbSNP: the NCBI database of genetic variation
Sherry, S. T. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.1.308 · Cited by 7,502 · see citing works
Accurate whole human genome sequencing using reversible terminator chemistry
Bentley, D. R., Balasubramanian, S., Swerdlow, H. P., Smith, G. P., Milton, J., Brown, C. G., Hall, K. P., Evers, D. J., Barnes, C. L., Bignell, H. R., et al. (2008) · Nature · doi:10.1038/nature07517 · Cited by 3,684 · see citing works
Self-citationCDD: a Conserved Domain Database for the functional annotation of proteins
Marchler‐Bauer, A., Lu, S., Anderson, J. B., Chitsaz, F., Derbyshire, M. K., DeWeese-Scott, C., Fong, J. H., Geer, L. Y., Geer, R. C., Gonzales, N. R., et al. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq1189 · Cited by 3,126 · see citing works
Wang, K., Li, M., Hadley, D., Liu, R., Glessner, J., Grant, S. F. A., Hakonarson, H., & Bucan, M. (2007) · Genome Research · doi:10.1101/gr.6861907 · Cited by 1,792 · see citing works
Gnirke, A., Melnikov, A., Maguire, J., Rogov, P., LeProust, E. M., Brockman, W., Fennell, T., Giannoukos, G., Fisher, S., Russ, C., et al. (2009) · Nature Biotechnology · doi:10.1038/nbt.1523 · Cited by 1,433 · see citing works
C ERULOPLASMIN M ETABOLISM AND F UNCTION
Hellman, N. E., & Gitlin, J. D. (2002) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.22.012502.114457 · Cited by 930 · see citing works
Siva, N. (2008) · Nature Biotechnology · doi:10.1038/nbt0308-256b · Cited by 629 · see citing works
Physiological roles for ecto-5’-nucleotidase (CD73)
Colgan, S. P., Eltzschig, H. K., Eckle, T. D. L. G., & Thompson, L. F. (2006) · Purinergic Signalling · doi:10.1007/s11302-005-5302-5 · Cited by 496 · see citing works
Advances in measuring cellular bioenergetics using extracellular flux
Ferrick, D. A., Neilson, A., & Beeson, C. C. (2008) · Drug Discovery Today · doi:10.1016/j.drudis.2007.12.008 · Cited by 455 · see citing works
NT5E Mutations and Arterial Calcifications
Hilaire, C. S., Ziegler, S. G., Markello, T. C., Brusco, A., Groden, C. A., Gill, F. A., Carlson-Donohoe, H., Lederman, R. J., Chen, M. Y., Yang, D., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa0912923 · Cited by 453 · see citing works
Self-citationLamin B1 duplications cause autosomal dominant leukodystrophy
Padiath, Q. S., Saigoh, K., Schiffmann, R., Asahara, H., Yamada, T., Koeppen, A. H., Hogan, K. J., Ptáček, L. J., & Fu, Y. (2006) · Nature Genetics · doi:10.1038/ng1872 · Cited by 407 · see citing works
Grohmann, K., Schuelke, M., Diers, A., Hoffmann, K., Lucke, B., Adams, C., Bertini, E., Leonhardt-Horti, H., Francesco Muntoni, A., Ouvrier, R., et al. (2001) · Nature Genetics · doi:10.1038/ng703 · Cited by 345 · see citing works
Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28
Bella, D. D., Lazzaro, F., Brusco, A., Plumari, M., Battaglia, G. S., Pastore, A., Finardi, A., Cagnoli, C., Tempia, F., Frontali, M., et al. (2010) · Nature Genetics · doi:10.1038/ng.544 · Cited by 345 · see citing works
Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Göhring, I., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/515583 · Cited by 317 · see citing works
Millecamps, S., Salachas, F., Cazeneuve, C., Gordon, P., Bricka, B., Camuzat, A., Guillot‐Noël, L., Russaouen, O., Bruneteau, G., Pradat, P., et al. (2010) · Journal of Medical Genetics · doi:10.1136/jmg.2010.077180 · Cited by 308 · see citing works
Brenner, C. (2002) · Biochemistry · doi:10.1021/bi025942q · Cited by 284 · see citing works
Systematic comparison of three genomic enrichment methods for massively parallel DNA sequencingPreprint
Teer, J. K., Bonnycastle, L. L., Chines, P. S., Hansen, N. F., Aoyama, N., Swift, A. J., Abaan, H. Ö., Albert, T. J., Program, N. C. S., Margulies, E. H., et al. (2010) · Genome Research · doi:10.1101/gr.106716.110 · Cited by 206 · see citing works
Self-citationPraeter, C. M. D., Gerwig, G. J., Bause, E., Nuytinck, L., Vliegenthart, J. F. G., Breuer, W., Kamerling, J. P., Espeel, M., Martin, J.-J. R., Paepe, A. M. D., et al. (2000) · The American Journal of Human Genetics · doi:10.1086/302948 · Cited by 189 · see citing works
Johnston, J. J., Teer, J. K., Cherukuri, P. F., Hansen, N. F., Loftus, S. K., Chong, K., Mullikin, J. C., & Biesecker, L. G. (2010) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2010.04.007 · Cited by 161 · see citing works
Self-citationThe NIH Undiagnosed Diseases Program
Gahl, W. A. (2011) · JAMA · doi:10.1001/jama.2011.613 · Cited by 124 · see citing works
Self-citationMutations of RAI1, a PHD-containing protein, in nondeletion patients with Smith-Magenis syndrome
Bi, W., Saifi, G. M., Shaw, C. J., Walz, K., Fonseca, P., Wilson, M., Potocki, L., & Lupski, J. R. (2004) · Human Genetics · doi:10.1007/s00439-004-1187-6 · Cited by 110 · see citing works
Paraplegin mutations in sporadic adult-onset upper motor neuron syndromes
Brugman, F., Scheffer, H., Wokke, J. H. J., et al. (2008) · Neurology · doi:10.1212/01.wnl.0000319700.11606.21 · Cited by 88 · see citing works
de Bot, S. T., van den Elzen, R. T. M., Mensenkamp, A. R., et al. (2010) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2009.201103 · Cited by 56 · see citing works
A Duplication in Chromosome 4q35 Is Associated with Hereditary Benign Intraepithelial Dyskeratosis
Allingham, R. R., Seo, B.-S., Rampersaud, E., et al. (2001) · The American Journal of Human Genetics · doi:10.1086/318194 · Cited by 52 · see citing works
Functional evaluation of paraplegin mutations by a yeast complementation assay
Bonn, F., Pantakani, K., Shoukier, M., et al. (2010) · Human Mutation · doi:10.1002/humu.21226 · Cited by 47 · see citing works
Highly Scalable Genotype Phasing by Entropy Minimization
Gusev, A., Măndoiu, I., & Paşaniuc, B. (2008) · IEEE Transactions on Computational Biology and Bioinformatics · doi:10.1109/tcbb.2007.70223 · Cited by 28 · see citing works
Infantile-onset spinal muscular atrophy with respiratory distress-1 diagnosed in a 20-year-old man
Pierson, T. M., Tart, G., Adams, D. R., et al. (2011) · Neuromuscular Disorders · doi:10.1016/j.nmd.2011.02.005 · Cited by 27 · see citing works
Self-citationManoli, I., Golas, G. A., Westbroek, W., Vilboux, T., Markello, T. C., Introne, W. J., Maynard, D., Pederson, B., Tsilou, E. T., Jordan, M. B., et al. (2010) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.33389 · Cited by 26 · see citing works
Self-citationWampler, J. E. (1990) · Analytical Biochemistry · doi:10.1016/0003-2697(90)90068-k · Cited by 8 · see citing works
Conlin, L. K., & Spinner, N. B. (2008) · Cited by 2 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Ashley, E. A. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.86 · Cited by 1,116 · see citing works
The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities
Chong, J. X., Buckingham, K. J., Jhangiani, S. N., Boehm, C., Sobreira, N., Smith, J. D., Harrell, T. M., McMillin, M. J., Wiszniewski, W., Gambin, T., et al. (2015) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2015.06.009 · Cited by 643 · see citing works
Next-generation diagnostics and disease-gene discovery with the Exomiser
Smedley, D., Jacobsen, J. O. B., Jäger, M., Köhler, S., Holtgrewe, M., Schubach, M., Siragusa, E., Zemojtel, T., Buske, O. J., Washington, N. L., et al. (2015) · Nature Protocols · doi:10.1038/nprot.2015.124 · Cited by 445 · see citing works
Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease
Splinter, K., Adams, D. R., Bacino, C. A., Bellen, H. J., Bernstein, J. A., Cheatle-Jarvela, A. M., Eng, C. M., Esteves, C., Gahl, W. A., Hamid, R., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1714458 · Cited by 359 · see citing works
Self-citationThe Undiagnosed Diseases Network of the National Institutes of Health: A National Extension
Gahl, W. A., Wise, A. L., & Ashley, E. A. (2015) · JAMA · doi:10.1001/jama.2015.12249 · Cited by 114 · see citing works
Self-citationFew shot learning for phenotype-driven diagnosis of patients with rare genetic diseases
Alsentzer, E., Li, M. M., Kobren, S. N., Noori, A., Undiagnosed Diseases Network, Kohane, I. S., & Zitnik, M. (2025) · npj Digital Medicine · doi:10.1038/s41746-025-01749-1 · Cited by 54 · see citing works
DeepTrio: Variant Calling in Families Using Deep Learning
Brambrink, L., Kolesnikov, A., Goel, S., Nattestad, M., Yun, T., Baid, G., Yang, H., McLean, C., Shafin, K., Chang, P.-C., et al. (2021) · doi:10.1101/2021.04.05.438434 · Cited by 32 · see citing works
Tarailo-Graovac, M., Wasserman, W. W., & Van Karnebeek, C. D. M. (2017) · Expert Review of Molecular Diagnostics · doi:10.1080/14737159.2017.1293527 · Cited by 23 · see citing works
Simulation of undiagnosed patients with novel genetic conditions
Alsentzer, E., Finlayson, S. G., Li, M. M., Undiagnosed Diseases Network, Kobren, S. N., & Kohane, I. S. (2023) · Nature Communications · doi:10.1038/s41467-023-41980-6 · Cited by 10 · see citing works
- Authors
- Gahl, W. A., Markello, T. C., Toro, C., Fajardo, K. F., Sincan, M., Gill, F., Carlson-Donohoe, H., Gropman, A., Pierson, T. M., Golas, G., Wolfe, L., Groden, C., Godfrey, R., Nehrebecky, M., Wahl, C., Landis, D. M. D., Yang, S., Madeo, A., Mullikin, J. C., Boerkoel, C. F., Tifft, C. J., & Adams, D.
- Affiliations
- National Institutes of Health (US)
- National Institutes of Health Clinical Center (US)
- Corresponding author
- Adams, David
- ORCID
- Venue
- Genetics in Medicine
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 14
- Issue
- 1
- Pages
- 51-59
- ISSN
- 1098-3600 (ISSN-L)
- PMC
- PMC4098846
- OpenAlex
- W2025464337
- Cited by
- 291
- References
- 30
- Citations by year
- 2026: 11 · 2025: 6 · 2024: 17 · 2023: 22 · 2022: 19 · 2021: 12 · 2020: 15 · 2019: 20 · 2018: 23 · 2017: 23 · 2016: 31 · 2015: 27 · 2014: 27 · 2013: 23 · 2012: 14
- FWCI
- 17.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Genetics in Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99 HG999999)
- National Human Genome Research Institute (ZIAHG000215, ZIDHG200352)
- NIH Office of the Director
- National Institute of Neurological Disorders and Stroke
- NIH Clinical Center
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Keywords
- rare diseases, ultra-rare diseases, diagnostic yield, genomic diagnostics, single nucleotide polymorphism array, exome sequencing, homozygosity, neurological disorders, multisystem disease, phenotyping
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Clinical Protocols, Female, Government Programs, Homozygote, Humans, Infant, Male, Middle Aged, National Health Programs, National Institutes of Health (U.S.), Phenotype, United States, Polymorphism, Single Nucleotide, Rare Diseases, Biomedical Research, Young Adult, DNA Copy Number Variations, Exome
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