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Rare & Undiagnosed Diseases

Many patients with rare diseases are undiagnosed for many years. This 'diagnostic odyssey' not only severely impacts the lives and quality of lives of patients and their family members, but is costly for our society. 

In collaboration with clinical geneticists, we facilitate disease diagnosis by performing functional studies of candidate genetic variants identified through whole-exome and whole-genome sequencing techniques.

This often leads to discovery of new human diseases or significant phenotypic expansion of known disease genes.

The Problem: Challenges in Interpreting Personal Genomes 

(Under Construction)

How Flies Can Help: Genetic Technology & Phenotypes

(Under Constrution

A 'Disease Model' versus a 'Living Test Tube'

(Under Construction)

Undiagnosed Diseases Network


The Undiagnosed Diseases Network (UDN) is a research study that is funded by the National Institutes of Health Common Fund. Its purpose is to bring together clinical and research experts from across the United States to solve the most challenging medical mysteries using advanced technologies.


Through this study, we hope to both help individual patients and families living with the burden of undiagnosed diseases, and contribute to the understanding of how the human body works.

Dr. Yamamoto serves as one of the Co-Directors of the Model Organisms Screening Center (MOSC) Drosophila Core for the UDN.

Listen to the dialog (~70 minutes) between Dr. Yamamoto, Dr. Bellen and a representative of the UDN PEER (Participant Engagement and Empowerment Resource) group, representing UDN patients and family members, regarding how model organisms can facilitate rare and undiagnosed diseases research in lay terms.

Undiagnosed Diseases Network International


Undiagnosed diseases are a global health issue, calling for an international scientific and healthcare effort. To meet this demand, the Undiagnosed Diseases Network International (UDNI) has built a consensus framework of principles, best practices and governance; the Board of Directors reflects its international character, as it includes experts from multiple countries. The UDNI involves centers with internationally recognized expertise, and its scientific resources and know-how aim to fill the knowledge gaps that impede diagnosis. Consequently, the UDNI fosters the translation of research into medical practice.

Dr. Yamamoto serves as the Chair of the Functional Study Working Group of the UDNI

Center for Precision Medicine Models (CPMM)


The Center for Precision Medicine Models (CPMM) at BCM brings together internationally recognized leaders in clinical genetics, bioinformatics, and model organism research. Our goal is to develop precision animal models that will end the diagnostic odyssey of patients with undiagnosed genetic diseases and serve as resources for exploring personalized approaches to their care.

Dr. Yamamoto serves as one of the Co-Leads of the Disease Modeling Unit.

New Human Diseases Discovered and Documented

Here are several examples in which our study led to creation of a new disease entry in OMIM (Online Mendelian Inheritance in Man), an organization that has the authority to name a new genetic condition

Related Publications

  1. Barish S, Senturk M, Schoch K, Minogue AL, Lopergolo D, Fallerini C, Harland J, Seemann JH, Stong N, Kranz PG, Kansagra S, Mikati MA, Jasien J, El-Dairi M; Undiagnosed Diseases Network, Galluzzi P, Ariani F, Renieri A, Mari F, Wangler MF, Arur S, Jiang YH, Yamamoto S, Shashi V, Bellen HJ. (2022) The microRNA processor DROSHA is a candidate gene for a severe progressive neurological disorder. Hum Mol Genet. doi: 10.1093/hmg/ddac085 (Online ahead of print). PMID: 35405010. PMCID: N/A (in progress).

  2. Marcogliese PC, Dutta D, Ray SS, Dang NDP, Zuo Z, Wang Y, Lu D, Fazal F, Ravenscroft TA, Chung H, Kanca O, Wan JJ, Douine ED, Undiagnosed Diseases Network, Pena LDM, Yamamoto S, Nelson SF, Might M, Meyer KC, Yeo NC, Bellen HJ (2022) Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling. Sci Adv. 8(3):eabl5613. PMID: 35044823. PMCID: PMC8769555.

  3. Andrews JC, Wangler MF, Yamamoto S, Posey JE (2022) Advances in Next-Generation Sequencing Technologies and Functional Investigation of Candidate Variants in Neurological and Behavioral Disorders. Encyclopedia of Behavioral Neuroscience, 2nd edition (Academic Press). ISBN: 9780128196410 (Book Chapter).

  4. Manivannan SN, Roovers J, Smal N, Mefford H, Turkdogan D, Roelens F, Kanca O, Chung HL, MAE working group of EuroEPINOMICS RES Consortium, de Jonghe P, Yamamoto S, Weckhuysen S, Bellen HJ (2021) De novo FZR1 loss-of-function variants cause developmental delay and epileptic encephalopathies. Brain. 145(5):1684-1697. PMID: 34788397. PMCID: PMC9166542.

  5. Goodman LD, Cope H, Nil Z, Ravenscroft TA, Charng WL, Lu S, Tien AC, Pfundt R, Koolen DA, Haaxma CA, Kanca O, Moulton MJ, Pfundt R, Veenstra-Knol HE, Wassink-Ruiter JSK, Wevers MR, Jones M, Walsh LE, Klee VH, Theunis M, Legius E, Steel D, Barwick KES, Kurian MA, Mohammad SS, Dale RC, Terhal PA, van Binsbergen E, Kirmse B, Robinette B, Cogné B, Isidor B, Grebe TA, Kulch P, Hainline BE, Sapp K, Morava E, Klee EW, Macke EL, Trapane P, Spencer C, Si Y, Begtrup A, Moulton MJ, Dutta D, Kanca O, Undiagnosed Diseases Network; Wangler MF, Yamamoto S, Bellen HJ, Tan QKG (2021) TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila. Am J Hum Genet. 108(9):1669-1691. PMID: 34314705. PMCID: PMC8456166.

  6. Ravenscroft TA, Phillips JB, Fieg E, Bajikar SS, Peirce J, Wegner J, Luna AA, Fox EJ, Yan YL, Rosenfeld JA, Zirin J, Kanca O, UDN, Benke PJ, Cameron ES, Strehlow V, Platzer K, Osmond M, Licata T, Rojas S, Dyment D, Chong JSC, Lincoln S, Stoler JM, Postlethwait J, Wangler MF, Yamamoto S, Krier J, Westerfield M, Bellen HJ (2021). Heterozygous loss-of-function variants significantly expand the phenotypes associated with loss of GDF11. Genet Med. 23(10)1889-. PMID: 34113007. PMCID: PMC8487929.

  7. Luo X, Schoch K, Jangam SV, Bhavana VH, Graves HK, Kansagra S, Jasien J, Stong N, Keren B, Mignot C, Ravelli C, UDN, Bellen HJ, Wangler MF, Shashi V†, Yamamoto S† (2021) Rare deleterious de novo missense variants in RNF2/RING2 are associated with a neurodevelopmental disorder with unique clinical features. Hum Mol Genet. 30(14):1283-1292. PMID: 33864376. PMCID: PMC8255132. (†corresponding authors).

  8. Baldridge D, Wangler MF, Bowman AN, Yamamoto S, Undiagnosed Diseases Network, Schedl T, Pak SC, Postlethwait JH, Solnica-Krezel L, Bellen HJ, Westerfield M (2021) Model Organisms Contribute to Diagnosis and Discovery in the Undiagnosed Diseases Network: the Current State and a Future Vision. Orphanet J Rare Dis. 16(1): 206. PMID: 33962631. PMCID: PMC8103593.

  9. Barish S, Barakat TS, Michel BC, Mashtalir N, Phillips JB, Valencia AM, Ugur B, Wegner J, Scott TM, Bostwick B; Undiagnosed Diseases Network, Murdock DR, Dai H, Perenthaler E, Nikoncuk A, van Slegtenhorst M, Brooks AS, Keren B, Nava C, Mignot C, Douglas J, Rodan L, Nowak C, Ellard S, Stals K, Lynch SA, Faoucher M, Lesca G, Edery P, Engleman KL, Zhou D, Thiffault I, Herriges J, Gass J, Louie RJ, Stolerman E, Washington C, Vetrini F, Otsubo A, Pratt VM, Conboy E, Treat K, Shannon N, Camacho J, Wakeling E, Yuan B, Chen CA, Rosenfeld JA, Westerfield M, Wangler M, Yamamoto S, Kadoch C, Scott DA, Bellen HJ (2020). BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms. Am J Hum Genet. 107: 1096-1112. PMID: 33232675. PMCID: PMC7820627.

  10. Dutta D, Briere LC, Kanca O, Marcogliese PC, Walker MA, High FA, Vanderver A, Vögtle FN, Krier J, Carmichael N, Callahan C, Taft RJ, Simons C, Guy Helman G, The Undiagnosed Diseases Network, Wangler MF, Yamamoto S, Sweetser DA, Bellen HJ (2020) De novo mutations in TOMM70, a receptor of the mitochondrial import translocase, cause neurological impairment. Hum Mol Genet. 29: 1568-1579. PMID: 32356556. PMCID: PMC7268787.

  11. Chung HL, Mao X, Wang H, Park YJ, Marcogliese PC, Rosenfeld JA, Burrage LC, Liu P, Murdock DR, Yamamoto S, Wangler MF; Undiagnosed Diseases Network, Chao HT, Long H, Feng L, Bacino CA, Bellen HJ, Xiao B (2020) De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy. Am J Hum Genet. 106: 717-725. PMID: 32330417. PMCID: PMC7212481.

  12. Chung HL, Wangler MF, Marcogliese PC, Jo J, Ravenscroft TA, Sadeghzadeh S, Li-Kroeger D,  Schmidt R, Pestronk A, Rosenfeld JA,  Burrage L, Herndon MJ, Undiagnosed Diseases Network,  Lee B, Moser A, Jones R, Watkins P, Yoo T, Mar S, Bucelli,  Choi M, Yamamoto S, Lee HK, Chae JH, Vogel TP, Bellen HJ (2020) Loss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different Mechanisms. Neuron. 106: 589-606. PMID: 32169171. PMCID: PMC7289150.

  13. Bellen HJ†, Wangler MF, Yamamoto S† (2019) The fruit fly at the interface of diagnosis and pathogenic mechanisms of rare and common human diseases. Hum Mol Genet. 28(R2):R207-R214. PMID: 31227826, PMCID: PMC6872428. (†corresponding authors).

  14. Guo H, Bettella E, Marcogliese PC, Zhao R, Andrews JC, Nowakowski TJ, Gillentine MA, Hoekzema K, Wang T, Wu H, Jangam S, Liu C, Ni H, Willemsen MH, van Bon BW, Rinne T, Stevens SJC, Kleefstra T, Brunner HG, Ijntema H, Long M, Zhao W, Hu Z, Colson C, Nicolas R, Schwartz C, Romano C, Castiglia L, Bottitta M, Dhar SU, Erwin DJ, Emrick L, Keren B, Afenjar A, Zhu B, Bai B, Stankiewicz P, Herman K, University of Washington Center for Mendelian Genomics, Mercimek-Andrews S, Juusola J, Wilfert AB, Jamra RA, Büttner B, Mefford HC, Muir AM, Scheffer IE, Regan BM, Malone S, Gecz J, Cobben J, Weiss MM, Waisfisz Q, Bijlsma EK, Hoffer MJV, Ruivenkamp CAL, Sartori S, Xia F, Rosenfeld JA, Bernier RA, Wangler MF, Yamamoto S, Xia K, Stegmann APA, Bellen HJ, Murgia A, Eichler EE (2019) Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders. Nat Commun. 10(1):4679. PMID: 31616000, PMCID: PMC6794285.

  15. Harnish JM*, Deal SL*, Undiagnosed Diseases Network, Chao HT, Wangler MF, Yamamoto S† (2019) In vivo functional study of disease-associated rare human variants using Drosophila. J Vis Exp. (150): 10.3791/59658. PMID: 31498321. PMCID: PMC7418855. (*equal contributions, †corresponding author).

  16. Kanca O, Andrews JC, Lee PT, Patel C, Braddock SR, Slavotinek AM, Cohen JS, Gubbels CS, Aldinger KA, Williams J, Indaram M, Fatemi A, Yu TW, Agrawal PB, Vezina G, Simons C, Crawford J, Lau CC; Undiagnosed Diseases Network, Chung WK, Markello TC, Dobyns WB, Adams DR, Gahl WA, Wangler MF, Yamamoto S, Bellen HJ, Malicdan MCV (2019) De Novo Variants in WDR37 are Associated with Epilepsy, Colobomas and Cerebellar hypoplasia. Am J Hum Genet. 105(2):413-424. PMID: 31327508, PMCID: PMC6699142.

  17. Splinter K, Adams D, Bellen HJ, Bernstein JA, Cheatle-Jarvela AM, Eng C, Esteves C, Gahl W, Rizwan Hamid, Jacob H, Kikani B, Koeller D, Kohane I, Loscalzo J, Luo X, Members of the Undiagnosed Diseases Network, McCray A, Metz TO, Mulvihill JJ, Nelson SF, Palmer C, Phillips JA III, Pick L, Postlethwait J, Shashi V, Sweetser D, Tifft C, Walley N, Wangler MF, Westerfield M, Wheeler M, Wise A, Worthey E,  Yamamoto S, Ashley EA, Undiagnosed Diseases Network (2018) Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease. N Engl J Med. 379:2131-2139. PMID: 30304647, PMCID: PMC6481166.

  18. Marcogliese PC, Shashi V, Spillmann RC, Stong N, Rosenfeld JA, Koenig MK, Martínez-Agosto JA, Herzog M, Chen AH, Dickson PI, Lin HJ, Vera MU, Salamon N, Ortiz D, Infante E, Steyaert W, Dermaut B, Poppe B, Chung H-L, Zuo Z, Lee P-T, Kanca O, Xia F, Yang Y, Smith EC, Jasien J, Kansagra S, Spiridigliozzi G, El-Dairi M, Lark R, Riley K, Koeberl DD, Golden-Grant K, Program for Undiagnosed Diseases (UD-PrOZA), Undiagnosed Diseases Network, Yamamoto S, Wangler MF, Mirzaa G, Hemelsoet D, Lee B, Nelson SF, Goldstein DB, Bellen HJ, Pena LDM (2018) Loss-of-function in IRF2BPL is associated with neurological phenotypes. Am J Hum Genet. 103(2):245-260. PMID: 30057031, PMICD: PMC6081494.

  19. Liu N, Schoch K, Luo X, Pena L, Bhavana VH, Kukolich M, Stringer S, Powis Z, Radtke K, Mroske C, Deak K, McDonald MT, McConkie-Rosell A, Markert ML, Kranz P, Stong N, Need AC, Bick D, Amaral MD, Worthey EA, Levy S, UDN, Wangler MF, Bellen HJ, Shashi V†, Yamamoto S† (2018) Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder.  Hum. Mol Genet. 27(14):2454-2465. PMID: 29726930, PMCID: PMC6030957. (†corresponding authors).

  20. Oláhová M, Yoon WH, Thompson K, Jangam S, Fernandez L, Davidson JM, Kyle JE, Grove ME, Fisk DG, Kohler JN, Holmes M, Dries AM, Huang Y, Zhao C, Contrepois K, Zappala Z, Frésard L, Waggott D, Zink EM,  Kim Y-M, Heyman HM, Stratton KG, Webb-Robertson BJM, Undiagnosed Diseases Network, Snyder M, Merker JD, Montgomery SB, Fisher PG, Feichtinger RG, Mayr JA, Hall J, Barbosa IA, Simpson MA, Deshpande C, Waters KM, Koeller D, Metz TO, Morris AA, Schelley S, Cowan T, Friederich MW, McFarland R, Van Hove JLK, Enns GM, Yamamoto S, Ashley EA, Wangler MF, Taylor RW, Bellen HJ, Bernstein JA, Wheeler MT (2018) Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder. Am J Hum Genet. 102(3):494-504. PMID: 29478781, PMCID: PMC6117612.

  21. Wangler MF*, Yamamoto S*, Chao H-T, Posey JE, Westerfield M, Postlethwait J, Members of the UDN, Hieter P, Boycott KM, Campeau PM, Bellen HJ (2017) Model organisms in undiagnosed rare diseases. Genetics. 207(1):9-27. PMID: 28874452. PMCID: PMC5586389 (*equal contribution).

  22. Luo X, Rosenfeld JA, Yamamoto S, Harel T, Zuo Z, Hall M, Wierenga KJ, Pastore MT, Bartholomew D, Delgado MR, Rotenberg J, Lewis RA, Emrick L, Bacino CA, Eldomery MK, Coban Akdemir Z, Xia F, Yang Y, Lalani SR, Lotze T, Lupski JR, Lee B, Bellen HJ, Wangler MF; Members of the UDN (2017) Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially. PLoS Genet. 13:e1006905. PMID: 28742085. PMCID: PMC5557584.

  23. Chao H-T, Davids M, Burke E, Pappas JG, Rosenfeld JA, McCarty A, Davis T, Wolfe L, Toro C, Tifft C, Xia F, Johnson TK, Warr CG, Members of the UDN, Yamamoto S, Adams D, Markello TC, Gahl WA, Bellen HJ, Wangler MF, Malicdan MCV (2017) A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3. Am J Hum Genet. 100(1):128-137. PMID: 28017372. PMICD: PMC5223093.

  24. Yoon WH, Sandoval H, Nagarkar-Jaiswal S, Jaiswal M, Yamamoto S, Haelterman NA, Putluri N, Putluri V, Sreekumar A, Tos T, Aksoy A, Donti T, Graham BH, Ohno M, Nishi E, Hunter J, Muzny DM, Carmichael J, Shen J, Arboleda VA, Nelson SF, Wangler MF, Karaca E, Lupski JR, Bellen HJ (2017) Loss of Nardilysin, a Mitochondrial Co-chaperone for α-Ketoglutarate Dehydrogenase, Promotes mTORC1 Activation and Neurodegeneration. Neuron. 93(1):115-131. PMID: 28017472. PMCID: PMC5242142.

  25. Bellen HJ, Yamamoto S (2015) Morgan’s legacy: fruit flies and the functional annotation of conserved genes. Cell. 163(1):12-14. PMID: 26406362. PMCID: PMC4783153.

  26. Wangler MF*, Yamamoto S*, Bellen HJ (2015) Fruit Flies in Biomedical Research. Genetics. 199(3):639-53. . PMID: 25624315. PMCID: PMC4349060. (*equal contribution).

  27. Yamamoto S*, Jaiswal M*, Charng WL, Gambin T, Karaca E, Mirzaa G, Wiszniewski W, Sandoval H, Haelterman NA, Xiong B, Zhang K, Bayat V, David G, Li T, Chen K, Gala U, Harel T, Pehlivan D, Penney S, Vissers LE, de Ligt J, Jhangiani SN, Xie Y, Tsang SH, Parman Y, Sivaci M, Battaloglu E, Muzny D, Wan YW, Liu Z, Lin-Moore AT, Clark RD, Curry CJ, Link N, Schulze KL, Boerwinkle E, Dobyns WB, Allikmets R, Gibbs RA, Chen R, Lupski JR, Wangler MF, Bellen HJ (2014) A Drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases. Cell. 159(1):200-214 . PMID: 25259927, PMCID: PMC4298142. (*equal contribution).

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