GeneMatcher

GeneMatcher is an online service and database that aims to match clinicians studying patients with a rare disease presentation based on genes of interest. When two or more clinicians submit the same gene to the database, the service matches them together to allow them to compare cases. It also allows matching genes from animal models to human cases. The service aims to establish novel relationships between genes and genetic diseases of unknown cause.

GeneMatcher
Content
DescriptionOnline service and database for matching clinicians based on genes of interest
Data types
captured		Genes, genomic loci, genetic disorders, physical symptoms
Contact
Research centerBaylor–Hopkins Center for Mendelian Genomics (BHCMG)
Primary citationPMID 26220891
Release dateSeptember 2013
Access
Websitewww.genematcher.org

The website was launched in September 2013 by a team from a government-funded collaborative project between Johns Hopkins Hospital and Baylor College of Medicine in the United States.[1]

As of December 2019, the site contained 11,855 genes from 7,724 submitters from 88 countries, and 6,609 matches had been made.[2] The service has aided geneticists in making several discoveries, including establishing the genetic causes of a form of autism spectrum disorder, syndromes of microcephaly with hearing loss, a mitochondrial disease and Au–Kline syndrome.

History

The website was launched in September 2013 by Nara Sobreira, François Schiettecatte, Ada Hamosh and others.[1] The team are part of a collaborative effort between Johns Hopkins Hospital in Baltimore, Maryland and Baylor College of Medicine in Houston, Texas, United States called the Baylor–Hopkins Center for Mendelian Genomics (BHCMG), one of three such Centers for Mendelian Genomics (CMGs) established and funded by the American National Institutes of Health (NIH) and National Human Genome Research Institute (NHGRI) in 2011.[3][4]

Features

The service allows researchers to submit candidate genes to a database and match based on a shared gene of interest. Researchers, healthcare providers or patients can create an account using their email, name and address. Upon doing this, they can post a gene by gene symbol, Entrez ID or Ensembl gene ID. They can also specify genes by OMIM number or genomic location. If an identical gene has already been posted by another user, the match is made immediately and both users receive an email with the contact details of the other user. Otherwise, the gene remains in the database until another user submits the same gene. The database of genes is not explorable, and no user contact details are accessible until a match has been made. Users may retract their submitted gene or delete their account at any time.[1]

Optionally, users are also able to query the database by genetic disorder or physical symptom. The service also encourages those working with animal models to submit their gene candidates and provides an option to specify the submission by model organism.[1]

Usage

As of December 2019, the site contained 11,855 genes from 7,724 submitters from 88 countries, and 6,609 matches had been made.[2] As of July 2015, roughly 14% of the genes were related to animal models, and the BHCMG itself had submitted at least 180 of the genes and generated 69 matches, 16 of which were also a phenotype match. Three of those phenotype–gene matches, involving SPATA5, HNRNPK and TELO2, were sufficient for publication of new outlines of diseases in medical journals.[1]

Collaboration with other databases

GeneMatcher is part of a collaboration between multiple gene-matching services called MatchmakerExchange, launched in October 2013. The other services part of the project include PhenomeCentral and DECIPHER.[5]

American genetic testing company GeneDx has uploaded genes from its database with likely pathogenic variants, leading to dozens of matches.[1]

Impact

GeneMatcher has helped geneticists to make several new discoveries, some examples of which include the following:

  • In 2015, the service matched three practices with cases of an unknown multi-system syndrome likely caused by a mutation in HNRNPK. The cause was confirmed, and the syndrome was named Au–Kline syndrome, after Ping-Yee Billie Au and Antonie D. Kline, two of the researchers involved.[5][6] The syndrome was later shown in 2019 to be identical to Okamoto syndrome, described in 1997.[7]
  • In 2015, the service allowed researchers to link SPATA5 to an autosomal recessive syndrome of microcephaly, seizures and hearing loss. They used GeneMatcher to find 4 of 14 patients with the syndrome and mutations.[8]
  • In 2015, GeneMatcher helped researchers to link TELO2 to an autosomal recessive syndrome of microcephaly, ataxia, hearing loss, congenital heart defects and other features. The service allowed them to find the fourth of four families with children with the condition and mutations. The syndrome was named You–Hoover-Fong syndrome, after researchers Jing You and Julie Hoover-Fong.[9]
  • In 2016, researchers in the Netherlands used GeneMatcher to identify 2 of 4 patients with a fatal autosomal recessive immunodeficiency condition called LICS syndrome, caused by mutations in NSMCE3.[10][11]
  • In 2017, it was discovered that mutations in KYNU or HAAO lead to an autosomal recessive syndrome of skeletal abnormalities, congenital heart defects, hypoplastic kidneys, hearing loss and other features. The researchers used GeneMatcher to identify the fourth of four families with children with the condition.[12][13]
  • In 2017, UK researchers identified mutations in ADCY3 as the cause of an autosomal recessive ciliary disorder causing obesity, anosmia and mild intellectual disability. GeneMatcher allowed them to find the fourth of four patients with the condition.[14][15][16]
  • In 2018, researchers were able to associate a mitochondrial complex I deficiency with a mutation in NDUFA6 using GeneMatcher. The service allowed them to locate 3 of 4 patients with the condition and mutation.[17][18]
  • In 2019, GeneMatcher allowed researchers to link DEGS1 to an autosomal recessive hypomyelinating leukodystrophy. They had found a homozygous mutation in the gene in one female patient, and the service helped them in finding 18 other patients with autosomal recessive mutations in the same gene with similar symptoms.[19][20][21]
  • In 2019, researchers were able to establish with the help of GeneMatcher that a mutation in BRSK1 leads to an autosomal dominant syndrome of intellectual disability and autism spectrum disorder. The service allowed them to find 5 of 9 patients with the condition and mutation. The nine patients were from cohorts totalling 3,429 individuals, which was considered a high prevalence for a rare disorder and led to surprise that the gene hadn't been linked to developmental delay before.[22][23]
gollark: That's only a third of potatOS in any case.
gollark: It is somewhat documented now, mind you.
gollark: I also had a blasphemy detector hooked up to ingame chat a while ago.
gollark: https://git.osmarks.tk/osmarks/potatOS
gollark: It has so very much telemetry.

References
  1. Sobreira, Nara; Schiettecatte, François; Valle, David; Hamosh, Ada (2015). "GeneMatcher: A Matching Tool for Connecting Investigators with an Interest in the Same Gene". Human Mutation. 36 (10): 928–930. doi:10.1002/humu.22844. ISSN 1098-1004. PMC 4833888. PMID 26220891.
  2. "GeneMatcher (GM)". 2019-12-28. Archived from the original on 2019-12-28. Retrieved 2019-12-28.
  3. Bamshad, Michael J.; Shendure, Jay A.; Rieder, Mark J.; Valle, David; Hamosh, Ada; Lupski, James R.; Gibbs, Richard A.; Boerwinkle, Eric; Lifton, Rick P.; Gerstein, Mark; Gunel, Murat (July 2012). "The Centers for Mendelian Genomics: a new large-scale initiative to identify the genes underlying rare Mendelian conditions". American Journal of Medical Genetics Part A. 0 (7): 1523–1525. doi:10.1002/ajmg.a.35470. ISSN 1552-4825. PMC 3702263. PMID 22628075.
  4. "Centers for Mendelian Genomics". Genome.gov. Retrieved 2019-12-28.
  5. Carina Storrs, Special to. "Matchmaker: New crowdsourced sites for rare diseases". CNN. Retrieved 2019-12-28.
  6. Au, P.Y. Billie; You, Jing; Caluseriu, Oana; Schwartzentruber, Jeremy; Majewski, Jacek; Bernier, Francois P.; Ferguson, Marcia; Valle, David; Parboosingh, Jillian S.; Sobreira, Nara; Innes, A. Micheil (October 2015). "GeneMatcher Aids in the Identification of a New Malformation Syndrome with Intellectual Disability, Unique Facial Dysmorphisms, and Skeletal and Connective Tissue Abnormalities Caused by De Novo Variants in HNRNPK". Human Mutation. 36 (10): 1009–1014. doi:10.1002/humu.22837. ISSN 1059-7794. PMC 4589226. PMID 26173930.
  7. Okamoto, Nobuhiko (May 2019). "Okamoto syndrome has features overlapping with Au-Kline syndrome and is caused by HNRNPK mutation". American Journal of Medical Genetics Part A. 179 (5): 822–826. doi:10.1002/ajmg.a.61079. ISSN 1552-4833. PMID 30793470.
  8. Tanaka, Akemi J.; Cho, Megan T.; Millan, Francisca; Juusola, Jane; Retterer, Kyle; Joshi, Charuta; Niyazov, Dmitriy; Garnica, Adolfo; Gratz, Edward; Deardorff, Matthew; Wilkins, Alisha (2015-09-03). "Mutations in SPATA5 Are Associated with Microcephaly, Intellectual Disability, Seizures, and Hearing Loss". American Journal of Human Genetics. 97 (3): 457–464. doi:10.1016/j.ajhg.2015.07.014. ISSN 0002-9297. PMC 4564988. PMID 26299366.
  9. You, Jing; Sobreira, Nara L.; Gable, Dustin L.; Jurgens, Julie; Grange, Dorothy K.; Belnap, Newell; Siniard, Ashley; Szelinger, Szabolcs; Schrauwen, Isabelle; Richholt, Ryan F.; Vallee, Stephanie E. (2016-05-05). "A Syndromic Intellectual Disability Disorder Caused by Variants in TELO2, a Gene Encoding a Component of the TTT Complex". American Journal of Human Genetics. 98 (5): 909–918. doi:10.1016/j.ajhg.2016.03.014. ISSN 0002-9297. PMC 4863664. PMID 27132593.
  10. Steijaert, Mickey (2017-07-07). "Na negen jaar een diagnose: dit gebeurde in de tussentijd". de Volkskrant (in Dutch). Retrieved 2019-12-29.
  11. van der Crabben, Saskia N.; Hennus, Marije P.; McGregor, Grant A.; Ritter, Deborah I.; Nagamani, Sandesh C.S.; Wells, Owen S.; Harakalova, Magdalena; Chinn, Ivan K.; Alt, Aaron; Vondrova, Lucie; Hochstenbach, Ron (2016). "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease". The Journal of Clinical Investigation. 126 (8): 2881–2892. doi:10.1172/JCI82890. ISSN 0021-9738. PMC 4966312. PMID 27427983.
  12. "Subscribe to The Australian | Newspaper home delivery, website, iPad, iPhone & Android apps". www.theaustralian.com.au. Retrieved 2019-12-29.
  13. Shi, Hongjun; Enriquez, Annabelle; Rapadas, Melissa; Martin, Ella M.M.A.; Wang, Roni; Moreau, Julie; Lim, Chai K.; Szot, Justin O.; Ip, Eddie; Hughes, James N.; Sugimoto, Kotaro (2017-08-10). "NAD Deficiency, Congenital Malformations, and Niacin Supplementation". New England Journal of Medicine. 377 (6): 544–552. doi:10.1056/NEJMoa1616361. ISSN 0028-4793. PMID 28792876.
  14. AGERPRES. "Asocierea dintre obezitate şi mutaţiile genetice, dovada că această boală nu înseamnă." www.agerpres.ro (in Romanian). Retrieved 2019-12-29.
  15. Saeed, Sadia; Bonnefond, Amélie; Tamanini, Filippo; Mirza, Muhammad Usman; Manzoor, Jaida; Janjua, Qasim M.; Din, Sadia M.; Gaitan, Julien; Milochau, Alexandra; Durand, Emmanuelle; Vaillant, Emmanuel (February 2018). "Loss-of-function mutations in ADCY3 cause monogenic severe obesity". Nature Genetics. 50 (2): 175–179. doi:10.1038/s41588-017-0023-6. hdl:10044/1/59066. ISSN 1546-1718. PMID 29311637.
  16. Grarup, Niels; Moltke, Ida; Andersen, Mette K.; Dalby, Maria; Vitting-Seerup, Kristoffer; Kern, Timo; Mahendran, Yuvaraj; Jørsboe, Emil; Larsen, Christina V. L.; Dahl-Petersen, Inger K.; Gilly, Arthur (February 2018). "Loss-of-function variants in ADCY3 increase risk of obesity and type 2 diabetes". Nature Genetics. 50 (2): 172–174. doi:10.1038/s41588-017-0022-7. ISSN 1546-1718. PMC 5828106. PMID 29311636.
  17. Walsh, Fergus (2019-06-10). "Gene 'revolution' in sick children diagnosis". Retrieved 2019-12-29.
  18. Alston, Charlotte L.; Heidler, Juliana; Dibley, Marris G.; Kremer, Laura S.; Taylor, Lucie S.; Fratter, Carl; French, Courtney E.; Glasgow, Ruth I.C.; Feichtinger, René G.; Delon, Isabelle; Pagnamenta, Alistair T. (2018-10-04). "Bi-allelic Mutations in NDUFA6 Establish Its Role in Early-Onset Isolated Mitochondrial Complex I Deficiency". American Journal of Human Genetics. 103 (4): 592–601. doi:10.1016/j.ajhg.2018.08.013. ISSN 0002-9297. PMC 6174280. PMID 30245030.
  19. "Newly discovered leukodystrophy in children: Potential cure: The gene that causes the disease is called DEGS1 and its defect may be counteracted with fingolimod". ScienceDaily. Retrieved 2019-12-29.
  20. "OMIM Entry - * 615843 - DELTA(4)-DESATURASE, SPHINGOLIPID, 1; DEGS1". omim.org. Retrieved 2019-12-29.
  21. Pant, Devesh C.; Dorboz, Imen; Schluter, Agatha; Fourcade, Stéphane; Launay, Nathalie; Joya, Javier; Aguilera-Albesa, Sergio; Yoldi, Maria Eugenia; Casasnovas, Carlos; Willis, Mary J.; Ruiz, Montserrat (2019). "Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy". The Journal of Clinical Investigation. 129 (3): 1240–1256. doi:10.1172/JCI123959. ISSN 0021-9738. PMC 6391109. PMID 30620337.
  22. "Matchmaking site for genes leads scientists to autism candidate". Spectrum | Autism Research News. 2019-05-06. Retrieved 2019-12-29.
  23. Hiatt, Susan M.; Thompson, Michelle L.; Prokop, Jeremy W.; Lawlor, James M.J.; Gray, David E.; Bebin, E. Martina; Rinne, Tuula; Kempers, Marlies; Pfundt, Rolph; van Bon, Bregje W.; Mignot, Cyril (2019-04-04). "Deleterious Variation in BRSK2 Associates with a Neurodevelopmental Disorder". American Journal of Human Genetics. 104 (4): 701–708. doi:10.1016/j.ajhg.2019.02.002. ISSN 0002-9297. PMC 6451696. PMID 30879638.
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