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GeneMatcher Team Plans Improvements for Researchers, Patients to Build on Recent Successes

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NEW YORK – GeneMatcher has become instrumental in the discovery of new genes underlying hereditary diseases. Since its inception in 2015, the "matchmaking" service, which connects researchers, clinicians, and patients interested in the same genes, has been used to help identify at least 416 novel disease-related genes and has been cited in 562 publications.

As the service continues to grow, its developers at the Baylor-Hopkins Center for Mendelian Genomics plan to make it easier for researchers to find information related to animal models and to add tools for patients as more of them start using the service to research their own conditions.

The growth in users is reflected in a huge uptick in publications referencing GeneMatcher, which increased from 20 publications in 2015 to 143 in 2021, with 58 already having been published this year.

"It's like 'Field of Dreams'," said Ada Hamosh, one of GeneMatcher's original developers and a professor of genetic medicine at Johns Hopkins University. "If you build it, they will come."

That said, both Hamosh and Nara Sobreira, the first author of the original GeneMatcher publication and an assistant professor of genetic medicine at Johns Hopkins, are quick to point out that initially building the service was no walk in the park.

"It took us years talking about GeneMatcher and convincing people to use it," Sobreira said. "Now it's all good and beautiful but at the beginning, we got a lot of pushback, with a lot of people thinking that it was not going to work."

GeneMatcher is part of the Matchmaker Exchange project, which also allows GeneMatcher submitters to query other connected databases through the Exchange's API. These include PhenomeCentral, Decipher, IRUD, MyGene2, and the newer ModelMatcher, which is geared toward researchers using animal models.

GeneMatcher allows individuals to submit genes of interest and automatically matches them with others submitting the same genes. Submitters may include other information along with the gene or genes, such as variants by base pair position, diagnoses from the OMIM database, and clinical/phenotypic features.

Submitters are currently limited to posting 10 candidate genes per submission, as a way to avoid unnecessary data dumping.

Most recently, GeneDx cited the service in a publication in Human Genetics, accrediting it with having helped the company and its collaborators discover over 200 new and expanded genetic conditions.

In its report, the company estimated that it accounts for some 20 percent of GeneMatcher submissions, an impressive quantity given the 11,883 total submitters from 98 countries that were recorded on the platform as of March 22.

GeneDx's GeneMatcher-mediated collaborations that have led to discoveries include a yet-unnamed neurological disorder caused by an autosomal dominant FAR1 variant, resulting in spastic paraparesis and bilateral cataracts.

Similarly, HudsonAlpha has cited GeneMatcher in having facilitated the research needed to identify a previously unknown rare variant of the EBF3 gene that causes intellectual disability, ataxia, and facial dysmorphism.

"This gene encodes an early B-cell factor, is a known developmental transcription factor, suspected to function in neuronal differentiation and maturation, and was a target of ARX, a known NDD gene," Michelle Thompson, a variant analyst with HudsonAlpha, said via email.

After submitting to GeneMatcher, the HudsonAlpha researchers were able to find a second patient within their own cohort and to connect with several other labs investigating EBF3 around the world.

Graduate students at HudsonAlpha performed functional analysis on the variants and helped establish EBF3 as a new neurodevelopmental disease gene.

"We were able to provide two diagnoses within our own study, and eight other patients were provided an answer, many of which had been on a diagnostic odyssey," Thompson added.

Thompson said that GeneMatcher has led to 23 publications from HudsonAlpha, with additional manuscripts in preparation.

More recently, a team of researchers from across the globe published the discovery of RECON (RECql ONe) syndrome, a rare disorder caused by mutations in the RECQL1 helicase gene, after researchers and clinicians studying that gene connected with each other through GeneMatcher and were able to share their findings.

In addition to genetics professionals, patients also increasingly turn to GeneMatcher as a means of seeking information on their own conditions.

"I get a lot of emails from patients asking me how to use it, what's the best way to use it, if GeneMatcher is the best tool to use," Sobreira said. While she thinks that the best tool for patients right now is probably MyGene2, "I completely support them using GeneMatcher," and the site includes a way for patients to identify themselves as such and say whether they're looking to connect with clinicians or researchers.

As of March 1, approximately 688 patients had submitted requests for information from GeneMatcher, according to Hamosh.

Thanks to patients and researchers, use of GeneMatcher has grown steadily since its launch, and Sobreira now employs one lab technician whose job is to field emails concerning the platform, mainly from submitters, while she finds herself sometimes responding to emails from patients.

GeneDx also noted a rise in queries and matches made through GeneMatcher, particularly over the course of the pandemic.

"With stay‐at‐home orders," the company wrote in its recent article, "perhaps many clinicians and researchers suddenly had time they had lacked previously and decided to work on research projects."

As a result, the firm's response time to requests through GeneMatcher has increased, and it has found itself unable to respond to them in real time.

"We have a triage process to prioritize inquiries and work to respond to the most urgent within a week or so, while other inquiries can take longer," Julie McKeough, GeneDx's chief communications officer, explained via email.

Sobreira and Hamosh mentioned that as GeneMatcher's user base keeps growing, they plan to make improvements and add features to ensure that it remains useful for all stakeholders.

ModelMatcher, the most recent addition to the Matchmaker Exchange, has brought more queries from animal model researchers into GeneMatcher, as these scientists seek to link genes found in animals to their human counterparts.

Because of this, Sobreira and her team recently added model organism statistics to the platform and are planning to add a feature allowing users to identify themselves as model organism researchers, along with an option to connect with other animal model researchers.

She also plans to add a link for Publication and Researchers - Rare Disease Gene Mechanisms (PaR-RaDiGM), a feature aimed at connecting rare disease researchers to relevant publications, to the match email notification system.

More changes may yet come from further user feedback.

"It would be useful to be able to search for genes that have already been submitted to GeneMatcher," Thompson commented. "Currently, you submit a gene of interest and get a 'match report,' ranging from 'no matches' to a list of other researchers/clinicians with the same gene of interest. However, one potential downside would be that it may discourage submitters to continue submitting that gene through the portal, as it may later develop as a gene of interest."

As with any public database, the more people use it, the more useful it becomes, increasing the chances of finding clinically relevant rare variants in particular candidate genes.

It has already proven a valuable resource to GeneDx in the company's numerous collaborations.

"We hope that [our] article inspires others to participate in GeneMatcher so that, together, we can advance our understanding of human genetic disease and ultimately help more patients," McKeough said.

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