Expansion and Impact of the Matchmaker Exchange
When the MME federated network was launched in 2015, it connected three matchmaking services (nodes) (Philippakis et al., 2015) : DECIPHER (DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources) (PRODUCTION: REFERENCE APPEARS IN THE SAME SPECIAL ISSUE(Foreman et al., 2022) ), GeneMatcher (PRODUCTION: REFERENCE APPEARS IN THE SAME SPECIAL ISSUE (Hamosh et al., 2022) ) and PhenomeCentral (PRODUCTION: REFERENCE APPEARS IN THE SAME SPECIAL ISSUE(Osmond, Hartley, Johnstone, et al., 2022 ). Since that time, the network (Figure 2 ) has grown to include five additional genomic matchmaking nodes: MyGene2 (Chong et al., 2016) , seqr(PRODUCTION: REFERENCE APPEARS IN THE SAME SPECIAL ISSUE (Pais et al., 2022) ), Initiative on Rare and Undiagnosed Disease (IRUD)(Adachi et al., 2017) , PatientMatcher (PRODUCTION: REFERENCE APPEARS IN THE SAME SPECIAL ISSUE (Rasi et al., 2022) ), and the RD-Connect Genome-Phenome Analysis Platform (GPAP) (PRODUCTION: REFERENCES APPEARS IN THE SAME SPECIAL ISSUE (Laurie et al., 2022) ) (Table 1 ). The “Matchmaker Exchange Participants” page on the MME website (www.matchmakerexchange.org/participants.html) provides users a set of tables comparing the types of data stored by each connected MME node, descriptions of matching and scoring output, MME connections, types of users, and summaries of matching and notification protocols. Most of the nodes provide matching services only to users who are storing their genomic data in the database and can flag candidate genes, along with additional information such as phenotype and inheritance pattern, for submission to MME. However, for many interested parties, they are lacking the means and opportunity to contribute this type of comprehensive data so use GeneMatcher (Sobreira et al., 2015) which has the lowest barrier to entry into the MME. As a result, GeneMatcher is the most widely used node of the MME with 11,780 submitters (PRODUCTION: REFERENCES APPEARS IN THE SAME SPECIAL ISSUE(Hamosh et al., 2022) ).
The collective dataset accessible across the MME currently includes more than 120,000 cases from over 12,000 contributors in 98 countries. Though it is difficult to track precisely, genomic matchmaking as an approach using one or more nodes of the MME has led to well over 500 publications. The MME provides an accessible approach to matchmaking for individual research labs as well as large-scale research programs. In 2019, Bruel and colleagues (Bruel et al., 2019) reported the outcomes of 2.5 years’ experience using GeneMatcher to share 71 novel candidate genes identified by exome sequencing (ES) and found that the subsequent follow-up of matches supported 39% of genes as causal. Care4Rare Canada has used the MME since its inception and attributes the discovery and publication of 26 novel disease-relationships to connections made via the MME over the last 7 years (unpublished data). Similarly, the Centers for Mendelian Genomics and the Undiagnosed Disease Network both use MME as a critical platform facilitating novel disease-gene discovery (Baxter et al., 2022; Macnamara et al., 2020) .
While MME was primarily developed as a platform to service the research community in discovering novel causes of rare disease, it is increasingly being used directly by clinical laboratories that identify candidates through routine clinical genomic sequencing. For example, ade novo variant occurring in a highly constrained gene not yet implicated in disease and identified in a trio sent for clinical genomic sequencing would be highly suspicious for novel disease-gene discovery. Entering this gene into MME, along with the phenotype, can often yield matches. This can connect clinical laboratories to investigators capable of statistical and functional analysis, and ultimately facilitate a diagnosis for a patient. Proof of this can be found in three papers in this special issue report on robust clinical laboratory experiences using MME, including those from Ambry Genetics (PRODUCTION: REFERENCE APPEARS IN THE SAME SPECIAL ISSUE (Towne et al., 2022) ), GeneDx (PRODUCTION: REFERENCE APPEARS IN THE SAME SPECIAL ISSUE (McWalter et al., 2022) ) and Illumina (PRODUCTION: REFERENCE APPEARS IN THE SAME SPECIAL ISSUE (Taylor et al., 2022) ). All three laboratories use GeneMatcher for their matchmaking services; GeneDx submitted entries spanning 3,507 genes, 908 (26%) of which have been validated as causal through evidence built from matchmaking; Ambry Genetics submitted cases spanning 243 unique genes with 111 (45%) now clinically characterized; Illumina has submitted 69 unique genes with 21 (30%) leading to publications or active collaborations with publication planned. Given that some of these genes will be overlapping, it still indicates that, at a minimum, over 900 novel disease genes were identified and validated through MME through just three clinical laboratories using the platform. This number represents more than 20% of the 4,224 genes underlying monogenic disorders and traits cataloged in OMIM (omim.org, accessed 3/4/22). The contributions of clinical laboratories to matchmaking cannot be understated; the 3,507 genes submitted by GeneDx comprised 25% of the 13,941 unique genes in GeneMatcher on 9/28/21 (PRODUCTION: REFERENCE APPEARS IN THE SAME SPECIAL ISSUE (McWalter et al., 2022) ).
Seven years from its launch, it is clear that the MME is making outstanding contributions to understanding the morbid anatomy of the genome. The number of unique genes present across the MME has steadily increased over time; there are currently >14,355 genes connected across the MME’s eight genomic matchmaking nodes. The discovery of potential new disease-gene relationships is happening daily and tens of thousands of patients and their family members have been directly or indirectly impacted by the discoveries facilitated by two-sided genomic matchmaking.