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.