Opportunities and Challenges for the Matchmaker Exchange
With greater than 14,000 unique genes connected across the MME, most
matchmaking submissions result in at least one match (Figure 3 )
and each of these matches requires review that will need additional
information to inform the matching parties as to whether or not the
match represents a valid novel disease-gene relationship discovery. A
matchmaking outcome analysis of 194 genes submitted to MME by the
Care4Rare Canada Consortium over a 2-year period highlighted the
effectiveness of MME in establishing collaborations for novel candidate
genes with a 15% success rate (Osmond, Hartley, Dyment, et al.,
2022) . The 194 genes entered by Care4Rare Canada resulted in over 1,500
matches returned by MME, with 93% receiving at least one match. Each of
these needed to be evaluated, consolidated, and, in the majority of
cases, have emails sent to determine the potential significance of the
match; this is a laborious process that requires dedicated time and
resources. Likewise, seqr users have supported manual
communication on >6,500 matches (PRODUCTION: REFERENCE
APPEARS IN THE SAME SPECIAL ISSUE (Pais et al., 2022) . One of the
largest contributing factors to the post-match workload is the lack of
phenotypic and inheritance information associated with the majority of
cases in GeneMatcher, the largest node of the MME (Osmond,
Hartley, Dyment, et al., 2022) . To date, only 2.5% of the over 63,000
submissions to GeneMatcher have included phenotype. However, the
majority of records in all other primary MME nodes do include this
information. The discovery community needs to carefully weigh the pros
and cons of a low barrier to entry into MME with the post-match
workload.
Moving forward, the MME has the opportunity to improve the efficiency of
the matchmaking (Table 2 ). Inclusion of additional information
(phenotype, variant details, zygosity) along with the gene will
facilitate the ruling out of matches without the email back-and-forth
that is difficult to scale. Osmond and colleagues (2022) showed that
~50% of matches could be ruled out when this type of
data was provided by the node at the time of match notification. It is
important for users to note that inclusion of high level phenotypic data
typically does not require additional consent (Dyke et al.,
2017) . In addition, the submission of only high quality candidate
genes, continuous updating of a group’s submissions, removal of cases
with ruled out/low priority candidate genes and removal or detailed
annotation of solved cases (Table 2 ) will all promote efficient
matchmaking using MME.
Several of the MME nodes have implemented additional features to help
users track the large number of matches that currently require
follow-up, such as those described for seqr (PRODUCTION:
REFERENCE APPEARS IN THE SAME SPECIAL ISSUE (Pais et al., 2022) ),
PhenomeCentral (PRODUCTION: REFERENCE APPEARS IN THE SAME SPECIAL ISSUE(Osmond, Hartley, Johnstone, et al., 2022) ), and GeneMatcher
(PRODUCTION: REFERENCE APPEARS IN THE SAME SPECIAL ISSUE (Hamosh et al.,
2022)) including auto-drafting emails as well as tracking match details,
communications and the outcomes of matches within the database. An
expanded use case for the MME is the secondary accumulation of
additional cases after the initial publication of a novel disease gene
relationship. Going forward, opportunities to support connections
between investigators made across the MME beyond email notification will
be considered, such as the equivalent of a gene ‘break-out’ room, to
help these teams organize with less back-and-forth correspondence.