Introduction
To understand the disease relationships for all genes and variants in
the Mendelian genome is nothing short of a grand challenge that
represents, and will continue to represent, decades of scientific
discovery. The Online Mendelian Inheritance in Man (OMIM) catalog lists
4,224 genes implicated in single gene disorders and traits (omim.org,
accessed 3/4/22), yet estimates suggest more than 10,000 genes are
likely to be found causal for monogenic disease (Bamshad et al.,
2019) and typical diagnostic rates for individuals with suspected
genetic disease are only around 25% (100,000 Genomes Project
Pilot Investigators et al., 2021) . Much more variant-gene-disease
discovery remains to be accomplished. As we continue to study
increasingly rare Mendelian diseases, the need for responsible data
sharing becomes even greater. A key driver of gene-disease discovery for
rare disease is the ability to connect two or more parties looking for
rare disease cases with the same candidate gene and an overlapping
phenotype to expedite the gene-discovery process. This approach has been
referred to as two-sided genome matchmaking and is the predominant use
case for the Matchmaker Exchange (MME) (Figure 1 )(Philippakis et al., 2015) .
The MME consortium was formed in 2013 as a collaborative effort to
launch a federated platform to enable two-sided genomic matchmaking
through a standardized application programming interface (API) and
procedural conventions. While the practice of matchmaking was already
occurring within individual databases before the launch of MME, the data
was siloed within each node. The MME network set out to connect
databases into a federated network, something that had never been done
before. The federated MME network launched in 2015 and the work to
launch MME was described in detail by Philippakis and colleagues(Philippakis et al., 2015) , including formation of a steering
committee and developing MME policies and approaches to queries and
notifications. The federated MME network API enables exchange of
information between the matchmakers through a set of required elements
(https://github.com/ga4gh/mme-apis). This API is described (Buske,
Schiettecatte, et al., 2015) , and was developed in collaboration with
members of the Global Alliance for Genomics and Health (GA4GH)(Rehm et al., 2021) and the International Rare Diseases Research
Consortium (IRDiRC) (Boycott et al., 2017) to ensure
interoperability with other genomic services. This early work was
described in a special issue of Human Mutation in 2015, The Matchmaker
Exchange, which also included papers describing individual matchmaking
services (Buske, Girdea, et al., 2015; Chatzimichali et al., 2015;
Gonzalez et al., 2015; Kirkpatrick et al., 2015; Lancaster et al., 2015;
Mungall et al., 2015; Sobreira et al., 2015) , case reports from
clinicians, laboratories and researchers describing novel gene
discoveries facilitated by genomic matchmaking (Au et al., 2015;
Jurgens et al., 2015; Loucks et al., 2015) as well as other relevant
topics (Akle et al., 2015; Brownstein et al., 2015; Krawitz et
al., 2015; Lambertson et al., 2015) . Seven years later, we now report
on the progress of the MME and advances in the field of genomic
matchmaking in this special issue.