The Matchmaker Exchange: A Platform for Rare Disease Gene Discovery

Abstract

There are few better examples of the need for data sharing than in the rare disease community, where patients, physicians, and researchers must search for “the needle in a haystack” to uncover rare, novel causes of disease within the genome. Impeding the pace of discovery has been the existence of many small siloed datasets within individual research or clinical laboratory databases and/or disease-specific organizations, hoping for serendipitous occasions when two distant investigators happen to learn they have a rare phenotype in common and can “match” these cases to build evidence for causality. However, serendipity has never proven to be a reliable or scalable approach in science. As such, the Matchmaker Exchange (MME) was launched to provide a robust and systematic approach to rare disease gene discovery through the creation of a federated network connecting databases of genotypes and rare phenotypes using a common application programming interface (API). The core building blocks of the MME have been defined and assembled. Three MME services have now been connected through the API and are available for community use. Additional databases that support internal matching are anticipated to join the MME network as it continues to grow.

Building dialogues between clinical and biomedical research through cross-species collaborations

“…What was once an esoteric collection of genetic and human phenotypic data is now organized into easy to consume and quick to access databases and websites that offer clinicians and scientists an unprecedented access to vast amounts of information. Databases such as Matchmaker Exchange [50] and GeneMatcher [51] greatly facilitate the transfer of human genetic data from bedside to bench. Matchmaker Exchange hosts collections of genetic information gathered from around the world and aims to address the challenges of finding genetic causes for patients with rare diseases.…”

MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death

“…Upon exchange of our data with the clinical exome laboratory, we identified two more patients with variants in MIPEP who both coincidentally had a similar phenotype; patient 2 was found to have compound heterozygous variants (p.E602*/p.L306F) and patient 3 had a homozygous variant (p.K343E). We next submitted MIPEP to the GeneMatcher tool, a part of the Matchmaker Exchange project (https://genematcher.org) [32, 33], and successfully matched one other patient with a paternally inherited MIPEP SNV (p.H512D) and maternally inherited 1.4-Mb deletion copy number variant (CNV) encompassing the entire gene. Sanger sequencing in the probands and family members confirmed the variants’ presence and their biallelic nature in the probands (Fig.…”

Genetics of neuromuscular fetal akinesia in the genomics era

“…These novel genotype–phenotype correlations are often surprising, and can be difficult to classify without additional cases or functional studies to confirm pathogenicity. The rise of genetic ‘match-making’ services such as Matchmaker Exchange83 greatly assists by providing additional cases to corroborate findings and justify further investigation. In the case of GLDN and GLE1 , phenotypic expansions demonstrated mutations in these genes are not universally fatal, radically altering the prognostic landscape.…”