Abstract:The use of whole-genome sequencing (WGS) has accelerated the pace of gene discovery and highlighted the need for open and collaborative data sharing in the search for novel disease genes and variants. GeneMatcher (GM) is designed to facilitate connections between researchers, clinicians, health-care providers, and others to help in the identification of additional patients with variants in the same candidate disease genes. The Illumina Clinical Services Laboratory offers a WGS test for patients with suspected … Show more
“…This can connect clinical laboratories to investigators capable of molecular and functional analysis, and ultimately facilitate a diagnosis for a patient. Proof of this can be found in three papers in this special issue that report on robust clinical laboratory experiences using the MME, including those from Ambry Genetics (Towne et al, 2022), GeneDx (McWalter et al, 2022 and Illumina (Taylor et al, 2022). All three laboratories use GeneMatcher for their matchmaking services; GeneDx submitted entries spanning 3507 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.…”
Section: Expansion and Impact Of The Mmementioning
The Matchmaker Exchange (MME) was launched in 2015 to provide a robust mechanism to discover novel disease-gene relationships. It operates as a federated network connecting databases holding relevant data using a common application programming interface, where two or more users are looking for a match for the same gene (two-sided matchmaking). 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 >13,520 unique genes (~68% of all proteincoding genes) connected across the MME's eight genomic matchmaking nodes, GeneMatcher, DECIPHER, PhenomeCentral, MyGene2, seqr, Initiative on Rare and Undiagnosed Disease, PatientMatcher, and the RD-Connect Genome-Phenome Analysis Platform. The collective data set accessible across the MME currently includes more than 120,000 cases from over 12,000 contributors in 98 countries. The discovery of potential new disease-gene relationships is happening daily and international collaborative teams are moving these advances forward to publication, now numbering well over 500. Expansion of data sharing into routine clinical practice by clinicians, genetic counselors, and clinical laboratories has ensured access to discovery for even more individuals with undiagnosed rare genetic diseases. Tens of thousands of patients and their family members have been directly or indirectly impacted by the discoveries facilitated by two-sided genomic matchmaking. MME supports further connections to the literature (PubCaseFinder) and to human and model organism resources (Monarch Initiative) and scientists (ModelMatcher).
“…This can connect clinical laboratories to investigators capable of molecular and functional analysis, and ultimately facilitate a diagnosis for a patient. Proof of this can be found in three papers in this special issue that report on robust clinical laboratory experiences using the MME, including those from Ambry Genetics (Towne et al, 2022), GeneDx (McWalter et al, 2022 and Illumina (Taylor et al, 2022). All three laboratories use GeneMatcher for their matchmaking services; GeneDx submitted entries spanning 3507 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.…”
Section: Expansion and Impact Of The Mmementioning
The Matchmaker Exchange (MME) was launched in 2015 to provide a robust mechanism to discover novel disease-gene relationships. It operates as a federated network connecting databases holding relevant data using a common application programming interface, where two or more users are looking for a match for the same gene (two-sided matchmaking). 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 >13,520 unique genes (~68% of all proteincoding genes) connected across the MME's eight genomic matchmaking nodes, GeneMatcher, DECIPHER, PhenomeCentral, MyGene2, seqr, Initiative on Rare and Undiagnosed Disease, PatientMatcher, and the RD-Connect Genome-Phenome Analysis Platform. The collective data set accessible across the MME currently includes more than 120,000 cases from over 12,000 contributors in 98 countries. The discovery of potential new disease-gene relationships is happening daily and international collaborative teams are moving these advances forward to publication, now numbering well over 500. Expansion of data sharing into routine clinical practice by clinicians, genetic counselors, and clinical laboratories has ensured access to discovery for even more individuals with undiagnosed rare genetic diseases. Tens of thousands of patients and their family members have been directly or indirectly impacted by the discoveries facilitated by two-sided genomic matchmaking. MME supports further connections to the literature (PubCaseFinder) and to human and model organism resources (Monarch Initiative) and scientists (ModelMatcher).
“…Indeed, some laboratories have developed extensive scoring and weighting systems for the evaluation of novel candidate genes, 31,34,35 while others have more streamlined criteria or lean more heavily on statistical analysis and/or internal and external matchmaking. 32,33…”
Section: Resultsmentioning
confidence: 99%
“…We first reviewed scoring and prioritization systems previously described by diagnostic laboratories and others [31][32][33][34][35]37,41 for use in assessing the strength and types of evidence for novel candidate genes and to determine whether to share and/or report variants in the corresponding genes with the patient/provider. From this review, it was clear that evaluation of the types and strengths of evidence for novel candidate genes is just as complex, if not more so, than evaluation of evidence of variant pathogenicity.…”
Section: Criteria For Novel Candidate Gene Inclusion In Clinical Es/gsmentioning
confidence: 99%
“…These are not rare occurrences: recently, a research group described matching immediately upon submission to MME to an existing cohort with phenotypic and genetic similarities for almost ~10% of their novel candidate genes 51 Finally, many large-scale clinical and hybrid clinical-research genomic testing efforts are already identifying, sharing, and reporting results in novel candidate genes and have described substantial benefits in identifying a genetic diagnosis for their patients. 28,[31][32][33]51,56 Thus we strongly encourage clinical laboratories and research programs to proactively identify, share, and report variants in novel candidate genes.…”
Section: Rationale For Sharing and Reporting Of Variants In Novel Can...mentioning
Since the first novel gene discovery for a Mendelian condition was made via exome sequencing (ES), the rapid increase in the number of genes known to underlie Mendelian conditions1 coupled with the adoption of exome (and more recently, genome) sequencing by diagnostic testing labs has changed the landscape of genomic testing for rare disease. Specifically, many individuals suspected to have a Mendelian condition are now routinely offered clinical ES. This commonly results in a precise genetic diagnosis but frequently overlooks the identification of novel candidate genes. Such candidates are also less likely to be identified in the absence of large-scale gene discovery research programs. Accordingly, clinical laboratories have both the opportunity, and some might argue a responsibility, to contribute to novel gene discovery which should in turn increase the diagnostic yield for many conditions. However, clinical diagnostic laboratories must necessarily balance priorities for throughput, turnaround time, cost efficiency, clinician preferences, and regulatory constraints, and often do not have the infrastructure or resources to effectively participate in either clinical translational or basic genome science research efforts. For these and other reasons, many laboratories have historically refrained from broadly sharing potentially pathogenic variants in novel genes via networks like Matchmaker Exchange, much less reporting such results to ordering providers. Efforts to report such results are further complicated by a lack of guidelines for clinical reporting and interpretation of variants in novel candidate genes. Nevertheless, there are myriad benefits for many stakeholders, including patients/families, clinicians, researchers, if clinical laboratories systematically and routinely identify, share, and report novel candidate genes. To facilitate this change in practice, we developed criteria for triaging, sharing, and reporting novel candidate genes that are most likely to be promptly validated as underlying a Mendelian condition and translated to use in clinical settings.
“…Genes with a limited or NKDR (with or without an animal model) GDR classification may be submitted to GeneMatcher if the proband, variant, and gene meet internal criteria. 26 Figure 3 Reactive gene curation supports clinical reporting for a cGS test for RUGDs (A) Use of GDR classification in variant classification and reporting. (B) Categorization of GDRs for clinical reporting as a percentage of total GDRs curated.…”
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