Diagnostic testing laboratories are valuable partners for disease gene discovery: 5‐year experience with GeneMatcher. Issue 6 (2nd March 2022)

• Record Type: Journal Article
• Authors: Towne, Meghan C.; Rossi, Mari; Wayburn, Bess; Huang, Jennifer M.; Radtke, Kelly; Alcaraz, Wendy; Farwell Hagman, Kelly D.; Shinde, Deepali N.
• Other Names: Boycott Kym guestEditor.; Hamosh Ada guestEditor.; Rehm Heidi guestEditor.
• Is Part Of: Human mutation. Volume 43:Issue 6(2022)
• Page Start: 772
• Page End: 781
• Publication Date: 2022-03-02
• Subjects: clinical validity -- data sharing -- disease gene discovery -- exome sequencing -- gene–disease validity -- GeneMatcher -- Matchmaker Exchange; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.24342
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: Although the rates of disease gene discovery have steadily increased with the expanding use of genome and exome sequencing by clinical and research laboratories, only ~16% of genes in the genome have confirmed disease associations. Here we describe our clinical laboratory's experience utilizing GeneMatcher, an online portal designed to promote disease gene discovery and data sharing. Since 2016, we submitted 246 candidates from 243 unique genes to GeneMatcher, of which 111 (45%) are now clinically characterized. Submissions meeting our candidate gene‐reporting criteria based on a scoring system using patient and molecular‐weighted evidence were significantly more likely to be characterized as of October 2021 versus genes that did not meet our clinical‐reporting criteria ( p = 0.025). We reported relevant findings related to these newly characterized gene–disease associations in 477 probands. In 218 (46%) instances, we issued reclassifications after an initial negative or candidate gene (uncertain) report. We coauthored 104 publications delineating gene–disease relationships, including descriptions of new associations (60%), additional supportive evidence (13%), subsequent descriptive cohorts (23%), and phenotypic expansions (4%). Clinical laboratories are pivotal for disease gene discovery efforts and can screen phenotypes based on genotype matches, contact clinicians of relevant cases, and issue proactive reclassification reports. Abstract : Selective sharing of candidates with strong evidence aids efficient gene characterization.