Abstract
Purpose :
Inherited ocular conditions are clinically and genetically heterogeneous. While clinical genetic testing is fundamental for providing an accurate diagnosis, the accuracy relies on gene:disease relationship validity and variant disambiguation. Further, FDA-approved variant classifications are paramount for expanding access to gene-directed therapies. In 2019, the Clinical Genome Resource (ClinGen) convened an Ocular Clinical Domain Working Group (CDWG) of international volunteers comprising multidisciplinary expertise. Here, we provide the 5 year update of progress in this endeavor.
Methods :
The Clinical Ocular CDWG has two arms, Glaucoma/Neuro-Ophthalmology and Retina. Each has a Gene Curation Expert Panel (GCEP) and multiple Variant Curation Expert Panels (VCEPs). Nearly 200 biocurators and experts across these panels include ophthalmologists, medical geneticists, genetic counselors clinical laboratory directors, scientists, genetic counselors, and patient advocates. The ClinGen framework guides gene:disease validations, nomenclature standards, and gene-specific variant classification rules. This effort was funded by federal, pharmaceutical, and foundation partnerships.
Results :
The ClinGen Ocular CDWG convened 9 expert multidisciplinary panels across neuro-ophthalmology, glaucoma, ocular malformations, and retinal dystrophies. For gene:disease validation, over 100 approved curations have been published, with nomenclatures and ontologies updating the Mondo Disease Ontology (MONDO). For variant classification, gene-specific rules have been released for RPE65 and MYOC, for which more than 300 FDA-approved variant classifications have been released. Pilot rules are currently in development and testing for ABCA4, CYP1B1, OPA1, PAX6, RPGR, and RS1, which will be released soon.
Conclusions :
The Clinical Genome Resource (ClinGen) is an international consortium dedicated to the standardization of gene and variant interpretation. Multidisciplinary teams comprehensively evaluate gene and variant data to establish standards for the field. Given the growing importance of diagnosis and access to gene therapy, it is imperative to standardize gene causality and variant interpretation for inherited eye disease. This sharing of data resources as well as mining available variant databases is a vital public resource.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.