Abstract
Purpose :
The Clinical Genome Resource (ClinGen) has established a Retina Gene Curation Expert Panel (GCEP) to evaluate the clinical validity of more than 200 genes implicated in inherited retinal disorders (IRD). The ClinGen clinical validity framework requires (1) defining the disease entity for gene curation, and (2) finding an appropriate standardized term (Mondo identifier). IRD nomenclature includes a variety of pathologic, morphologic, gene locus, and eponymous terms. These challenges are exacerbated by variable expressivity, locus heterogeneity, and allelic disorders among IRDs. Thus, the Retina GCEP has sought to revise the Mondo ontology and terminology for IRDs to capture the phenotypic spectrum in a standardized nomenclature.
Methods :
The Retina GCEP is using the ClinGen gene-disease clinical validity framework (version 8.0) to evaluate the clinical validity of over 200 IRD-implicated genes. The group follows ClinGen guidance (clinicalgenome.org). Subsequently, a Mondo ID is used to label the disease entity (mondo.monarchinitiative.org).
Results :
To date, the ClinGen Retina GCEP has finalized the clinical validity of over 30 gene-IRD relationships. For many genes currently under review, identification and systematic merging or splitting of multiple overlapping retinal phenotypes into unified disease terms is required to capture the phenotypic spectrum for causal genotypes and observed inheritance patterns. To name these disease entities, the Retina GCEP proposes a gene-first nomenclature system with the gene first followed by a disease descriptor (e.g. TSPAN12-related vitreoretinopathy). For genes associated with IRD with multiple inheritance patterns, or distinct genotype-phenotype relationships, the disease entities can be split (e.g. RPE65-related dominant retinopathy, and RPE65-related recessive retinopathy). Disease terms are periodically updated in the Mondo disease ontology database. Historical names of the lumped disease entities are included as synonyms for improved search purposes.
Conclusions :
Due to the significant locus heterogeneity and the broad, overlapping spectrum of clinical presentations linked to many genes implicated in IRD, a unified nomenclature system is optimal for capturing the spectrum of IRD gene:disease relationships. We anticipate that these efforts will clarify clinical indications for gene augmentation and similar gene-based therapies as they emerge.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.