eP137: Defining the disease entity for inherited retinal disorders – Lump or split?

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). Defining the disease entity for gene curation has presented a challenge for this group due to the significant clinical and genetic heterogeneity associated with IRD; these disorders can be non-syndromic (ie, affecting only the eye) or they can occur with additional manifestations as part of a syndrome. Furthermore, multiple disease entities in OMIM and/or multiple phenotypes associated with the same gene or genotypes exist. Many of these entities are historic and are likely to represent a single disease entity for a single gene with a phenotypic spectrum. Here, we present pertinent examples of the lumping and splitting process when defining the disease entity for clinical validity curation of IRD genes. 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 the guidance of the ClinGen Lumping and Splitting Working Group, performing precuration of IRD genes in order to decide which phenotypes should be lumped or split for curation. To date, the ClinGen Retina GCEP has classified the clinical validity of over 30 gene-IRD relationships and posted the results on the ClinGen website (www.clinicalgenome.org). Some genes are associated with one well-defined clinical phenotype eg, CHM: Choroideremia, RS1: X-linked retinoschisis, and GRK1: Oguchi disease. However, for many genes, precuration has led to the identification of multiple overlapping retinal phenotypes. For example, precuration of RPE65 identified Leber congenital amaurosis 2 and Retinitis pigmentosa 20 as autosomal recessive disease entities that share a common molecular mechanism and exhibit phenotypic overlap and intrafamilial heterogeneity consistent with a spectrum of disease. The Retina GCEP found this evidence sufficient to lump these disease entities into a single recessive RPE65 curation. Multiple autosomal recessive disease entities associated with the RLBP1, RDH5, CDH3, and GUCY2D genes were similarly found suitable for lumping, based on evidence consistent with a single spectrum of disease for each gene. While autosomal dominant disease entities associated with RPE65 and GUCY2D were considered for lumping with their recessive counterparts according to a semidominant mode of inheritance, their underlying molecular mechanisms were sufficiently distinct to justify splitting them into separate curations. Due to the significant locus heterogeneity and the broad, overlapping spectrum of clinical presentations linked to many genes implicated in IRD, defining the disease entity for curation of genes implicated in IRD is challenging. The ClinGen Retina GCEP has followed the ClinGen Lumping and Splitting guidelines to determine the appropriate disease entity, or entities, for curation. This process has also led to questions around terminology, including assigning an appropriate Mondo ID to the introduced disease entities. As this is a requirement of the ClinGen framework, the Retina GCEP is also working on revising the Mondo ontology for IRD. We expect these efforts to result in improved classification and coding, and to have a significant impact on routine care.