The Challenge of VUS in Inherited Retinal Degeneration: Insight from Functional Studies

Advances in DNA sequencing technologies have resulted in an exponential increase in the identification of genetic variants, accompanied by the challenge of variant interpretation. Variants of uncertain significance (VUS) represent a significant problem in the diagnosis and associated patient care pathways for many conditions including inherited retinal degenerations (IRDs). The scale of the challenge is significant, with >40% of variants in genes associated with IRDs classified as VUS. Functional analyses can clarify the pathogenicity of variants, deepen our understanding of disease mechanisms, and importantly, impact patient care. This mini-review focuses on the application of functional analyses in the interpretation of variants in IRD genes: types of assays used and their utility in understanding pathogenicity.