Rare variants in MIR184 are a novel genetic cause of Fuchs endothelial corneal dystrophy.
PURPOSE: To identify novel genetic causes of Fuchs endothelial corneal dystrophy (FECD) within a genetically unsolved patient cohort lacking repeat expansions in the TCF4 gene (Exp-). METHODS: A rare variant analysis framework (CoCoRV) was applied to exome data, in combination with in silico modeling, luciferase reporter, and RNA-seq analysis to characterize transcriptome-wide consequences of identified variants. RESULTS: A gene burden analysis identified MIR184, a microRNA encoding gene, to be enriched for rare pathogenic variants within the studied Exp- FECD cohort. In total, 2 noncoding rare variants were identified in 4 unrelated FECD probands: NR_029705.1:n.58G>A and n.73G>T. Both variants altered highly conserved mature sequence residues, were predicted to induce hairpin structural changes, and were experimentally determined to disrupt microRNA-mRNA interactions. RNA-seq of transfected human corneal endothelial cells revealed that the mutants elicited distinct transcriptomic profiles. Enriched KEGG pathways included PI3K-Akt signaling, focal adhesion, and immune response, revealing shared pathogenic mechanisms between MIR184-associated FECD and the more common TCF4 repeat expansion-mediated form of disease. CONCLUSION: MIR184 variants are a novel rare genetic cause of FECD, and common pathways of transcriptomic dysregulation are shared across genetically distinct subtypes of the disease. These pathways may serve as future gene agnostic targets for therapeutic interventions.