FOXP4 Variants Are Associated With Plateau Iris and Angle Closure Glaucoma.

PURPOSE: Angle closure glaucoma (ACG) is a common cause of adult-onset vision loss that often presents with iris abnormalities and short axial lengths. Although it is heritable, little is known about the genetic risk factors underlying this condition. We thus conducted a disease gene discovery study in a family exhibiting an autosomal dominant triad of ACG, plateau iris, and short axial lengths. METHODS: Pooled exome sequencing was performed to identify coding variants contributing to disease. The spatiotemporal expression pattern of candidate gene FOXP4 was evaluated via immunostaining in embryonic mouse eyes. YFP-tagged mutant and wild-type FOXP4 proteins were expressed in HEK-293T and ARPE-19 cells to evaluate nuclear localization, and an SRPX2-Luciferase reporter was used to ascertain variant effects on transcriptional regulation. We also reviewed more than 20,000 patients (primarily from the UK Biobank) diagnosed with glaucoma and/or disorders of the iris and ciliary body for additional FOXP4 variants and functionally validated them as described. RESULTS: We identified a single likely pathogenic variant in transcription factor FOXP4: c.1433A>G (p.Q478R). FOXP4 is highly expressed in multiple structures relevant to the drainage angle, such as the periocular mesenchyme, iris, ciliary body, and cornea. The p.Q478R variant appears to be a hypomorphic allele that retains its transcriptional activity, but often mislocalizes to cytosolic aggregates. Comparable variants, including one found in another glaucoma patient, show similar mislocalization that may indicate protein instability. CONCLUSIONS: These data suggest that FOXP4 is important for anterior segment development and that variants therein are rare risk factors for ACG.