Juvenile open‐angle glaucoma (JOAG) is a severe type of glaucoma with onset before age 40 and dominant inheritance. Using exome sequencing we identified 3 independent families from the Philippines with novel EFEMP1 variants (c.238A>T, p.Asn80Tyr; c.1480T>C, p.Ter494Glnext*29; and c.1429C>T, p.Arg477Cys) co‐segregating with disease. Affected variant carriers (N = 34) exhibited severe disease with average age of onset of 16 years and with 76% developing blindness. To investigate functional effects, we transfected COS7 cells with vectors expressing the three novel EFEMP1 variants and showed that all three variants found in JOAG patients caused significant intracellular protein aggregation and retention compared to wild type and also compared to EFEMP1 variants associated with other ocular phenotypes including an early‐onset form of macular degeneration, Malattia Leventinese/Doyne's Honeycomb retinal dystrophy. These results suggest that rare EFEMP1 coding variants can cause JOAG through a mechanism involving protein aggregation and retention, and that the extent of intracellular retention correlates with disease phenotype. This is the first report of EFEMP1 variants causing JOAG, expanding the EFEMP1 disease spectrum. Our results suggest that EFEMP1 mutations appear to be a relatively common cause of JOAG in Filipino families, an ethnically diverse population.

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Purpose We compare anterior segment characteristics of Filipino- versus Chinese- and Caucasian-Americans to describe the differences in risk factors among each ethnic group. Methods A cross-sectional study was conducted among Filipino, Chinese, and Caucasian subjects without glaucoma who underwent a standardized set of ocular examinations and anterior segment optical coherence tomography (Visante ASOCT) imaging. Zhongshan Angle Assessment Program (ZAAP) 4 was used for ASOCT image analysis. The following quantitative parameters wereobtained from ZAAP: (1) angle opening distance (AOD500, AOD750), angle recess area at 750 μm (ARA), and trabecular-iris space area at 500 and 750 μm (TISA500, TISA750); (2) iris parameters, including iris thickness at 750 μm from the scleral spur (IT750), iris area (IArea), iris curvature or convexity (ICurv), and pupil diameter; 3) anterior chamber parameters; and (4) lens vault. Results The Filipino (122 eyes), Chinese (121 eyes), and Caucasian (111 eyes) subject groups were similar in terms of demographic and clinical characteristics. We reported pairwise comparisons of Filipino parameter values to Chinese or Caucasian values, represented as B-coefficients and P values. In multivariate analysis, Filipinos had narrower angles than Caucasians (AOD750, TISA 500, TISA 750, ARA, P < 0.001). Filipinos had thicker and more convex irises than Caucasians (IT750, IT 2000, ICurv P < 0.003). Angle and iris parameters were similar overall for Filipino and Chinese. Conclusions Filipinos appear to have more convex and thicker irises, smaller lens vault and narrower angles compared to Caucasians. Filipino eyes closely resembled Chinese eyes with similar iris and angle parameters. Translational Relevance The anatomic angle parameters of Filipinos may contribute to angle closure risk among this population, thus ASOCT and thorough angle analysis is recommended in this population.

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