Seeing in Color: Inclusion and Characterization of Hereditary Eye Disease in African Americans.

Purpose: Hereditary eye diseases (HEDs) are individually rare but affect millions globally. The era of molecular genetics has ushered major advances in the study of these disorders; however, the inclusivity and population diversity of this research is unknown. Questions on the accuracy and applicability of these findings in diverse populations, especially African American patients, came up consistently during counselling sessions. This also raised the possibility of missed opportunities for broader understanding of these rare diseases. We conducted a literature review to measure the representation of African Americans in genomic research surrounding nine HEDs. Methods: A detailed literature search using a predetermined set of search terms for each of nine HED categories was performed across PubMed, Embase, Web of Science, and Scopus focusing on studies published between Jan 1990 and July 2021. Predetermined inclusion criteria were applied to filter the sources. Results: We identified 46 studies clearly reporting HED characterization in African Americans. Analysis of these inclusive studies revealed unique findings demonstrating the known usefulness of including diverse cohorts in genomics research. Conclusions: HED characterization in diverse participants, specifically African Americans, is identified as a knowledge gap area. Genomic research is more applicable to patients when conducted in populations that share their ancestral background. Greater inclusion of African Americans in ophthalmic genetics research is a scientific imperative and a needed step in the pursuit of the best possible patient care for populations of all ancestries. Translational Relevance: This work reveals gaps in genomic research in African Americans with HEDs.

Biallelic Loss-of-Function Variants in UBAP1L and Nonsyndromic Retinal Dystrophies.

Importance: Inherited retinal dystrophies (IRDs) present a challenge in clinical diagnostics due to their pronounced genetic heterogeneity. Despite advances in next-generation sequencing (NGS) technologies, a substantial portion of the genetic basis underlying IRDs remains elusive. Addressing this gap seems important for gaining insights into the genetic landscape of IRDs, which may help improve diagnosis and prognosis and develop targeted therapies in the future. Objective: To provide a clinical and molecular characterization of 6 patients with IRDs with biallelic disease-causing variants in a novel candidate IRD disease gene. Design, Setting, and Participants: This multicenter case series study included 6 patients with IRDs from 4 tertiary hospitals (in the US: National Eye Institute, National Institutes of Health Clinical Center; in the UK: Moorfields Eye Hospital, Royal Liverpool University Hospital, Birmingham Women's and Children's). Exposures: Biallelic disease-causing variants in the novel candidate IRD disease gene, UBAP1L. Main Outcome and Measures: Participants underwent comprehensive clinical ophthalmic assessments to characterize the features of retinal dystrophy. Exome and genome sequencing revealed candidate variants in the UBAP1L gene; no other plausible disease variants in known IRD genes were identified. A minigene assay provided functional insights for a noncanonical splice variant, and a knockout mouse model was used for in vivo functional elucidation. Results: Four homozygous UBAP1L variants were identified in the affected individuals from 6 families, including 2 frameshift variants (c.710del and c.634_644del), 1 canonical splice variant (c.121-2A>C), and 1 noncanonical splice variant (c.910-7G>A), which was shown to cause aberrant splicing and frameshift in a minigene assay. Participants presented with retinal dystrophy including maculopathy, cone dystrophy, and cone-rod dystrophy. Single-cell RNA sequencing of the retina showed that human UBAP1L is highly expressed in both cones and retinal pigment epithelium, whereas mouse Ubap1l is highly expressed in cone cells only. Mice with truncation of the C-terminal SOUBA domain did not manifest retinal degeneration up to 15 months of age. Conclusions and Relevance: Study results reveal clinical and genetic evidence that loss of UBAP1L function was associated with inherited retinopathy in humans. These findings hold promise for improved clinical diagnostics, prognosis, and the potential development of targeted therapies for individuals affected by IRDs.

OUTER RETINAL MICROCAVITATIONS IN RETINITIS PIGMENTOSA : A Novel Optical Coherence Tomography Finding Common in RP1 -Related Retinopathy.

PURPOSE: To describe a novel optical coherence tomography (OCT) finding of outer retina microcavitations in RP1 -related retinopathy and other retinal degenerations. METHODS: Medical charts and OCT images of 28 patients with either autosomal dominant retinitis pigmentosa or autosomal recessive retinitis pigmentosa RP1 -related retinopathy were reviewed. Outer retina microcavitations were defined as hyporeflective OCT structures of at least 30 µ m in diameter between the ellipsoid zone and retinal pigment epithelium. Comparison was made based on the following metrics: (1) functional measures including best-corrected visual acuity and color discrimination errors on D-15 test; and (2) structural measures, including central subfield, average macular thickness, and preserved transfoveal ellipsoid zone width. Mann-Whitney tests were used for comparisons with significance set at P < 0.05. The specificity of microcavitations for RP1 -related retinopathy was estimated against 26 patients with non- RP1 retinitis pigmentosa. RESULTS: Among 15 included patients, microcavitations were found in at least one eye of all patients with arRP and 7/12 (58%) of patients with adRP. Patients with adRP and microcavitations were older at the time of examination (51 vs. 43 years of age; P = 0.04) and their eyes demonstrated worse best-corrected visual acuity (0.09 vs. 0 logMAR; P = 0.008), reduced central subfield (256 vs. 293 µ m; P = 0.01), average macular thickness (241 vs. 270 µ m; P = 0.02), and shorter transfoveal ellipsoid zone widths (1.67 vs. 4.98 mm; P < 0.0001). The finding of microcavitations showed a specificity of 0.92 for RP1 -related retinopathy. CONCLUSION: A novel OCT finding of outer retina microcavitations was commonly observed in patients with RP1 -related retinopathy. Eyes with outer retinal OCT microcavitations had worse visual function and more affected central retinal structure.

RPGR: Deep Phenotyping and Genetic Characterization With Findings Specific to the 3'-end of ORF15.

Purpose: To describe a group of patients with retinitis pigmentosa GTPase regulator (RPGR)-related retinopathy with a tapetal-like retinal sheen and corresponding changes in the reflectivity of the ellipsoid zone on optical coherence tomography (OCT) imaging. Methods: A retrospective case series of 66 patients with a disease-causing variant in RPGR was performed. An expert examiner, masked to patient demographics, clinical evaluations, and specific RPGR variant, analyzed color fundus photographs for the presence of a tapetal-like retinal sheen and assessed OCT images for the presence of an abnormally broad hyper-reflective band in the outer retina. Longitudinal reflectivity profiles were generated and compared with healthy controls. Results: Twelve patients (18.2%) had a retinal sheen on color images that cosegregated with an abnormally broad hyper-reflective ellipsoid zone band on OCT imaging. Three-fourths of these patients were male, had a cone-rod dystrophy, and had pathogenic RPGR variants located toward the 3'-end of ORF15. This group had a different longitudinal reflectivity profile signature compared with controls. After a period of prolonged dark adaptation, the abnormal hyper-reflective band on OCT became less apparent, and the outer retinal layers adopted a more normal appearance. Conclusions: RPGR-related retinopathy should be considered for males presenting with retinal sheen, abnormal ellipsoid zone hyper-reflectivity, and cone or cone-rod dysfunction on ERG, and pursued with molecular testing. Our results have implications for understanding the role of the C-terminal domain encoded by RPGR ORF15 in the phototransduction cascade. Further, the findings may be important to incorporate into both inclusion criteria and outcome measure developments in future RPGR-related cone or cone-rod dystrophy clinical trials.