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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.

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.