Abstract
Eyes shut homolog (EYS) is an eye-specific gene that encodes a protein essential for maintaining photoreceptor integrity. The aim of this study was to identify the parameters that characterize the clinical features of EYS-associated retinitis pigmentosa (RP) in patients carrying the c.2528G > A (p.Gly843Glu; G843E) variant. We retrospectively analyzed 127 Japanese patients carrying biallelic pathogenic variants in the EYS gene. To delineate the phenotypic impact of the hypomorphic G843E variant, the cohort was divided into the G843E group (n = 32) and the non-G843E group (n = 52). To account for age-related effects, clinical parameters—including best-corrected visual acuity (BCVA), Humphrey Field Analyzer mean deviation (MD), and ellipsoid zone (EZ) width—were compared between groups within the 40–60-year age range. The G843E group showed a significantly later age of disease onset (p = 0.0085), while BCVA and MD did not differ significantly between groups. Conversely, EZ width was significantly higher in the G843E group (p = 0.019), and multivariable logistic regression identified EZ width as the only statistically significant predictor of G843E variant presence (pseudo-R2 = 0.52). These results suggest that the G843E variant is associated with a milder clinical course, characterized by later onset and better preservation of photoreceptor structure. EZ width may serve as a key structural biomarker for genotype–phenotype correlations in EYS-RP.
Data availability
The datasets generated and/or analyzed during the current study are available in the ClinVar repository. The specific variant reported in this study, *EYS* c.2528G> A (p.Gly843Glu), has been deposited under the accession number SCV004707555. These data, along with other related variants from this cohort (Submission ID: SUB14253519), can be accessed at (https://www.ncbi.nlm.nih.gov/clinvar/submitters/509444).
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Acknowledgements
This study was supported by the Japan Society for the Promotion of Science KAKENHI (grant number 23K15929 to TK and 23H03059 to KMN), grants from the Japan Agency for Medical Research and Development (23ym0126071h0002 and 23ek0109660h0001 to KMN, and 25gm1510006s0105 to TK), Research on Rare and Intractable Diseases, Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan (JPMH23FC1043), and Japan Retinitis Pigmentosa Registry Project. KM was supported by the Nagoya University Doctoral Program for World-leading Innovative and Smart Education and the Nagoya University Convolution of Informatics and Biomedical Sciences on Glocal Alliances program, funded by the Ministry of Education, Culture, Sports, Science and Technology, and from the Japan Science and Technology Support for Pioneering Research Initiated by the Next Generation, Grant Number JPMJSP2125. KM gratefully acknowledges the “Tokai National Higher Education and Research System Make New Standards Program for Next Generation Researchers.” KM also expresses sincere gratitude to Professor Chan of Adelaide University for their valuable academic guidance and support as part of the joint degree program between Nagoya University and Adelaide University.The manuscript was reviewed by a professional English-language editing service (Enago).
Funding
This study was supported by the Japan Society for the Promotion of Science KAKENHI (grant numbers 23K15929 to TK and 23H03059 to KMN) and grants from the Japan Agency for Medical Research and Development (23ym0126071h0002 and 23ek0109660h0001 to KMN and 25gm1510006s0105 to TK), Research on Rare and Intractable Diseases, Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan (JPMH23FC1043), and the Japan Retinitis Pigmentosa Registry Project.
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K.M. analyzed the data and drafted the manuscript. T.K. acquired and analyzed the data, drafted the manuscript, and secured funding for the study. A.F.S., K.G., Y.K., J.O., H.A., and H.U. acquired and analyzed the data. KMN conceptualized the study, drafted the manuscript, and obtained funding. All authors contributed to the study concept and design, and approved the final version of the manuscript.
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Muto, K., Sajiki, A.F., Goto, K. et al. Phenotypic features of EYS-associated retinitis pigmentosa with the c.2528 G > A (p.Gly843Glu) mutation in a Japanese cohort. Sci Rep (2026). https://doi.org/10.1038/s41598-026-46464-3
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DOI: https://doi.org/10.1038/s41598-026-46464-3
