韩国EYS相关视网膜变性：遗传、表型和自然史

PURPOSE: To delineate the clinical and genetic spectrum of EYS-associated retinal degeneration (EYS-RD) and to quantify longitudinal progression of retinal structure and visual function.

DESIGN, SETTING, AND PARTICIPANTS: Multicenter retrospective cohort study at eight tertiary referral centers in South Korea, enrolling 126 patients with biallelic EYS variants.

MAIN OUTCOME MEASURES: Annual progression rates of best-corrected visual acuity (BCVA, logMAR), ellipsoid zone width (EZW,) and area (EZA) on serial spectral-domain OCT, estimated using three-level linear mixed-effects models.

RESULTS: Among 126 patients (63 females, 50.0%; median follow-up, 5.2 years [IQR, 1.2-9.0]), serial OCT was analyzable in 163 eyes of 84 patients, of which 113 eyes had four time points and 152 had three or more, giving 591 EZW observations. In three-level mixed-effects models, EZW declined by 124.1 μm/year (95% CI, 106.4-141.8) and square root-transformed EZA by 0.105 mm/year (95% CI, 0.089-0.120), while BCVA deteriorated by 0.043 logMAR/year (95% CI, 0.025-0.060). Decline was linear over the observed interval: the median within-eye R² for a straight-line fit was 0.900 and a quadratic term for time was not significant (P = .239). A total of 66 unique EYS variants were identified, including 20 novel variants; structural variants occurred in 11 patients (8.7%), including large deletions encompassing non-coding exons 1-2 and a deep-intronic variant (c.1766+2635G>A) activating a cryptic exon. Progression did not differ between patients with biallelic LoF genotypes and carriers of at least one missense allele (time × genotype interaction, P = .923).

CONCLUSIONS: This large multicenter study provides quantitative benchmarks for EZW and EZA progression in EYS-RD, with a relative EZW losses of approximately 4.6% per year and that may serve as reference endpoints for gene therapy trials. Despite linear structural decline, the absence of genotype-phenotype correlation underscores phenotypic heterogeneity and suggests that factors beyond the primary genetic defect contribute to disease variability.