Two-dimensional inner- and outer-retinal OCT phenotyping in X-linked retinoschisis: cross-sectional associations with visual acuity

X-linked retinoschisis (XLRS) exhibits substantial phenotypic heterogeneity, but existing optical coherence tomography (OCT) classifications emphasize schisis morphology without independently assessing outer-retinal integrity. To better characterize structure–function relationships, we developed a two-dimensional inner-/outer-retinal (I/O) OCT classification and evaluated its cross-sectional associations with best-corrected visual acuity (BCVA) and age, while describing RS1 variant distribution. This retrospective study included 72 patients (139 eyes) with molecularly confirmed XLRS. Foveal OCT scans were classified by inner-retinal morphology (I1–I4) and outer-retinal integrity (O1–O3). Age-adjusted linear mixed-effects models with patient-specific random intercepts assessed associations with logMAR BCVA, with I and O entered simultaneously. Exploratory analyses assessed nine combined phenotypes using Holm-adjusted comparisons and the cross-sectional age–I4 association using a patient-clustered logistic generalized estimating equation. I1, I2, I3, and I4 occurred in 97 (69.8%), 4 (2.9%), 9 (6.5%), and 29 (20.9%) eyes, respectively. O1, O2, and O3 occurred in 58 (41.7%), 39 (28.1%), and 42 (30.2%) eyes, respectively. Inner-retinal morphology was associated with BCVA overall ( P = 0.009). Compared with I1, adjusted logMAR BCVA was worse by 0.485 for I2 (95% CI, 0.165–0.805, P = 0.003) and 0.281 for I3 (95% CI, 0.038–0.523, P = 0.023). Outer-retinal integrity was also associated with BCVA overall ( P < 0.001). Compared with O1, adjusted logMAR BCVA was worse by 0.232 for O2 (95% CI, 0.105–0.359, P < 0.001) and 0.459 for O3 (95% CI, 0.311–0.608, P < 0.001). Combined I/O phenotype was associated with BCVA overall ( P < 0.001). Each additional year of age was associated with higher odds of exhibiting I4 morphology (OR, 1.131, 95% CI, 1.058–1.210, P < 0.001). RS1 variants were missense in 64 patients (123 eyes), protein-truncating in 7 (14 eyes), and an in-frame duplication in 1 (2 eyes). The I/O framework captures two complementary dimensions of central macular structure, each independently associated with concurrent BCVA. With prospective longitudinal validation, it may support standardized phenotype-based severity stratification and structural assessment in XLRS natural-history studies and gene therapy trials.