X-Linked Retinoschisis: Deep Phenotyping and Genetic Characterization

Purpose: To examine the genetic and clinical features in children and adults with X-linked retinoschisis (XLRS). Design: Single-center consecutive, retrospective, observational study. Participants: Adults and children with molecularly confirmed XLRS followed up between 1999 and 2020. Methods: Analysis of genetic, clinical, and retinal imaging findings, including OCT and fundus autofluorescence (FAF), cross-sectionally and longitudinally, was performed. Main Outcomes Measures: RS1, variants, type of variants and phenotype correlations, age of onset, complications rates and types, fundoscopy findings, OCT metrics, FAF patterns, correlations including between best corrected visual acuity (BCVA) and age, and OCT characteristics. Results: One hundred thirty-two male patients were identified harboring 66 retinoschisin 1 variants, with 7 being novel. The mean age at onset was 16.5 years (range, 0–58 years). Seventy-one patients (71/75 [94.7%]) were symptomatic at presentation; all had decreased best-corrected visual acuity (BCVA). Funduscopy findings were symmetric in 104 patients (104/108 [96.3%]), with the most common finding being macular schisis (82.4%), whereas peripheral retinoschisis was present in 38.9% and macular atrophy was present in 11.1%. Twenty patients (18.5%) demonstrated complications (vitreous hemorrhage, retinal detachment, or both). Mean BCVA was 0.65 logarithm of the minimum angle of resolution (logMAR; Snellen equivalent, 20/89) in the right eye and 0.64 logMAR (Snellen equivalent, 20/87) in the left eye. Mean BCVA change over a mean interval of 6.7 years was 0.04 and 0.01 logMAR for right and left eyes, respectively. A normal FAF pattern was identified in 16 of 106 eyes (15.1%); 45 eyes (42.5%) showed a spoke-wheel pattern, 13 eyes (12.3%) showed foveal hyperautofluorescence, and 18 eyes (17.0%) showed a central reduction in signal. In total, 14 patients demonstrated evidence of progression on FAF over time. On OCT, foveoschisis was observed in 172 eyes (172/215 [80%]), parafoveal schisis was observed in 171 eyes (171/215 [79.5%]), and foveal atrophy was observed in 44 eyes (44/215 [20.5%]). Cystoid changes were localized to the inner nuclear layer (172/181 eyes [95%]), the outer nuclear layer (97/181 [53.6%]), and the ganglion cell layer (92/181 [50.8%]). Null variants were associated with worse final BCVA and aforementioned complications. Conclusions: X-linked retinoschisis is highly phenotypically variable, but with relative foveal and BCVA preservation until late adulthood, allowing more accurate prognostication. The slowly (often minimally) progressive disease course may pose a challenge in identification of early end points for therapeutic trials aimed at altering the kinetics of degeneration.