X-linked Retinoschisis: Deep Phenotyping and Genetic Characterization

ABSTRACT Objective To examine the genetic and clinical features in children and adults with XLRS. Design Single-center consecutive, retrospective, observational study. Setting Single tertiary referral center. Participants Adults and children, with molecularly confirmed XLRS, followed up between 1999 and 2020. Main Outcomes and Measures Genetic, clinical and retinal imaging findings, including optical coherence tomography (OCT) and fundus autofluorescence (FAF), cross-sectionally and longitudinally; and explore correlations including between best corrected visual acuity (BCVA) and age, and OCT characteristics. Results One hundred and thirty-two males were identified, harbouring 66 RS1 variants, with seven being novel. The mean age of onset was 16.5 years (range 2 to 55 years). Seventy-one patients (71/75, 94.7%) were symptomatic at presentation; all had decreased BCVA. Fundoscopy 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 in 11.1%. Twenty patients (18.5%) developed complications (vitreous haemorrhage and/or retinal detachment). Mean BCVA was 0.65 LogMAR (20/89 Snellen) in the right eye and 0.64 LogMAR (20/87 Snellen) 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. FAF was normal in 16 of 106 eyes (15.1%); 45 eyes (42.5%) showed a spoke-wheel pattern, 13 (12.3%) had foveal hyperautofluorescence, while 18 (17.0%) had central reduction in signal. In total, 14 patients had evidence of FAF progression over time, indicated by change in the FAF pattern. On OCT, foveoschisis was observed in 172 eyes (172/215, 80%), parafoveal schisis in 171 (171/215, 79.5%), and foveal atrophy in 44 (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 and Relevance XLRS is highly phenotypically variable but with relative foveal preservation (and associated BCVA) until late adulthood, allowing more accurate prognostication. The slowly (often minimally) progressive disease course may pose a challenge in identification of early endpoints for therapeutic trials aimed at altering kinetics of degeneration.