Purpose: This study investigated a three-dimensional indicator in spectral-domain optical coherence tomography (SD-OCT) and established phenotype-genotype correlation in X-linked retinoschisis (XLRS).
Methods: Thirty-seven patients with XLRS underwent comprehensive ophthalmic examinations, including visual acuity (VA), fundus examination, electroretinogram (ERG), and SD-OCT. SD-OCT parameters of central foveal thickness (CFT), cyst cavity volume (CCV), and photoreceptor outer segment length were assessed. CCV was defined as the sum of the areas of cyst cavities in uential B-scans, measured automatically by self-developed software (OCT-CCSEG). Structural changes of the protein associated with missense variants were quantified by molecular dynamics (MD). The correlation between genotype and phenotype was analyzed.
Results: Twenty-seven different RS1 variants were identified, including a novel variant c.336_337insT(p.L113Sfs*8). The average age of onset was 14.76 ± 15.75 years, and the mean VA was 0.84 ± 0.43 logMAR. The mean CCV was 1.69 ± 1.87 mm3, correlating significantly with CFT (R = 0.66; P < 0.01). In the genotype-phenotype analysis of missense variants, CCV significantly correlated with the structural effect on the protein of mutational changes referred to as wild type, including root-mean-square deviation (R = 0.34; P = 0.04), solvent accessible surface area (R = 0.38; P = 0.02), and surface hydrophobic area (R = 0.37; P = 0.03). The amplitude of scotopic 3.0 ERG a-waves and b-waves significantly correlated with the percentage change of the β-strand in the secondary structure (a-wave: R = -0.58, P < 0.01; b-wave: R = -0.53, P < 0.01).
Conclusions: CCV is a promising indicator to quantify the structural disorganization of XLRS retina. The OCT-CCSEG software calculated CCV automatically, potentially facilitating prognosis assessment and development of personalized treatment. Moreover, MD-involved genotype-phenotype analysis suggests an association between protein structural alterations and XLRS severity measured by CCV and ERG.