A Classification System Using Optical Coherence Tomography for X-linked Retinoschisis and Its Association with Genetic Variants

A Classification System Using Optical Coherence Tomography for X-linked Retinoschisis and Its Association with Genetic Variants | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A Classification System Using Optical Coherence Tomography for X-linked Retinoschisis and Its Association with Genetic Variants Seok Jae Lee, Richul Oh, Hyun Chul Jeong, Seung Woo Choi, Eun Kyoung Lee, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7363735/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Background To develop and apply a novel optical coherence tomography (OCT)-based classification system for X-linked retinoschisis (XLRS) and evaluate its association with best-corrected visual acuity (BCVA) and RS1 genotypes. Methods In this retrospective cohort study, 72 patients (139 eyes) with molecularly confirmed XLRS from a tertiary referral center were analyzed. Spectral-domain OCT images were classified into five phenotypic types (1A, 1B, 2, 3, 4, and 5A, 5B) based on foveoschisis configuration and outer retinal layer integrity. Associations between OCT types and BCVA, age, and genotype (truncating vs. missense) were evaluated. Results A total of 139 eyes were analyzed (mean age 15.5 ± 9.3 years). BCVA ranged from 2.0 to 0.18 logMAR (mean 0.68 ± 0.39). Type 1A had the best BCVA, significantly outperforming Types 2, 3, 4, and 5B ( p <0.01). Type 5A showed comparable BCVA to 1A and outperformed all other types except 1A and 1B. Types 3, 4, and 5B exhibited worse BCVA, with complete outer retinal layer loss. No significant BCVA or age differences were observed between truncating and missense variants ( p =0.692, p =0.559). However, truncating variants were associated with older age within Type 1 (OR = 1.13, 95% CI: 1.02–1.24, p=0.016), suggesting a slower but progressive visual decline compared to missense variants. Conclusions This OCT-based classification reflects structural severity and correlates with visual function in XLRS. It supports phenotype-based risk stratification and may guide patient selection and monitoring in gene therapy trials for XLRS. Genotype Mutation spectrum Optical coherence tomography X-linked Retinoschisis Figures Figure 1 Figure 2 INTRODUCTION X-linked retinoschisis (XLRS; Online Mendelian Inheritance in Man [OMIM], #312700) is a rare inherited retinal disorder first described by Haas in 1898. It is caused by mutations in the RS1 gene, located on the distal short arm of the X chromosome (Xp22.13; OMIM, #300839),[ 1 ] which encodes retinoschisin, a 224-amino acid extracellular lectin that binds to the retinal cell plasma membrane and enables cell-to-cell adhesion [ 2 ]. This X-linked monogenic disease is characterized by splitting of the neural retinal layer, fovea-macular cystic schisis cavities, and central vision loss [ 3 ]. XLRS almost exclusively occurs in males and leads to progressive vision loss, often presenting as school-age reading difficulties [ 4 – 6 ]. To date, over 450 distinct variants in the RS1 gene have been identified as underlying causes of XLRS, the majority of which include point mutations, insertions, deletions, and splice-site alterations [ 7 – 9 ] ( https://databases.lovd.nl/shared/genes/RS1 ). Several studies have investigated the genotypic and phenotypic characteristics of patients with XLRS, focusing primarily on clinical features such as visual acuity (VA), fundus photography, optical coherence tomography (OCT), and electroretinogram (ERG) findings in relation to specific mutation types [ 10 – 14 ]. However, to date, no definitive genotype-phenotype correlations have been reported, due to the relatively small sample sizes of individual studies and variability in phenotypic expression, even among members of the same families [ 4 , 14 , 15 ]. Among the methods for phenotypic measurements, OCT is widely utilized to assess anatomical changes such as macular schisis, outer retina atrophy, and retinal detachment. Compared to fundoscopy [ 4 ] or ERG [ 16 , 17 ], OCT plays a pivotal role in the objective diagnosis, staging, and monitoring of XLRS [ 18 ]. It is also serves as a reliable endpoint in preclinical studies [ 19 , 20 ] and clinical trials [ 21 , 22 ] of gene therapy for XLRS. In 2006, Prenner et al. introduced a classification system for XLRS based on time domain (TD)-OCT findings and fundus examination, categorizing patients into four phenotypes: foveal, foveo-lamellar, complex, and foveo-peripheral types [ 23 ]. Among these, the complex type was the most common, followed by the foveal-lamellar type. However, no correlation was identified between schisis type, layer involvement, and specific mutations [ 24 , 25 ]. This earlier system lacks critical information regarding disease progression and its correlation to VA, as it does not consider the status of outer retinal layers, such as ellisoid zone (EZ), and interdigitation zone (IZ). The association between the integrity of outer retinal layers and VA changes has been well established in numerous retinal diseases, including diabetic retinopathy [ 26 – 28 ], age-related macular degeneration [ 29 , 30 ], and even in XLRS, as demonstrated in our previous study [ 31 ]. To the best of our knowledge, no studies have evaluated differences in VA and genetic variants across detailed OCT types. In this context, we have systemically reviewed and classified OCT findings to better reflect VA and disease progression, as well as to assess potential genotype-phenotype associations among the OCT types. PATIENTS AND METHODS Study Population Patients clinically diagnosed with X-linked retinoschisis (XLRS) who had at least two recorded clinical visits at a single tertiary care center, Seoul National University Hospital (Seoul, Republic of Korea), were retrospectively identified for this study. Inclusion criteria required a confirmed XLRS diagnosis based on clinical findings, family history, and molecular confirmation of a potentially pathogenic variant in the RS1 gene. Patients were excluded if they were unable to undergo spectral-domain optical coherence tomography (SD-OCT), had a history of vitrectomy, or presented with the retinal detachment or disorganized retinal phenotypes. A total of 72 patients from 64 families, encompassing 35 distinct RS1 genetic variants, were included in the analysis (Table 1 ). The study was approved by the Institutional Review Board (IRB) of Seoul National University Hospital, Seoul, South Korea (IRB number: E-2406-001-1539). All research procedures adhered to the ethical principles outlined in the Declaration of Helsinki. The requirement for informed consent was waived by the local ethics committee due to the use of pseudonymized patient data. Table 1. Flow Chart of X-Linked Retinoschisis Patients. SD-OCT = Spectral-domain optical coherence tomography; RD = retinal detachment; RS1 = retinoschisin 1; M = missense mutation; T = truncated mutation Clinical Data Collection For 72 patients, the specific variant in the RS1 gene was identified either directly or derived from a family member. These variants were molecularly confirmed through Sanger sequencing or whole-exome sequencing. BCVA was assessed at the last OCT follow-up. To evaluate VA across genotype variants, Snellen chart measurements were converted to logarithm of the minimum angle of resolution (logMAR) values: 2.0 logMAR used for counting fingers, 3.0 logMAR for hand motions, 3.7 logMAR for light perception. All patients included in the study underwent OCT scans using a Spectralis SD-OCT (Heidelberg Engineering, Heidelberg, Germany). Automated alignment and data analysis were performed using Heidelberg Eye Explorer (HEYEX) software. Defects in outer retinal microstructures, including the interdigitation zone (IZ), ellipsoid zone (EZ), were evaluated within a 1-mm radius from the foveal center using vertical and horizontal central OCT images. These defects were categorized into three categories: intact, partially disrupted, and absent. The presence of specific OCT findings, including foveoschisis and defects, was determined by consensus among three observers (Seok Jae Lee, Richul Oh, and Kihwang Lee). In cases where the vertical and horizontal scans showed discordant findings — for example, an intact EZ in the vertical scan but partial disruption in the horizontal scan — we categorized the microstructure based on the more preserved direction, prioritizing structural preservation. Qualitative and quantitative analysis of OCT findings were performed at the patients’ latest follow-up. For genotype-phenotype association analysis, RS1 variants were classified as missense variants or truncating variants (including deletions, nonsense mutations, splice site mutations, and frameshift mutations). Truncation status was confirmed through literature review [ 7 , 11 , 17 , 32 – 36 ]. Classification of OCT Findings The OCT-based phenotypes of XLRS patients were classified into five distinct types (Fig. 1 ). Types 1A, 1B, 2, 5A, and 5B are all categorized primarily by the status of the outer retinal layers (EZ and IZ), which are visibly preserved, partially disrupted, or absent in the respective representative images. In contrast, Types 3 and 4 are defined by distinct morphological features: lamellar hole and extreme thickening, respectively. Type 1A: Foveoschisis with intact outer retinal layers, regardless of the involvement of schisis in the outer nuclear layer (ONL) and/or inner nuclear layer (INL). Type 1B: Foveoschisis with partially intact outer retinal layers, regardless of the involvement of schisis in the ONL and/or INL. Type 2: Foveoschisis with total loss of the outer retinal layers, regardless of the involvement of schisis in the ONL and/or INL. Type 3: Degenerative lamellar hole with or without outer retintal layers. The term “degenerative lamellar hole” refers to a central macular lesion characterized by a foveal depression with residual inner retinal tissue. This condition reflects a degenerative remodeling process, likely following the collapse of a schisis cavity, and is anatomically distinct from a full-thickness macular hole. Only four eyes were classified as Type 3, with three demonstrating complete loss of the outer retinal layers and one eye showing preserved outer retinal layers. However, all of these eyes exhibited poor visual outcomes, with BCVA worse than 0.05. Type 4: Extensive foveoschisis (macular average thickness exceeding 800 µm with no outer retinal layers) The cut-off value of 800 µm used to define Type 4 was determined based on the internal distribution of macular thickness within our cohort. This threshold was chosen to distinguish eyes with anatomically excessive foveoschisis from those with only moderate thickening, such as in Type 2. Given that typical XLRS-related foveoschisis usually falls within the 400–600 µm range, values exceeding 800 µm were rare—occurring in fewer than 10% of eyes in our cohort.. Type 5A: Atrophic type with intact outer retinal layers. Type 5B: Atrophic type with loss of the outer retinal layers. Statistical Analysis All statistical analyses were performed using Python version 3.9.19 ( https://www.python.org ), along with SciPy library (version 1.13.1) and the Statsmodels library (version 0.14.4). For descriptive analyses, continuous variables were presented as either means with standard deviations (SD) or medians with interquartile ranges (IQRs)., and categorical variables were expressed as frequency (%). Statistical significance was set at p < 0.05. To account for the confounding effects of binocular data from the same patients, a linear mixed model was used to analyze continuous variables, and a generalized estimating equation was applied for categorical variables. For multiple pairwise comparisons, the Benjamini-Hochberg adjustment method was employed to minimize the risk of type I errors. RESULTS Clinical Characteristics and Visual Function in X-linked Retinoschisis A total of 72 patients from 64 families, harboring 35 distinct RS1 genetic variants, were included in this analysis. Among these patients, 40 (55.6%) reported a positive family history. The median age at the last OCT examination was 12.7 years (IQR, 9.0–19.6 years; range, 4.3–43.6 years). The mean best-corrected visual acuity (BCVA) at the last OCT examination was 0.68 ± 0.39 logMAR (range, 0.18-2.0) (Table 2 ). Table 2 Demographics and Baseline Characteristics of X-Linked Retinoschisis Patients. General information of 72 patients from families with RS1 mutation Characteristics Data XRLS patients (n = 72) Positive family history 55.6% (40/72) Gender Male 100.0% (72/72) Age at the last OCT examination (years) Mean ± SD 15.5 ± 9.3 Median (IQR) 12.7 (Q1: 9.0, Q3: 19.6) Range 4.3–43.6 BCVA (n = 139 eyes) Mean ± SD, in logMAR 0.68 ± 0.39 Median BCVA, in logMAR (IQR) 0.50 (Q1: 0.40, Q3: 0.80) Range 0.18-2.0 BCVA = best corrected visual acuity; IQR = interquartile range; logMAR = logarithm of the minimum angle of resolution; n. = number; OCT = optical coherence tomography; Q = quarter; RS1 = retinoschisin 1; SD = standard deviation; XLRS = X-linked retinoschisis Demographic Data based on the OCT Types in Patients with X-linked Retinoschisis A total of 139 eyes of 72 patients were included in the analysis. Among the OCT types, Type 1 was the most common, with Type 1A observed in 51 eyes (36.7%) and Type 1B observed in 31 eyes (22.3%) out of 139 eyes. The mean age of patients with Type 1A and Type 1B was 12.08 ± 6.42 years and 15.03 ± 8.38 years, respectively. Type 2 was identified in 15 eyes (10.8%), with a mean age of 14.95 ± 6.07 years. Type 3, representing the least common OCT type, was identified in 4 eyes (2.9%) with a mean age of 13.61 ± 4.92 years. Type 4 was present in 9 eyes (6.5%) with a mean age of 13.29 ± 5.32 years. Type 5 had the oldest mean age, being atrophic type. Type 5A was observed in 14 eyes (10.0%) with a mean age of 20.64 ± 14.75 years, while type 5B was identified in 15 eyes (10.8%) with a mean age of 26.07 ± 10.18 years (Table 3 ). Table 3 Frequency, BCVA, and Age According to OCT Types. OCT types n/total (%) (n = 139 eyes) 1A 51/139 (36.7%) Mean ± SD in logMAR 0.46 ± 0.18 Mean ± SD in age 12.08 ± 6.42 1B 31/139 (22.3%) Mean ± SD in logMAR 0.69 ± 0.33 Mean ± SD in age 15.03 ± 8.38 2 15/139 (10.8%) Mean ± SD in logMAR 0.74 ± 0.28 Mean ± SD in age 14.95 ± 6.07 3 4/139 (2.9%) Mean ± SD in logMAR 1.35 ± 0.47 Mean ± SD in age 13.61 ± 4.92 4 9/139 (6.5%) Mean ± SD in logMAR 1.17 ± 0.44 Mean ± SD in age 13.29 ± 5.32 5A 14/139 (10.0%) Mean ± SD in logMAR 0.48 ± 0.27 Mean ± SD in age 20.64 ± 14.75 5B 15/139 (10.8%) Mean ± SD in logMAR 1.03 ± 0.47 Mean ± SD in age 26.07 ± 10.18 BCVA = best corrected visual acuity; logMAR = logarithm of the minimum angle of resolution; n = number; OCT = optical coherence tomography; SD = standard deviation Comparison of BCVA based on the OCT Types in Patients with X-linked Retinoschisis The BCVA outcomes showed significant variation across OCT types (Fig. 2 and Table 4 ). Type 1A demonstrated the best BCVA (mean ± SD, 0.46 ± 0.18 logMAR), which was statistically superior to Type 1B (0.69 ± 0.33 logMAR), Type 2 (0.74 ± 0.28 logMAR), Type 4 (1.17 ± 0.44 logMAR), and Type 5B (1.03 ± 0.47 logMAR) (all p < 0.01). Type 5A exhibited BCVA comparable to Type 1A ( p = 0.958) and significantly better than that of Type 2 ( p = 0.023), Type 4 ( p < 0.001), and Type 5B ( p < 0.001). BCVA in Type 1B (0.70 ± 0.33 logMAR) and Type 2 (0.74 ± 0.28 logMAR) was intermediate, significantly worse than that of Type 1A ( p = 0.009, p = 0.004, respectively) but better than Type 4 ( p < 0.001, p = 0.004, respectively) and Type 5B ( p < 0.001, p = 0.009, respectively). However, they differed in that the mean BCVA of Type 1B was marginally lower than that of Type 5A ( p = 0.060), whereas Type 2 had a significantly lower BCVA compared to Type 5A ( p = 0.023). It should be noted that the number of eyes in Type 3 was too small for inclusion in the statistical analysis. However, Type 3 had the worst vision, with a mean BCVA of 1.35 ± 0.47 logMAR. Overall, Type 3, 4 and 5B demonstrated the poorest BCVA values, reflecting OCT phenotypes commonly characterized by severe structural disruptions, including extensive loss of the outer retinal layers and atrophic change of macula. Table 4 Comparison of BCVA Based on OCT Types in X-Linked Retinoschisis Patients. Baseline Type 1A 1B 2 4 5A 5B 1A N/A 0.21 ( p = 0.009) 0.29 ( p = 0.004) 0.71 ( p ≤ 0.001) -0.01 ( p = 0.958) 0.62 ( p ≤ 0.001) 1B -0.21 ( p = 0.009) N/A 0.08 ( p = 0.467) 0.50 ( p ≤ 0.001) -0.21 ( p = 0.060) 0.41 ( p ≤ 0.001) 2 -0.29 ( p = 0.004) -0.08 ( p = 0.467) N/A 0.41 ( p = 0.004) -0.30 ( p = 0.023) 0.33 ( p = 0.009) 4 -0.71 ( p ≤ 0.001) -0.50 ( p ≤ 0.001) -0.41 ( p = 0.004) N/A -0.71 ( p ≤ 0.001) -0.09 ( p = 0.558) 5A 0.01 ( p = 0.958) 0.21 ( p = 0.060) 0.30 ( p = 0.023) 0.71 ( p ≤ 0.001) N/A 0.62 ( p ≤ 0.001) 5B -0.62 ( p ≤ 0.001) -0.41 ( p ≤ 0.001) -0.33 ( p = 0.009) 0.09 ( p = 0.558) -0.62 ( p ≤ 0.001) N/A BCVA = best corrected visual acuity; N/A = Not applicable * Continuous variables were analyzed by Generalized linear mixed model. Genetic Characteristics in X-Linked Retinoschisis Patients A total of 35 disease-causing variants in the RS1 gene were identified in this cohort. Among these, 27 (77.1%) were missense variants, 1 (2.9%) was a nonsense variant, 3 (8.6%) were splice-site variants, and 4 (11.4%) were frameshift variants. Missense variants were the most common, accounting for 64 of the 72 patients (88.9%), whereas truncating variants—including nonsense, splice-site, and frameshift mutations—were observed in 8 of 72 patients (11.1%). The majority of genetic variants were localized in the discoidin domain-encoding exons (exons 4, 5, and 6). The three most common variants were the founder variant c.286T > C (p.Trp96Arg), identified in 7 patients (9.7%); c.589C > T (p.Arg197Cys), observed in 7 patients (9.7%); and c.590G > A (p.Arg197His), found in 6 patients (8.3%). Meanwhile, c.499A > G (p.Lys167Glu), known as one of the most common variants causing XLRS, was found in only 1 patient (1.4%). A comprehensive summary of frequent genetic variants and their distribution with OCT types is presented in Table 5 and Supplementary Table S1 . Table 5 Frequent Variants in X-Linked Retinoschisis Patients. Variants No. Complementary DNA Protein Location (Exon/Intron) Protein domain Mutation type Patients (n) Pedigree (n) Patients (%) Pedigree (%) 1 c.78 + 1G > T Splice_donor_variant & intron_variant Intron 2 RS domain Splice site mutation 1 1 1.4 1.5 2 c.97delT p.Trp33fs Exon 3 RS domain Frameshift mutation 1 1 1.4 1.5 3 c.130_140del* p.Gly44fs Exon 3 RS domain Frameshift mutation 1 1 1.4 1.5 4 c.150G > A p.Trp50* premature stop Exon 3 RS domain Nonsense mutation 1 1 1.4 1.5 5 c.188G > A p.Cys63Tyr Exon 3 RS domain Missense mutation 1 1 1.4 1.5 6 Exon 4 deletion Exon 4 DS domain Frameshift mutation 1 1 1.4 1.5 7 c.214G > A p.Glu72Lys Exon 4 DS domain Missense mutation 3 3 4.1 4.7 8 c.286T > C p.Trp96Arg Exon 4 DS domain Missense mutation 7 7 9.7 10.9 9 c.302C > A p.Ala101Asp Exon 4 DS domain Missense mutation 1 1 1.4 1.5 10 c.305G > A p.Arg102Gln Exon 4 DS domain Missense mutation 1 1 1.4 1.5 11 c.306_308dupGCT p.Leu103dup Exon 4 DS domain Frameshift mutation 1 1 1.4 1.5 12 c.325G > A p.Gly109Arg Exon 4 DS domain Missense mutation 1 1 1.4 1.5 13 c.326 + 2T > G Splice_donor_variant & intron_variant Exon 4 DS domain Splice site mutation 1 1 1.4 1.5 14 c.328T > C p.Cys110Arg Exon 4 DS domain Missense mutation 1 1 1.4 1.5 15 c.331G > A* p.Ala111Thr Exon 5 DS domain Missense mutation 1 1 1.4 1.5 16 c.404G > A p.Gly135Glu Exon 5 DS domain Missense mutation 1 1 1.4 1.5 17 c.410T > C p.Leu137Pro Exon 5 DS domain Missense mutation 5 4 6.9 6.3 18 c.421C > T p.Arg141Cys Exon 5 DS domain Missense mutation 2 1 2.8 1.5 19 c.422G > A p.Arg141His Exon 5 DS domain Missense mutation 5 3 6.9 4.7 20 c.426T > G p.Cys142Trp Exon 5 DS domain Missense mutation 1 1 1.4 1.5 21 c.433G > T* p.Asp145Tyr Exon 5 DS domain Missense mutation 1 1 1.4 1.5 22 c.499A > G* p.Lys167Glu Exon 5 DS domain Missense mutation 1 1 1.4 1.5 23 c.522 + 1G > T Splice_donor_variant & intron_variant Intron 5 DS domain Splice site mutation 1 1 1.4 1.5 24 c.544C > T p.Arg182Cys Exon 6 DS domain Missense mutation 2 2 2.8 3.1 25 c.574C > T p.Pro192Ser Exon 6 DS domain Missense mutation 2 2 2.8 3.1 26 c.577C > T p.Pro193Ser Exon 6 DS domain Missense mutation 1 1 1.4 1.5 27 c.578C > G p.Pro193Arg Exon 6 DS domain Missense mutation 1 1 1.4 1.5 28 c.589C > T p.Arg197Cys Exon 6 DS domain Missense mutation 7 6 9.7 9.3 29 c.590G > A p.Arg197His Exon 6 DS domain Missense mutation 6 5 8.3 7.8 30 c.608C > T p.Pro203Leu Exon 6 DS domain Missense mutation 1 1 1.4 1.5 31 c.617G > C* p.Trp206Ser Exon 6 DS domain Missense mutation 1 1 1.4 1.5 32 c.625C > T p.Arg209Cys Exon 6 DS domain Missense mutation 5 4 6.9 6.3 33 c.638G > A p.Arg213Gln Exon 6 DS domain Missense mutation 1 1 1.4 1.5 34 c.647T > C p.Leu216Pro Exon 6 DS domain Missense mutation 4 4 5.5 6.3 35 c.668G > A p.Cys223Tyr Exon 6 DS domain Missense mutation 1 1 1.4 1.5 72 64 100.0 100.0 A = adenine; Ala = Alanine; Arg = Arginine; Asp = Aspartic acid; C = cytosine; Cys = Cysteine; del = deletion; DS domain = discoidin domain; dup = duplication; fs = frameshift; G = guanine; Gln = Glutamine; Glu = Glutamic acid; Gly = Glycine; His = Histidine ; Leu = Leucine; Lys = Lysine; n = number; Pro = Proline; RS domain = Retinoschisin 1 domain; Ser = Serine; T = thymine; Thr = Threonine; Trp = Tryptophan; Tyr = Tyrosine; Val = Valine Genotype-Phenotype Association: Comparison of Truncating and Missense Variants The BCVA, age, and OCT types were compared among genotype groups (truncating vs. missense variants). No significant differences were observed in BCVA or age between the truncating variant group (BCVA: 0.64 ± 0.42 logMAR, age: 18.43 ± 10.76 years) and the missense variant group (BCVA: 0.70 ± 0.39 logMAR, age: 15.16 ± 9.09 years) ( p = 0.692, p = 0.559, respectively). By excluding the OCT types with perfect separation (Types 2, 3, 4, and 5A) and a single case (Type 5B) in the truncating variant group, older age was associated with the truncating variant compared to the missense variant (OR = 1.13, 95% CI: 1.02–1.24, P = 0.016), while OCT Type and BCVA were not significant factors ( p = 0.225, and p = 0.395, respectively) (Table 6 and Supplementary Table S2). Table 6 Factors Associated with Truncating Mutations Using a Generalied Estimating Equation OR (95% CI) P -value BCVA 3.10 (0.23, 42.1) 0.395 Age 1.13 (1.02, 1.24) 0.016 * OCT Subtype (1A, baseline) 1B 0.29 (0.04, 2.14) 0.225 BCVA = best corrected visual acuity; OCT = optical coherence tomography; OR = odds ratio DISCUSSION In the present study, we reviewed the clinical and genetic features in a Korean cohort of 72 XLRS patients, each harboring one of 35 RS1 genetic variants, from Seoul National University Hospital. This study introduces a novel OCT-based classification system for XLRS, delineating five distinct phenotypic types with implications for visual outcomes and genotype-phenotype associations. The results demonstrate that the integrity of the outer retinal layers is a critical determinant of BCVA. Specifically, Types 1A and 5A exhibited the best BCVA, whereas severe structural disruption on OCT (Types 3, 4, and 5B) was associated with significantly worse visual outcomes. No significant differences were observed in BCVA and age between the truncating variant group and the missense variant group. However, older age was significantly associated with the truncating variant compared to the missense variant within Type 1. Overall, XLRS patients in the current study demonstrated mild to moderate visual impairment, with a mean last available BCVA of 0.68 ± 0.39 logMAR at a mean age of 15.5 ± 9.3 years (Table 2 ). The BCVA in this cohort is slightly worse than that reported in an Italian pediatric cohort, which observed a mean BCVA of 0.55 logMAR at a younger mean age of 12.5 years, possibly due to earlier diagnosis [ 37 ]. Similarly, the Japanese and French cohorts reported comparable BCVA values of approximately 0.6 logMAR at slightly older mean age of 19.1 and 24 years, respectively, suggesting relatively worse visual acuity in the current study when age is considered [ 11 , 24 ]. In contrast, a Chinese cohort reported a mean BCVA of 0.81 logMAR with a comparable mean age of 17.3 years, indicating worse visual outcomes compared to the present cohort, which may reflect a higher prevalence of severe genotypes in their sample [ 10 ]. These comparisons highlight the varying degrees of visual impairment across diverse populations, emphasizing the influence of age, and genotype-associated disease severity on visual outcomes in XLRS patients. Through OCT analysis, we classified the phenotypes of XLRS patients into five main types; 1A, 1B, 2, 3, 4, 5A, 5B (Fig. 1 ). The most common type was Type 1A, accounting for 36.7% of eyes, with a mean BCVA of 0.46 logMAR at a mean age of 12.1 years. Type 1B comprised 22.3% of eyes, showing slightly worse BCVA (0.70 logMAR) and an older mean age of 15.0 years. Types associated with more extensive outer retinal damage, such as Type 2 (10.8%), Type 3 (2.9%), Type 4 (6.5%) and Type 5B (10.8%), demonstrated progressively worse BCVA, with the poorest mean BCVA of 1.35 logMAR observed in Type 3. Type 5 was further categorized into 5A (10.0%) and 5B (10.8%) based on the integrity of outer retina layers. This type exhibited a notable trend, with increasing mean age (20.6 years in 5A and 26.1 years in 5B) compared to the other types, as the development of retinal atrophy becomes more evident with age. Although Type 5A and 5B share common features, such as the absence of schisis and temporal retinal thinning due to atrophic changes, they showed an inverse relationship in BCVA from 0.48 logMAR in 5A to 1.03 logMAR in 5B. It is natural that 5B has the poor BCVA because of atrophy of neuroretina and retinal pigment epithelium with age, and our findings are consistent with previous studies suggesting that outer retinal atrophy typically develops between the ages of 20 and 40 [ 38 ]. However, Type 5A differs significantly from Type 5B in many ways. First, Type 5A demonstrated the best visual outcomes, comparable to Type 1A. Secondly, the mean age of Type 5A is five to six years younger than Type 5B. Lastly, Type 5B is definitely the end stage of XLRS in terms of visual acuity and anatomical figure, while Type 5A appears to be a transitional form evolving from Type 1A or 1B to Type 2 or Type 4 based on its intermediate structural characteristics observed across the cohort, although longitudinal OCT follow-up was not performed to confirm this progression. The mechanisms behind the fluctuation of macular thickness and the presence or absence of schisis remain unclear. However, the role of Müller cells is considered to be involved, as the appearance of temporal thinning in Type 5 closely resembles that seen in MacTel type 2. Given that Müller cells play a critical role in regulating water homeostasis and retinal blood flow, their dysfunction may contribute to these findings [ 39 , 40 ]. Generalized linear mixed model analysis revealed significant differences in BCVA across OCT types, underscoring the prognostic value of OCT-based typing in XLRS (Fig. 2 and Table 4 ). As described in the results, disease progression in terms of BCVA can be categorized as follows; Types 1A and 5A represent early-stage, 1B and 2 as intermediate stage, and 3, 4, and 5B as end-stage. Interestingly, the mean BCVA of Type 1B (characterized by partial loss of outer retinal layers) resulted in a similar moderate visual deficit compared to that of Type 2, which exhibited complete loss of outer retinal integrity. This finding may be explained by the discrepancy between OCT and histologic findings reported in MacTel type2 patients. Histological studies have identified the presence of cone cells one year after the ellipsoid zone was observed to be absent on OCT. Thus, the absence of ellipsoid zone on OCT should not be interpreted as a complete loss of photoreceptors but rather as an indication of conditions that degrade the ellipsoid zone signal from the fovea [ 41 ]. Additionally, we aimed to explore potential genotype-phenotype correlations within these OCT types. Among the 35 disease-causing RS1 gene variants identified in our cohort, missense variants were most prevalent (77.1%, 27/35), consistent with previous reports [ 3 , 25 , 31 , 37 ]. Truncating variants, including nonsense, splice-site, and frameshift mutations, accounted for 11.1% (8/72) of patients. Most variants were located in the discoidin domain-encoding exons (exons 4–6), with the three most frequent variants being c.286T > C (p.Trp96Arg) and c.589C > T (p.Arg197Cys) in 9.7% each, and c.590G > A (p.Arg197His) in 8.3% of patients (Table 5 ). Although no significant differences in BCVA or age at the time of OCT were observed between patients with truncating and missense variants overall, a subgroup analysis within Type 1 revealed that older age was significantly associated with truncating variants (OR = 1.13, 95% CI: 1.02–1.24, p = 0.016). Considering that XLRS patients may experience an annual decline in visual acuity after their twenties, as reported in previous studies [ 4 ], this finding may indicate that patients with the truncating variants experience a gradual deterioration of the outer retinal layers that occurs more slowly than in patients with missense variants. This result suggests that earlier intervention with future therapies may be particularly beneficial for patients with missense variants to prevent deterioration of photoreceptor function. However, given the relatively low proportion of truncating variants in this cohort, the statistical power to detect genotype-phenotype correlations was limited. This may partly explain the discrepancy between our findings and those of a larger multicenter study that reported worse visual acuity among patients with truncating variants [ 5 ]. Future investigations involving larger, multinational cohorts are warranted to confirm this finding and better understand the progression of XLRS across different genotypes. The main limitations of our study are the retrospective design and relatively small sample size. The absence of longitudinal OCT data may limit the ability to assess disease progression over time or establish robust genotype–phenotype correlations. Moreover, as the study cohort consisted exclusively of Korean patients, the generalizability of our findings to other ethnic populations may be limited. Despite these limitations, this study presents a well-characterized and genetically confirmed cohort within a relatively homogeneous population, allowing for a focused investigation of structural phenotypes using a novel OCT-based classification system. In conclusion, this study introduces a clinically useful OCT-based classification system for patients with XLRS, enabling a more precise assessment of structural phenotypes and their relationship to visual function. This comparative analysis highlights the utility of the proposed OCT-based classification system in bridging genotype-phenotype variability across different populations, complemented by detailed structural insights that enhance our understanding of visual function in XLRS. Despite the aforementioned limitations, this OCT-based classification system would provide a valuable framework for guiding the natural history and personalized therapeutic strategies, including the selection of suitable candidates for emerging treatments like gene therapy for XLRS patients. Abbreviations BCVA = best corrected visual acuity; D = diopter; IQR = interquartile range; logMAR = logarithm of the minimum angle of resolution; RS1 = retinoschisin 1; XLRS = X-linked retinoschisis Declarations Acknowledgements We thank all the participants included in the cohorts analyzed in this study, as well as all the team members of the pediatric ophthalmology department at Seoul National University Children’s Hospital. Funding This research was supported by the Seoul National University Hospital Research Grant (04-2024-0420 to K.H. Lee); the Seoul National University Hospital Research Grant (18-2023-0010 to J.H.K.); the Kun-hee Lee Child Cancer & Rare Disease Project, Republic of Korea (202200004004 to J.H.K.); and the National Research Council of Science & Technology (NST) Grant by the Korean government (GTL24021-520 to J.H.K.). Author Contributions Conception and design: Kihwang Lee Draft writing: Seok Jae Lee, Kihwang Lee Analysis and interpretation: Seok Jae Lee, Richul Oh, Kihwang Lee Data collection: Seok Jae Lee, Richul Oh, Hyun Chul Jeong, Seung Woo Choi, Eun Kyoung Lee, Dong Hyun Jo, Chang Ki Yoon, Un Chul Park, Jeong Hun Kim, Kyu Hyung Park Overall responsibilit y: Kihwang Lee Ethics approval and consent to participate The study protocol was reviewed and approved by the Institutional Review Board of Seoul National University Hospital (IRB No. E-2406-001-1539), and all procedures were conducted in accordance with the ethical standards of the Declaration of Helsinki. Given the retrospective nature of the study and use of de-identified data, the requirement for written informed consent was waived by the IRB. Consent to publish declaration Not Applicable. Competing interests All the authors have declared no conflicts of interest in connection with this article. Data availability The authors declare that all data supporting the findings of this study are available within the paper and its extended data and supplemental information files. The datasets generated during or analyzed in the current study are available from the corresponding author upon reasonable request. References Sauer CG, Gehrig A, Warneke-Wittstock R, Marquardt A, Ewing CC, Gibson A, Lorenz B, Jurklies B, Weber BH. Positional cloning of the gene associated with X-linked juvenile retinoschisis. Nat Genet. 1997;17(2):164–70. Heymann JB, Vijayasarathy C, Fariss RN, Sieving PA. 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ERG variability in X-linked congenital retinoschisis patients with mutations in the RS1 gene and the diagnostic importance of fundus autofluorescence and OCT. Doc Ophthalmol. 2008;116(2):97–109. Bowles K, Cukras C, Turriff A, Sergeev Y, Vitale S, Bush RA, Sieving PA. X-linked retinoschisis: RS1 mutation severity and age affect the ERG phenotype in a cohort of 68 affected male subjects. Invest Ophthalmol Vis Sci. 2011;52(12):9250–6. Daich Varela M, Esener B, Hashem SA, Cabral de Guimaraes TA, Georgiou M, Michaelides M. Structural evaluation in inherited retinal diseases. Br J Ophthalmol. 2021;105(12):1623–31. van der Veen I, Heredero Berzal A, Koster C, Ten Asbroek A, Bergen AA, Boon CJF. The Road towards Gene Therapy for X-Linked Juvenile Retinoschisis: A Systematic Review of Preclinical Gene Therapy in Cell-Based and Rodent Models of XLRS. Int J Mol Sci 2024, 25(2). Duan C, Ding C, Sun X, Mao S, Liang Y, Liu X, Ding X, Chen J, Tang S. Retinal organoids with X-linked retinoschisis RS1 (E72K) mutation exhibit a photoreceptor developmental delay and are rescued by gene augmentation therapy. Stem Cell Res Ther. 2024;15(1):152. Pennesi ME, Yang P, Birch DG, Weng CY, Moore AT, Iannaccone A, Comander JI, Jayasundera T, Chulay J. Intravitreal Delivery of rAAV2tYF-CB-hRS1 Vector for Gene Augmentation Therapy in Patients with X-Linked Retinoschisis: 1-Year Clinical Results. Ophthalmol Retina. 2022;6(12):1130–44. Cukras C, Wiley HE, Jeffrey BG, Sen HN, Turriff A, Zeng Y, Vijayasarathy C, Marangoni D, Ziccardi L, Kjellstrom S, et al. Retinal AAV8-RS1 Gene Therapy for X-Linked Retinoschisis: Initial Findings from a Phase I/IIa Trial by Intravitreal Delivery. Mol Ther. 2018;26(9):2282–94. Prenner JL, Capone A Jr., Ciaccia S, Takada Y, Sieving PA, Trese MT. Congenital X-linked retinoschisis classification system. Retina. 2006;26(7 Suppl):S61–64. Orès R, Mohand-Said S, Dhaenens CM, Antonio A, Zeitz C, Augstburger E, Andrieu C, Sahel JA, Audo I. Phenotypic Characteristics of a French Cohort of Patients with X-Linked Retinoschisis. Ophthalmology. 2018;125(10):1587–96. Gao FJ, Dong JH, Wang DD, Chen F, Hu FY, Chang Q, Xu P, Liu W, Li JK, Huang Y, et al. Comprehensive analysis of genetic and clinical characteristics of 30 patients with X-linked juvenile retinoschisis in China. Acta Ophthalmol. 2021;99(4):e470–9. Muftuoglu IK, Mendoza N, Gaber R, Alam M, You Q, Freeman WR. INTEGRITY OF OUTER RETINAL LAYERS AFTER RESOLUTION OF CENTRAL INVOLVED DIABETIC MACULAR EDEMA. Retina. 2017;37(11):2015–24. Uji A, Murakami T, Suzuma K, Yoshitake S, Arichika S, Ghashut R, Fujimoto M, Yoshimura N. INFLUENCE OF VITRECTOMY SURGERY ON THE INTEGRITY OF OUTER RETINAL LAYERS IN DIABETIC MACULAR EDEMA. Retina. 2018;38(1):163–72. Hagenau F, Vogt D, Ziada J, Guenther SR, Haritoglou C, Wolf A, Priglinger SG, Schumann RG. Vitrectomy for Diabetic Macular Edema: Optical Coherence Tomography Criteria and Pathology of the Vitreomacular Interface. Am J Ophthalmol. 2019;200:34–46. Landa G, Su E, Garcia PM, Seiple WH, Rosen RB. Inner segment-outer segment junctional layer integrity and corresponding retinal sensitivity in dry and wet forms of age-related macular degeneration. Retina. 2011;31(2):364–70. Ooto S, Vongkulsiri S, Sato T, Suzuki M, Curcio CA, Spaide RF. Outer retinal corrugations in age-related macular degeneration. JAMA Ophthalmol. 2014;132(7):806–13. Lee SJ, Jiang H, Jeong HC, Jo DH, Song HB, Gee HY, Lee KH, Kim JH. Genotype-Phenotype Correlations in 83 Korean X-linked Retinoschisis Patients: Impact of Retinoschisin 1 Secretion Profiles on Clinical Phenotypes. Ophthalmol Retina 2024. Xiao S, Sun W, Xiao X, Li S, Luo H, Jia X, Ouyang J, Li X, Wang Y, Jiang Y, et al. Clinical and genetic features of retinoschisis in 120 families with RS1 mutations. Br J Ophthalmol. 2023;107(3):367–72. Li H, Li J, Huang Y, Sui R. Clinical and genetic study of a pseudo-dominant retinoschisis pedigree: the first female patient reported in Chinese population. Ophthalmic Genet. 2022;43(4):433–7. Maggi J, Koller S, Bähr L, Feil S, Kivrak Pfiffner F, Hanson JVM, Maspoli A, Gerth-Kahlert C, Berger W. Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases. Int J Mol Sci 2021, 22(4). Dockery A, Stephenson K, Keegan D, Wynne N, Silvestri G, Humphries P, Kenna PF, Carrigan M, Farrar GJ. Target 5000: Target Capture Sequencing for Inherited Retinal Degenerations. Genes (Basel) 2017, 8(11). Lai YH, Huang SP, Chen SP, Hu PS, Lin SF, Sheu MM, Wang HZ, Tsai RK. A novel gene mutation in a family with X-linked retinoschisis. J Formos Med Assoc. 2015;114(9):872–80. Fortunato P, Pagliazzi A, Bargiacchi S, Marziali E, Sodi A, Caputo R, Passerini I, Pelo E, Bacci GM. X-linked retinoschisis: mutation spectrum and genotype-phenotype relationship in an Italian pediatric cohort. Ophthalmic Genet 2022:1–8. Fenner BJ, Russell JF, Drack AV, Dumitrescu AV, Sohn EH, Russell SR, Boldt HC, Affatigato LM, Hoffmann JM, Andorf JL, et al. Long-term functional and structural outcomes in X-linked retinoschisis: implications for clinical trials. Front Med (Lausanne). 2023;10:1204095. Daruich A, Matet A, Moulin A, Kowalczuk L, Nicolas M, Sellam A, Rothschild PR, Omri S, Gélizé E, Jonet L, et al. Mechanisms of macular edema: Beyond the surface. Prog Retin Eye Res. 2018;63:20–68. Bringmann A, Pannicke T, Grosche J, Francke M, Wiedemann P, Skatchkov SN, Osborne NN, Reichenbach A. Müller cells in the healthy and diseased retina. Prog Retin Eye Res. 2006;25(4):397–424. Powner MB, Gillies MC, Zhu M, Vevis K, Hunyor AP, Fruttiger M. Loss of Müller's cells and photoreceptors in macular telangiectasia type 2. Ophthalmology. 2013;120(11):2344–52. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7363735","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":503239044,"identity":"8ccff805-0508-4133-9b5d-9f06f359af4b","order_by":0,"name":"Seok Jae Lee","email":"","orcid":"","institution":"Seoul National University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Seok","middleName":"Jae","lastName":"Lee","suffix":""},{"id":503239046,"identity":"9b94e1cb-83ec-46e5-99dd-19472e97d166","order_by":1,"name":"Richul Oh","email":"","orcid":"","institution":"Seoul National University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Richul","middleName":"","lastName":"Oh","suffix":""},{"id":503239048,"identity":"9accd3fa-db8f-4d8a-8f12-b9f86470b79f","order_by":2,"name":"Hyun Chul Jeong","email":"","orcid":"","institution":"Seoul National University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hyun","middleName":"Chul","lastName":"Jeong","suffix":""},{"id":503239049,"identity":"0ec7e8e3-ecb7-4471-ae4b-5302a062ca52","order_by":3,"name":"Seung Woo Choi","email":"","orcid":"","institution":"Seoul National University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Seung","middleName":"Woo","lastName":"Choi","suffix":""},{"id":503239050,"identity":"55af4b36-c6d9-415d-b23f-14583261f737","order_by":4,"name":"Eun Kyoung Lee","email":"","orcid":"","institution":"Seoul National University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Eun","middleName":"Kyoung","lastName":"Lee","suffix":""},{"id":503239051,"identity":"51fa53eb-0300-44a2-ac1b-365e190811d9","order_by":5,"name":"Dong Hyun Jo","email":"","orcid":"","institution":"Seoul National University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Dong","middleName":"Hyun","lastName":"Jo","suffix":""},{"id":503239052,"identity":"18d3ed9b-4d84-4e43-ab07-bac23747d016","order_by":6,"name":"Chang Ki Yoon","email":"","orcid":"","institution":"Seoul National University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chang","middleName":"Ki","lastName":"Yoon","suffix":""},{"id":503239053,"identity":"3a1cb3fe-06b8-4725-9a2f-b64ae93d1c2d","order_by":7,"name":"Un Chul Park","email":"","orcid":"","institution":"Seoul National University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Un","middleName":"Chul","lastName":"Park","suffix":""},{"id":503239054,"identity":"fb54f6e1-1073-498e-92f0-c98c5126261b","order_by":8,"name":"Kihwang H. Lee","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAt0lEQVRIiWNgGAWjYBACfvbm459/VABZEsRqkew5lsbMcIYULQYzfMyYGdtI0iLBYPa4cF5dnsHtBsbHFb+I0GIu3ZBuPHPb4WKDOweYDc/2EaHFcs6BAxK82w4kbriRwCbZ2EOMw24kNkjwzqkjSUsymzRvAzNES8MPIrQAA5nZcMaxw4kzbyQ2GzY2EKGFn73/44MPNXWJfTeSDz5s+EOEFiTA2MAAjiASAYm2jIJRMApGwcgAAJNzPltZq9iCAAAAAElFTkSuQmCC","orcid":"","institution":"Seoul National University Hospital","correspondingAuthor":true,"prefix":"","firstName":"Kihwang","middleName":"H.","lastName":"Lee","suffix":""},{"id":503239055,"identity":"75032ec8-cb74-4b30-8db4-20cef10c3316","order_by":9,"name":"Jeong Hun Kim","email":"","orcid":"","institution":"Seoul National University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jeong","middleName":"Hun","lastName":"Kim","suffix":""},{"id":503239056,"identity":"43000a23-1a82-4251-a71d-ff5392f07226","order_by":10,"name":"Kyu Hyung Park","email":"","orcid":"","institution":"Seoul National University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kyu","middleName":"Hyung","lastName":"Park","suffix":""}],"badges":[],"createdAt":"2025-08-13 10:08:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7363735/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7363735/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90312784,"identity":"4a80ecd2-3b3a-4ab3-a03e-b93078283170","added_by":"auto","created_at":"2025-09-01 10:03:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":705393,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRepresentative Images based on OCT Types of X-Linked Retinoschisis Patients. \u003c/strong\u003eRepresentative images of spectral-domain optical coherence tomography (OCT) types of XLRS. The phenotype of OCT in patients with X-linked retinoschisis was classified into five types; 1A; foveoschisis with intact outer retinal layers, regardless of the involvement of schisis in the outer nuclear layer (ONL) and inner nuclear layer (INL), 1B; Foveoschisis with partially intact outer retinal layers, regardless of the involvement of schisis in the ONL and INL, 2; Foveoschisis with total loss of the outer retinal layers, regardless of the involvement of schisis in the ONL and INL, 3; Degenerative lamellar hole, 4; Extensive foveoschisis with the macular average thickness exceeding 800 μm, 5A; Atrophic type with intact outer retinal layers, 5B; Atrophic type with loss of the outer retinal layers.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7363735/v1/11a1c628c5207ddae54db7d0.png"},{"id":90310894,"identity":"54775c66-be5b-421b-9a54-8fcffa0a886c","added_by":"auto","created_at":"2025-09-01 09:47:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":41667,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBCVA Based on OCT Types of X-Linked Retinoschisis Patients. \u003c/strong\u003eGraph demonstrating the best corrected visual acuity (BCVA) outcomes in relation to the spectral-domain optical coherence tomography (OCT) types. Snellen BCVA data were transformed into logarithm of the minimum angle of resolution (logMAR) values.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7363735/v1/ffea663be42906c2135dfe87.png"},{"id":90316223,"identity":"2e6f3316-714a-41a1-a9fa-11bb720c1c34","added_by":"auto","created_at":"2025-09-01 10:19:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3232859,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7363735/v1/ee16ccbf-362f-42a6-92ef-13885901ed1d.pdf"},{"id":90310899,"identity":"018651c9-6ca1-43c2-a37c-4af53a787f8b","added_by":"auto","created_at":"2025-09-01 09:47:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":174017,"visible":true,"origin":"","legend":"","description":"","filename":"3.Supplementaryfile.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7363735/v1/a427e06e2159b36551df59b3.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Classification System Using Optical Coherence Tomography for X-linked Retinoschisis and Its Association with Genetic Variants","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eX-linked retinoschisis (XLRS; Online Mendelian Inheritance in Man [OMIM], #312700) is a rare inherited retinal disorder first described by Haas in 1898. It is caused by mutations in the \u003cem\u003eRS1\u003c/em\u003e gene, located on the distal short arm of the X chromosome (Xp22.13; OMIM, #300839),[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] which encodes retinoschisin, a 224-amino acid extracellular lectin that binds to the retinal cell plasma membrane and enables cell-to-cell adhesion [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This X-linked monogenic disease is characterized by splitting of the neural retinal layer, fovea-macular cystic schisis cavities, and central vision loss [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. XLRS almost exclusively occurs in males and leads to progressive vision loss, often presenting as school-age reading difficulties [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. To date, over 450 distinct variants in the \u003cem\u003eRS1\u003c/em\u003e gene have been identified as underlying causes of XLRS, the majority of which include point mutations, insertions, deletions, and splice-site alterations [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://databases.lovd.nl/shared/genes/RS1\u003c/span\u003e\u003cspan address=\"https://databases.lovd.nl/shared/genes/RS1\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eSeveral studies have investigated the genotypic and phenotypic characteristics of patients with XLRS, focusing primarily on clinical features such as visual acuity (VA), fundus photography, optical coherence tomography (OCT), and electroretinogram (ERG) findings in relation to specific mutation types [\u003cspan additionalcitationids=\"CR11 CR12 CR13\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, to date, no definitive genotype-phenotype correlations have been reported, due to the relatively small sample sizes of individual studies and variability in phenotypic expression, even among members of the same families [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAmong the methods for phenotypic measurements, OCT is widely utilized to assess anatomical changes such as macular schisis, outer retina atrophy, and retinal detachment. Compared to fundoscopy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] or ERG [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], OCT plays a pivotal role in the objective diagnosis, staging, and monitoring of XLRS [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. It is also serves as a reliable endpoint in preclinical studies [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] and clinical trials [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] of gene therapy for XLRS.\u003c/p\u003e\u003cp\u003eIn 2006, Prenner et al. introduced a classification system for XLRS based on time domain (TD)-OCT findings and fundus examination, categorizing patients into four phenotypes: foveal, foveo-lamellar, complex, and foveo-peripheral types [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Among these, the complex type was the most common, followed by the foveal-lamellar type. However, no correlation was identified between schisis type, layer involvement, and specific mutations [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. This earlier system lacks critical information regarding disease progression and its correlation to VA, as it does not consider the status of outer retinal layers, such as ellisoid zone (EZ), and interdigitation zone (IZ). The association between the integrity of outer retinal layers and VA changes has been well established in numerous retinal diseases, including diabetic retinopathy [\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], age-related macular degeneration [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], and even in XLRS, as demonstrated in our previous study [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTo the best of our knowledge, no studies have evaluated differences in VA and genetic variants across detailed OCT types. In this context, we have systemically reviewed and classified OCT findings to better reflect VA and disease progression, as well as to assess potential genotype-phenotype associations among the OCT types.\u003c/p\u003e"},{"header":"PATIENTS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy Population\u003c/h2\u003e\n \u003cp\u003ePatients clinically diagnosed with X-linked retinoschisis (XLRS) who had at least two recorded clinical visits at a single tertiary care center, Seoul National University Hospital (Seoul, Republic of Korea), were retrospectively identified for this study. Inclusion criteria required a confirmed XLRS diagnosis based on clinical findings, family history, and molecular confirmation of a potentially pathogenic variant in the \u003cem\u003eRS1\u003c/em\u003e gene. Patients were excluded if they were unable to undergo spectral-domain optical coherence tomography (SD-OCT), had a history of vitrectomy, or presented with the retinal detachment or disorganized retinal phenotypes. A total of 72 patients from 64 families, encompassing 35 distinct \u003cem\u003eRS1\u003c/em\u003e genetic variants, were included in the analysis (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). The study was approved by the Institutional Review Board (IRB) of Seoul National University Hospital, Seoul, South Korea (IRB number: E-2406-001-1539). All research procedures adhered to the ethical principles outlined in the Declaration of Helsinki. The requirement for informed consent was waived by the local ethics committee due to the use of pseudonymized patient data.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTable 1. Flow Chart of X-Linked Retinoschisis Patients.\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003cimg 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\" alt=\"image\"\u003e\u003c/strong\u003e\u003c/p\u003e\u003cstrong\u003eSD-OCT = Spectral-domain optical coherence tomography; RD = retinal detachment; RS1 = retinoschisin 1; M = missense mutation; T = truncated mutation\u0026nbsp;\u003c/strong\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003ch3\u003eClinical Data Collection\u003c/h3\u003e\n\u003cp\u003eFor 72 patients, the specific variant in the \u003cem\u003eRS1\u003c/em\u003e gene was identified either directly or derived from a family member. These variants were molecularly confirmed through Sanger sequencing or whole-exome sequencing. BCVA was assessed at the last OCT follow-up. To evaluate VA across genotype variants, Snellen chart measurements were converted to logarithm of the minimum angle of resolution (logMAR) values: 2.0 logMAR used for counting fingers, 3.0 logMAR for hand motions, 3.7 logMAR for light perception. All patients included in the study underwent OCT scans using a Spectralis SD-OCT (Heidelberg Engineering, Heidelberg, Germany). Automated alignment and data analysis were performed using Heidelberg Eye Explorer (HEYEX) software. Defects in outer retinal microstructures, including the interdigitation zone (IZ), ellipsoid zone (EZ), were evaluated within a 1-mm radius from the foveal center using vertical and horizontal central OCT images. These defects were categorized into three categories: intact, partially disrupted, and absent. The presence of specific OCT findings, including foveoschisis and defects, was determined by consensus among three observers (Seok Jae Lee, Richul Oh, and Kihwang Lee). In cases where the vertical and horizontal scans showed discordant findings \u0026mdash; for example, an intact EZ in the vertical scan but partial disruption in the horizontal scan \u0026mdash; we categorized the microstructure based on the more preserved direction, prioritizing structural preservation. Qualitative and quantitative analysis of OCT findings were performed at the patients\u0026rsquo; latest follow-up. For genotype-phenotype association analysis, \u003cem\u003eRS1\u003c/em\u003e variants were classified as missense variants or truncating variants (including deletions, nonsense mutations, splice site mutations, and frameshift mutations). Truncation status was confirmed through literature review [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eClassification of OCT Findings\u003c/h3\u003e\n\u003cp\u003eThe OCT-based phenotypes of XLRS patients were classified into five distinct types (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Types 1A, 1B, 2, 5A, and 5B are all categorized primarily by the status of the outer retinal layers (EZ and IZ), which are visibly preserved, partially disrupted, or absent in the respective representative images. In contrast, Types 3 and 4 are defined by distinct morphological features: lamellar hole and extreme thickening, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eType 1A: Foveoschisis with intact outer retinal layers, regardless of the involvement of schisis in the outer nuclear layer (ONL) and/or inner nuclear layer (INL).\u003c/p\u003e\n\u003cp\u003eType 1B: Foveoschisis with partially intact outer retinal layers, regardless of the involvement of schisis in the ONL and/or INL.\u003c/p\u003e\n\u003cp\u003eType 2: Foveoschisis with total loss of the outer retinal layers, regardless of the involvement of schisis in the ONL and/or INL.\u003c/p\u003e\n\u003cp\u003eType 3: Degenerative lamellar hole with or without outer retintal layers.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eThe term \u0026ldquo;degenerative lamellar hole\u0026rdquo; refers to a central macular lesion characterized by a foveal depression with residual inner retinal tissue. This condition reflects a degenerative remodeling process, likely following the collapse of a schisis cavity, and is anatomically distinct from a full-thickness macular hole.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eOnly four eyes were classified as Type 3, with three demonstrating complete loss of the outer retinal layers and one eye showing preserved outer retinal layers. However, all of these eyes exhibited poor visual outcomes, with BCVA worse than 0.05.\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eType 4: Extensive foveoschisis (macular average thickness exceeding 800 \u0026micro;m with no outer retinal layers)\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eThe cut-off value of 800 \u0026micro;m used to define Type 4 was determined based on the internal distribution of macular thickness within our cohort. This threshold was chosen to distinguish eyes with anatomically excessive foveoschisis from those with only moderate thickening, such as in Type 2. Given that typical XLRS-related foveoschisis usually falls within the 400\u0026ndash;600 \u0026micro;m range, values exceeding 800 \u0026micro;m were rare\u0026mdash;occurring in fewer than 10% of eyes in our cohort..\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eType 5A: Atrophic type with intact outer retinal layers.\u003c/p\u003e\n\u003cp\u003eType 5B: Atrophic type with loss of the outer retinal layers.\u003c/p\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical Analysis\u003c/h2\u003e\n \u003cp\u003eAll statistical analyses were performed using Python version 3.9.19 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.python.org\u003c/span\u003e\u003c/span\u003e), along with SciPy library (version 1.13.1) and the Statsmodels library (version 0.14.4). For descriptive analyses, continuous variables were presented as either means with standard deviations (SD) or medians with interquartile ranges (IQRs)., and categorical variables were expressed as frequency (%). Statistical significance was set at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. To account for the confounding effects of binocular data from the same patients, a linear mixed model was used to analyze continuous variables, and a generalized estimating equation was applied for categorical variables. For multiple pairwise comparisons, the Benjamini-Hochberg adjustment method was employed to minimize the risk of type I errors.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eClinical Characteristics and Visual Function in X-linked Retinoschisis\u003c/h2\u003e\u003cp\u003eA total of 72 patients from 64 families, harboring 35 distinct \u003cem\u003eRS1\u003c/em\u003e genetic variants, were included in this analysis. Among these patients, 40 (55.6%) reported a positive family history. The median age at the last OCT examination was 12.7 years (IQR, 9.0\u0026ndash;19.6 years; range, 4.3\u0026ndash;43.6 years). The mean best-corrected visual acuity (BCVA) at the last OCT examination was 0.68\u0026thinsp;\u0026plusmn;\u0026thinsp;0.39 logMAR (range, 0.18-2.0) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDemographics and Baseline Characteristics of X-Linked Retinoschisis Patients.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eGeneral information of 72 patients from families with \u003cem\u003eRS1\u003c/em\u003e mutation\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eData XRLS patients (n\u0026thinsp;=\u0026thinsp;72)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePositive family history\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e55.6% (40/72)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMale\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e100.0% (72/72)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge at the last OCT examination (years)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e15.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMedian (IQR)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e12.7 (Q1: 9.0, Q3: 19.6)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRange\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e4.3\u0026ndash;43.6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBCVA (n\u0026thinsp;=\u0026thinsp;139 eyes)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, in logMAR\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e0.68\u0026thinsp;\u0026plusmn;\u0026thinsp;0.39\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMedian BCVA, in logMAR (IQR)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e0.50 (Q1: 0.40, Q3: 0.80)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRange\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e0.18-2.0\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003cb\u003eBCVA\u0026thinsp;=\u0026thinsp;best corrected visual acuity; IQR\u0026thinsp;=\u0026thinsp;interquartile range; logMAR\u0026thinsp;=\u0026thinsp;logarithm of the minimum angle of resolution; n. = number; OCT\u0026thinsp;=\u0026thinsp;optical coherence tomography; Q\u0026thinsp;=\u0026thinsp;quarter; RS1\u0026thinsp;=\u0026thinsp;retinoschisin 1; SD\u0026thinsp;=\u0026thinsp;standard deviation; XLRS\u0026thinsp;=\u0026thinsp;X-linked retinoschisis\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eDemographic Data based on the OCT Types in Patients with X-linked Retinoschisis\u003c/h3\u003e\n\u003cp\u003eA total of 139 eyes of 72 patients were included in the analysis. Among the OCT types, Type 1 was the most common, with Type 1A observed in 51 eyes (36.7%) and Type 1B observed in 31 eyes (22.3%) out of 139 eyes. The mean age of patients with Type 1A and Type 1B was 12.08\u0026thinsp;\u0026plusmn;\u0026thinsp;6.42 years and 15.03\u0026thinsp;\u0026plusmn;\u0026thinsp;8.38 years, respectively. Type 2 was identified in 15 eyes (10.8%), with a mean age of 14.95\u0026thinsp;\u0026plusmn;\u0026thinsp;6.07 years. Type 3, representing the least common OCT type, was identified in 4 eyes (2.9%) with a mean age of 13.61\u0026thinsp;\u0026plusmn;\u0026thinsp;4.92 years. Type 4 was present in 9 eyes (6.5%) with a mean age of 13.29\u0026thinsp;\u0026plusmn;\u0026thinsp;5.32 years. Type 5 had the oldest mean age, being atrophic type. Type 5A was observed in 14 eyes (10.0%) with a mean age of 20.64\u0026thinsp;\u0026plusmn;\u0026thinsp;14.75 years, while type 5B was identified in 15 eyes (10.8%) with a mean age of 26.07\u0026thinsp;\u0026plusmn;\u0026thinsp;10.18 years (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eFrequency, BCVA, and Age According to OCT Types.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOCT types\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003en/total (%)\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;139 eyes)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1A\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e51/139 (36.7%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD in logMAR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.46\u0026thinsp;\u0026plusmn;\u0026thinsp;0.18\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD in age\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e12.08\u0026thinsp;\u0026plusmn;\u0026thinsp;6.42\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e1B\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e31/139 (22.3%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD in logMAR\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e0.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.33\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD in age\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e15.03\u0026thinsp;\u0026plusmn;\u0026thinsp;8.38\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e15/139 (10.8%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD in logMAR\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e0.74\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD in age\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e14.95\u0026thinsp;\u0026plusmn;\u0026thinsp;6.07\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e4/139 (2.9%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD in logMAR\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e1.35\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD in age\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e13.61\u0026thinsp;\u0026plusmn;\u0026thinsp;4.92\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e9/139 (6.5%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD in logMAR\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e1.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.44\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD in age\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e13.29\u0026thinsp;\u0026plusmn;\u0026thinsp;5.32\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e5A\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e14/139 (10.0%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD in logMAR\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e0.48\u0026thinsp;\u0026plusmn;\u0026thinsp;0.27\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD in age\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e20.64\u0026thinsp;\u0026plusmn;\u0026thinsp;14.75\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e5B\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e15/139 (10.8%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD in logMAR\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e1.03\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD in age\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e26.07\u0026thinsp;\u0026plusmn;\u0026thinsp;10.18\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003cb\u003eBCVA\u0026thinsp;=\u0026thinsp;best corrected visual acuity; logMAR\u0026thinsp;=\u0026thinsp;logarithm of the minimum angle of resolution; n\u0026thinsp;=\u0026thinsp;number; OCT\u0026thinsp;=\u0026thinsp;optical coherence tomography; SD\u0026thinsp;=\u0026thinsp;standard deviation\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eComparison of BCVA based on the OCT Types in Patients with X-linked Retinoschisis\u003c/h3\u003e\n\u003cp\u003eThe BCVA outcomes showed significant variation across OCT types (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Type 1A demonstrated the best BCVA (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, 0.46\u0026thinsp;\u0026plusmn;\u0026thinsp;0.18 logMAR), which was statistically superior to Type 1B (0.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.33 logMAR), Type 2 (0.74\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28 logMAR), Type 4 (1.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.44 logMAR), and Type 5B (1.03\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47 logMAR) (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Type 5A exhibited BCVA comparable to Type 1A (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.958) and significantly better than that of Type 2 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023), Type 4 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and Type 5B (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). BCVA in Type 1B (0.70\u0026thinsp;\u0026plusmn;\u0026thinsp;0.33 logMAR) and Type 2 (0.74\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28 logMAR) was intermediate, significantly worse than that of Type 1A (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004, respectively) but better than Type 4 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004, respectively) and Type 5B (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009, respectively). However, they differed in that the mean BCVA of Type 1B was marginally lower than that of Type 5A (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.060), whereas Type 2 had a significantly lower BCVA compared to Type 5A (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023). It should be noted that the number of eyes in Type 3 was too small for inclusion in the statistical analysis. However, Type 3 had the worst vision, with a mean BCVA of 1.35\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47 logMAR. Overall, Type 3, 4 and 5B demonstrated the poorest BCVA values, reflecting OCT phenotypes commonly characterized by severe structural disruptions, including extensive loss of the outer retinal layers and atrophic change of macula.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComparison of BCVA Based on OCT Types in X-Linked Retinoschisis Patients.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaseline Type\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1A\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1B\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e5A\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e5B\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1A\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.21\u003c/p\u003e\u003cp\u003e(\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.29\u003c/p\u003e\u003cp\u003e(\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.71\u003c/p\u003e\u003cp\u003e(\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026le;\u0026thinsp;0.001)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0.01\u003c/p\u003e\u003cp\u003e(\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.958)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.62\u003c/p\u003e\u003cp\u003e(\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026le;\u0026thinsp;0.001)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1B\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.21\u003c/p\u003e\u003cp\u003e(\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.08\u003c/p\u003e\u003cp\u003e(\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.467)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.50\u003c/p\u003e\u003cp\u003e(\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026le;\u0026thinsp;0.001)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0.21\u003c/p\u003e\u003cp\u003e(\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.060)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.41\u003c/p\u003e\u003cp\u003e(\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026le;\u0026thinsp;0.001)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e-0.29\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;0.004)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e-0.08\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;0.467)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003eN/A\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.41\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;0.004)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e-0.30\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;0.023)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e0.33\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;0.009)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e-0.71\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e\u0026le;\u0026thinsp;0.001)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e-0.50\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e\u0026le;\u0026thinsp;0.001)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e-0.41\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;0.004)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eN/A\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e-0.71\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e\u0026le;\u0026thinsp;0.001)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e-0.09\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;0.558)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e5A\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e0.01\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;0.958)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e0.21\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;0.060)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.30\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;0.023)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.71\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e\u0026le;\u0026thinsp;0.001)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003eN/A\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e0.62\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e\u0026le;\u0026thinsp;0.001)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e5B\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e-0.62\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e\u0026le;\u0026thinsp;0.001)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e-0.41\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e\u0026le;\u0026thinsp;0.001)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e-0.33\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;0.009)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.09\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;0.558)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e-0.62\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e\u0026le;\u0026thinsp;0.001)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003eN/A\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cb\u003eBCVA\u0026thinsp;=\u0026thinsp;best corrected visual acuity; N/A\u0026thinsp;=\u0026thinsp;Not applicable\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cb\u003e* Continuous variables were analyzed by Generalized linear mixed model.\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eGenetic Characteristics in X-Linked Retinoschisis Patients\u003c/h2\u003e\u003cp\u003eA total of 35 disease-causing variants in the \u003cem\u003eRS1\u003c/em\u003e gene were identified in this cohort. Among these, 27 (77.1%) were missense variants, 1 (2.9%) was a nonsense variant, 3 (8.6%) were splice-site variants, and 4 (11.4%) were frameshift variants. Missense variants were the most common, accounting for 64 of the 72 patients (88.9%), whereas truncating variants\u0026mdash;including nonsense, splice-site, and frameshift mutations\u0026mdash;were observed in 8 of 72 patients (11.1%). The majority of genetic variants were localized in the discoidin domain-encoding exons (exons 4, 5, and 6). The three most common variants were the founder variant c.286T\u0026thinsp;\u0026gt;\u0026thinsp;C (p.Trp96Arg), identified in 7 patients (9.7%); c.589C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg197Cys), observed in 7 patients (9.7%); and c.590G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Arg197His), found in 6 patients (8.3%). Meanwhile, c.499A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Lys167Glu), known as one of the most common variants causing XLRS, was found in only 1 patient (1.4%). A comprehensive summary of frequent genetic variants and their distribution with OCT types is presented in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e and Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eFrequent Variants in X-Linked Retinoschisis Patients.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"10\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariants No.\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eComplementary DNA\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eProtein\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLocation (Exon/Intron)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eProtein domain\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMutation type\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePatients (n)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePedigree (n)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePatients (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePedigree (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.78\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSplice_donor_variant \u0026amp; intron_variant\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIntron 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSplice site mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.97delT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Trp33fs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFrameshift mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.130_140del*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Gly44fs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFrameshift mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.150G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Trp50* premature stop\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNonsense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.188G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Cys63Tyr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExon 4 deletion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFrameshift mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e7\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.214G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Glu72Lys\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e4.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e4.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.286T\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Trp96Arg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e9.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e10.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e9\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.302C\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Ala101Asp\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.305G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Arg102Gln\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e11\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.306_308dupGCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Leu103dup\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFrameshift mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e12\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.325G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Gly109Arg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e13\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.326\u0026thinsp;+\u0026thinsp;2T\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSplice_donor_variant \u0026amp; intron_variant\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSplice site mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e14\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.328T\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Cys110Arg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e15\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.331G\u0026thinsp;\u0026gt;\u0026thinsp;A*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Ala111Thr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e16\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.404G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Gly135Glu\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e17\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.410T\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Leu137Pro\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e6.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e6.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e18\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.421C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Arg141Cys\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e2.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e19\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.422G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Arg141His\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e6.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e4.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e20\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.426T\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Cys142Trp\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e21\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.433G\u0026thinsp;\u0026gt;\u0026thinsp;T*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Asp145Tyr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e22\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.499A\u0026thinsp;\u0026gt;\u0026thinsp;G*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Lys167Glu\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e23\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.522\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSplice_donor_variant \u0026amp; intron_variant\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIntron 5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSplice site mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e24\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.544C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Arg182Cys\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e2.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e25\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.574C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Pro192Ser\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e2.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e26\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.577C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Pro193Ser\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e27\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.578C\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Pro193Arg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e28\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.589C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Arg197Cys\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e9.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e9.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e29\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.590G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Arg197His\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e8.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e7.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e30\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.608C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Pro203Leu\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e31\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.617G\u0026thinsp;\u0026gt;\u0026thinsp;C*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Trp206Ser\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e32\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.625C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Arg209Cys\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e6.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e6.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e33\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.638G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Arg213Gln\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e34\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.647T\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Leu216Pro\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e5.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e6.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e35\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.668G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Cys223Tyr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExon 6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDS domain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMissense mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e72\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e64\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e100.0\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e100.0\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"10\"\u003e\u003cb\u003eA\u0026thinsp;=\u0026thinsp;adenine; Ala\u0026thinsp;=\u0026thinsp;Alanine; Arg\u0026thinsp;=\u0026thinsp;Arginine; Asp\u0026thinsp;=\u0026thinsp;Aspartic acid; C\u0026thinsp;=\u0026thinsp;cytosine; Cys\u0026thinsp;=\u0026thinsp;Cysteine; del\u0026thinsp;=\u0026thinsp;deletion; DS domain\u0026thinsp;=\u0026thinsp;discoidin domain; dup\u0026thinsp;=\u0026thinsp;duplication; fs\u0026thinsp;=\u0026thinsp;frameshift; G\u0026thinsp;=\u0026thinsp;guanine; Gln\u0026thinsp;=\u0026thinsp;Glutamine; Glu\u0026thinsp;=\u0026thinsp;Glutamic acid; Gly\u0026thinsp;=\u0026thinsp;Glycine; His\u0026thinsp;=\u0026thinsp;Histidine ; Leu\u0026thinsp;=\u0026thinsp;Leucine; Lys\u0026thinsp;=\u0026thinsp;Lysine; n\u0026thinsp;=\u0026thinsp;number; Pro\u0026thinsp;=\u0026thinsp;Proline; RS domain\u0026thinsp;=\u0026thinsp;Retinoschisin 1 domain; Ser\u0026thinsp;=\u0026thinsp;Serine; T\u0026thinsp;=\u0026thinsp;thymine; Thr\u0026thinsp;=\u0026thinsp;Threonine; Trp\u0026thinsp;=\u0026thinsp;Tryptophan; Tyr\u0026thinsp;=\u0026thinsp;Tyrosine; Val\u0026thinsp;=\u0026thinsp;Valine\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eGenotype-Phenotype Association: Comparison of Truncating and Missense Variants\u003c/h2\u003e\u003cp\u003eThe BCVA, age, and OCT types were compared among genotype groups (truncating vs. missense variants). No significant differences were observed in BCVA or age between the truncating variant group (BCVA: 0.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.42 logMAR, age: 18.43\u0026thinsp;\u0026plusmn;\u0026thinsp;10.76 years) and the missense variant group (BCVA: 0.70\u0026thinsp;\u0026plusmn;\u0026thinsp;0.39 logMAR, age: 15.16\u0026thinsp;\u0026plusmn;\u0026thinsp;9.09 years) (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.692, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.559, respectively). By excluding the OCT types with perfect separation (Types 2, 3, 4, and 5A) and a single case (Type 5B) in the truncating variant group, older age was associated with the truncating variant compared to the missense variant (OR\u0026thinsp;=\u0026thinsp;1.13, 95% CI: 1.02\u0026ndash;1.24, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016), while OCT Type and BCVA were not significant factors (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.225, and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.395, respectively) (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e and Supplementary Table S2).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eFactors Associated with Truncating Mutations Using a Generalied Estimating Equation\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOR (95% CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBCVA\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3.10 (0.23, 42.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.395\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.13 (1.02, 1.24)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.016\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eOCT Subtype (1A, baseline)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e1B\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.29 (0.04, 2.14)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.225\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003cb\u003eBCVA\u0026thinsp;=\u0026thinsp;best corrected visual acuity; OCT\u0026thinsp;=\u0026thinsp;optical coherence tomography; OR\u0026thinsp;=\u0026thinsp;odds ratio\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn the present study, we reviewed the clinical and genetic features in a Korean cohort of 72 XLRS patients, each harboring one of 35 \u003cem\u003eRS1\u003c/em\u003e genetic variants, from Seoul National University Hospital. This study introduces a novel OCT-based classification system for XLRS, delineating five distinct phenotypic types with implications for visual outcomes and genotype-phenotype associations. The results demonstrate that the integrity of the outer retinal layers is a critical determinant of BCVA. Specifically, Types 1A and 5A exhibited the best BCVA, whereas severe structural disruption on OCT (Types 3, 4, and 5B) was associated with significantly worse visual outcomes. No significant differences were observed in BCVA and age between the truncating variant group and the missense variant group. However, older age was significantly associated with the truncating variant compared to the missense variant within Type 1.\u003c/p\u003e\u003cp\u003eOverall, XLRS patients in the current study demonstrated mild to moderate visual impairment, with a mean last available BCVA of 0.68\u0026thinsp;\u0026plusmn;\u0026thinsp;0.39 logMAR at a mean age of 15.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.3 years (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The BCVA in this cohort is slightly worse than that reported in an Italian pediatric cohort, which observed a mean BCVA of 0.55 logMAR at a younger mean age of 12.5 years, possibly due to earlier diagnosis [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Similarly, the Japanese and French cohorts reported comparable BCVA values of approximately 0.6 logMAR at slightly older mean age of 19.1 and 24 years, respectively, suggesting relatively worse visual acuity in the current study when age is considered [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. In contrast, a Chinese cohort reported a mean BCVA of 0.81 logMAR with a comparable mean age of 17.3 years, indicating worse visual outcomes compared to the present cohort, which may reflect a higher prevalence of severe genotypes in their sample [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. These comparisons highlight the varying degrees of visual impairment across diverse populations, emphasizing the influence of age, and genotype-associated disease severity on visual outcomes in XLRS patients.\u003c/p\u003e\u003cp\u003eThrough OCT analysis, we classified the phenotypes of XLRS patients into five main types; 1A, 1B, 2, 3, 4, 5A, 5B (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The most common type was Type 1A, accounting for 36.7% of eyes, with a mean BCVA of 0.46 logMAR at a mean age of 12.1 years. Type 1B comprised 22.3% of eyes, showing slightly worse BCVA (0.70 logMAR) and an older mean age of 15.0 years. Types associated with more extensive outer retinal damage, such as Type 2 (10.8%), Type 3 (2.9%), Type 4 (6.5%) and Type 5B (10.8%), demonstrated progressively worse BCVA, with the poorest mean BCVA of 1.35 logMAR observed in Type 3. Type 5 was further categorized into 5A (10.0%) and 5B (10.8%) based on the integrity of outer retina layers. This type exhibited a notable trend, with increasing mean age (20.6 years in 5A and 26.1 years in 5B) compared to the other types, as the development of retinal atrophy becomes more evident with age. Although Type 5A and 5B share common features, such as the absence of schisis and temporal retinal thinning due to atrophic changes, they showed an inverse relationship in BCVA from 0.48 logMAR in 5A to 1.03 logMAR in 5B. It is natural that 5B has the poor BCVA because of atrophy of neuroretina and retinal pigment epithelium with age, and our findings are consistent with previous studies suggesting that outer retinal atrophy typically develops between the ages of 20 and 40 [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. However, Type 5A differs significantly from Type 5B in many ways. First, Type 5A demonstrated the best visual outcomes, comparable to Type 1A. Secondly, the mean age of Type 5A is five to six years younger than Type 5B. Lastly, Type 5B is definitely the end stage of XLRS in terms of visual acuity and anatomical figure, while Type 5A appears to be a transitional form evolving from Type 1A or 1B to Type 2 or Type 4 based on its intermediate structural characteristics observed across the cohort, although longitudinal OCT follow-up was not performed to confirm this progression. The mechanisms behind the fluctuation of macular thickness and the presence or absence of schisis remain unclear. However, the role of M\u0026uuml;ller cells is considered to be involved, as the appearance of temporal thinning in Type 5 closely resembles that seen in MacTel type 2. Given that M\u0026uuml;ller cells play a critical role in regulating water homeostasis and retinal blood flow, their dysfunction may contribute to these findings [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eGeneralized linear mixed model analysis revealed significant differences in BCVA across OCT types, underscoring the prognostic value of OCT-based typing in XLRS (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). As described in the results, disease progression in terms of BCVA can be categorized as follows; Types 1A and 5A represent early-stage, 1B and 2 as intermediate stage, and 3, 4, and 5B as end-stage. Interestingly, the mean BCVA of Type 1B (characterized by partial loss of outer retinal layers) resulted in a similar moderate visual deficit compared to that of Type 2, which exhibited complete loss of outer retinal integrity. This finding may be explained by the discrepancy between OCT and histologic findings reported in MacTel type2 patients. Histological studies have identified the presence of cone cells one year after the ellipsoid zone was observed to be absent on OCT. Thus, the absence of ellipsoid zone on OCT should not be interpreted as a complete loss of photoreceptors but rather as an indication of conditions that degrade the ellipsoid zone signal from the fovea [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAdditionally, we aimed to explore potential genotype-phenotype correlations within these OCT types. Among the 35 disease-causing RS1 gene variants identified in our cohort, missense variants were most prevalent (77.1%, 27/35), consistent with previous reports [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Truncating variants, including nonsense, splice-site, and frameshift mutations, accounted for 11.1% (8/72) of patients. Most variants were located in the discoidin domain-encoding exons (exons 4\u0026ndash;6), with the three most frequent variants being c.286T\u0026thinsp;\u0026gt;\u0026thinsp;C (p.Trp96Arg) and c.589C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg197Cys) in 9.7% each, and c.590G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Arg197His) in 8.3% of patients (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Although no significant differences in BCVA or age at the time of OCT were observed between patients with truncating and missense variants overall, a subgroup analysis within Type 1 revealed that older age was significantly associated with truncating variants (OR\u0026thinsp;=\u0026thinsp;1.13, 95% CI: 1.02\u0026ndash;1.24, p\u0026thinsp;=\u0026thinsp;0.016). Considering that XLRS patients may experience an annual decline in visual acuity after their twenties, as reported in previous studies [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], this finding may indicate that patients with the truncating variants experience a gradual deterioration of the outer retinal layers that occurs more slowly than in patients with missense variants. This result suggests that earlier intervention with future therapies may be particularly beneficial for patients with missense variants to prevent deterioration of photoreceptor function. However, given the relatively low proportion of truncating variants in this cohort, the statistical power to detect genotype-phenotype correlations was limited. This may partly explain the discrepancy between our findings and those of a larger multicenter study that reported worse visual acuity among patients with truncating variants [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Future investigations involving larger, multinational cohorts are warranted to confirm this finding and better understand the progression of XLRS across different genotypes.\u003c/p\u003e\u003cp\u003eThe main limitations of our study are the retrospective design and relatively small sample size. The absence of longitudinal OCT data may limit the ability to assess disease progression over time or establish robust genotype\u0026ndash;phenotype correlations. Moreover, as the study cohort consisted exclusively of Korean patients, the generalizability of our findings to other ethnic populations may be limited. Despite these limitations, this study presents a well-characterized and genetically confirmed cohort within a relatively homogeneous population, allowing for a focused investigation of structural phenotypes using a novel OCT-based classification system.\u003c/p\u003e\u003cp\u003eIn conclusion, this study introduces a clinically useful OCT-based classification system for patients with XLRS, enabling a more precise assessment of structural phenotypes and their relationship to visual function. This comparative analysis highlights the utility of the proposed OCT-based classification system in bridging genotype-phenotype variability across different populations, complemented by detailed structural insights that enhance our understanding of visual function in XLRS. Despite the aforementioned limitations, this OCT-based classification system would provide a valuable framework for guiding the natural history and personalized therapeutic strategies, including the selection of suitable candidates for emerging treatments like gene therapy for XLRS patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eBCVA\u003c/strong\u003e = best corrected visual acuity;\u0026nbsp;\u003cstrong\u003eD\u003c/strong\u003e = diopter;\u003cstrong\u003e\u0026nbsp;IQR\u003c/strong\u003e= interquartile range;\u0026nbsp;\u003cstrong\u003elogMAR\u003c/strong\u003e= logarithm of the minimum angle of resolution;\u0026nbsp;\u003cstrong\u003eRS1\u003c/strong\u003e = retinoschisin 1;\u0026nbsp;\u003cstrong\u003eXLRS\u0026nbsp;\u003c/strong\u003e= X-linked retinoschisis\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all the participants included in the cohorts analyzed in this study, as well as all the team members of the pediatric ophthalmology department at Seoul National University Children\u0026rsquo;s Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was supported by the Seoul National University Hospital Research Grant (04-2024-0420 to K.H. Lee); the Seoul National University Hospital Research Grant (18-2023-0010 to J.H.K.); the Kun-hee Lee Child Cancer \u0026amp; Rare Disease Project, Republic of Korea (202200004004 to J.H.K.); and the National Research Council of Science \u0026amp; Technology (NST) Grant by the Korean government (GTL24021-520 to J.H.K.).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConception and design:\u003c/strong\u003e Kihwang Lee\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDraft writing:\u003c/strong\u003e Seok Jae Lee, Kihwang Lee\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnalysis and interpretation:\u003c/strong\u003e Seok Jae Lee, Richul Oh, Kihwang Lee\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection:\u003c/strong\u003e Seok Jae Lee, Richul Oh, Hyun Chul Jeong, Seung Woo Choi, Eun Kyoung Lee, Dong Hyun Jo, Chang Ki Yoon, Un Chul Park, Jeong Hun Kim, Kyu Hyung Park\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOverall responsibilit\u003c/strong\u003ey: Kihwang Lee\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was reviewed and approved by the Institutional Review Board of Seoul National University Hospital (IRB No. E-2406-001-1539), and all procedures were conducted in accordance with the ethical standards of the Declaration of Helsinki. Given the retrospective nature of the study and use of de-identified data, the requirement for written informed consent was waived by the IRB.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish declaration\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors have declared no conflicts of interest in connection with this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that all data supporting the findings of this study are available within the paper and its extended data and supplemental information files. The datasets generated during or analyzed in the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSauer CG, Gehrig A, Warneke-Wittstock R, Marquardt A, Ewing CC, Gibson A, Lorenz B, Jurklies B, Weber BH. Positional cloning of the gene associated with X-linked juvenile retinoschisis. Nat Genet. 1997;17(2):164\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHeymann JB, Vijayasarathy C, Fariss RN, Sieving PA. Advances in understanding the molecular structure of retinoschisin while questions remain of biological function. Prog Retin Eye Res. 2023;95:101147.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMolday RS, Kellner U, Weber BH. X-linked juvenile retinoschisis: Clinical diagnosis, genetic analysis, and molecular mechanisms. 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Ophthalmic Genet 2022:1\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFenner BJ, Russell JF, Drack AV, Dumitrescu AV, Sohn EH, Russell SR, Boldt HC, Affatigato LM, Hoffmann JM, Andorf JL, et al. Long-term functional and structural outcomes in X-linked retinoschisis: implications for clinical trials. Front Med (Lausanne). 2023;10:1204095.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDaruich A, Matet A, Moulin A, Kowalczuk L, Nicolas M, Sellam A, Rothschild PR, Omri S, G\u0026eacute;liz\u0026eacute; E, Jonet L, et al. Mechanisms of macular edema: Beyond the surface. Prog Retin Eye Res. 2018;63:20\u0026ndash;68.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBringmann A, Pannicke T, Grosche J, Francke M, Wiedemann P, Skatchkov SN, Osborne NN, Reichenbach A. M\u0026uuml;ller cells in the healthy and diseased retina. Prog Retin Eye Res. 2006;25(4):397\u0026ndash;424.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePowner MB, Gillies MC, Zhu M, Vevis K, Hunyor AP, Fruttiger M. Loss of M\u0026uuml;ller's cells and photoreceptors in macular telangiectasia type 2. Ophthalmology. 2013;120(11):2344\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Genotype, Mutation spectrum, Optical coherence tomography, X-linked Retinoschisis","lastPublishedDoi":"10.21203/rs.3.rs-7363735/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7363735/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo develop and apply a novel optical coherence tomography (OCT)-based classification system for X-linked retinoschisis (XLRS) and evaluate its association with best-corrected visual acuity (BCVA) and \u003cem\u003eRS1 \u003c/em\u003egenotypes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this retrospective cohort study, 72 patients (139 eyes) with molecularly confirmed XLRS from a tertiary referral center were analyzed. Spectral-domain OCT images were classified into five phenotypic types (1A, 1B, 2, 3, 4, and 5A, 5B) based on foveoschisis configuration and outer retinal layer integrity. Associations between OCT types and BCVA, age, and genotype (truncating vs. missense) were evaluated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 139 eyes were analyzed (mean age 15.5 ± 9.3 years). BCVA ranged from 2.0 to 0.18 logMAR (mean 0.68 ± 0.39). Type 1A had the best BCVA, significantly outperforming Types 2, 3, 4, and 5B (\u003cem\u003ep\u003c/em\u003e\u0026lt;0.01). Type 5A showed comparable BCVA to 1A and outperformed all other types except 1A and 1B. Types 3, 4, and 5B exhibited worse BCVA, with complete outer retinal layer loss. No significant BCVA or age differences were observed between truncating and missense variants (\u003cem\u003ep\u003c/em\u003e=0.692, \u003cem\u003ep\u003c/em\u003e=0.559). However, truncating variants were associated with older age within Type 1 (OR = 1.13, 95% CI: 1.02–1.24, p=0.016), suggesting a slower but progressive visual decline compared to missense variants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis OCT-based classification reflects structural severity and correlates with visual function in XLRS. It supports phenotype-based risk stratification and may guide patient selection and monitoring in gene therapy trials for XLRS.\u003c/p\u003e","manuscriptTitle":"A Classification System Using Optical Coherence Tomography for X-linked Retinoschisis and Its Association with Genetic Variants","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-01 09:46:59","doi":"10.21203/rs.3.rs-7363735/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"186242811306084136435386590861060854049","date":"2026-05-01T18:25:24+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-29T16:35:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"67647812318069610596887521107339740714","date":"2025-10-15T13:26:10+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-20T16:08:48+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-08-18T05:23:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-13T23:25:37+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-13T23:25:04+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Ophthalmology","date":"2025-08-13T10:03:14+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ee99dd52-c883-4aff-b0ec-5fb402f1cac7","owner":[],"postedDate":"September 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-09-01T09:46:59+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-01 09:46:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7363735","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7363735","identity":"rs-7363735","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}