Natural History of Retinitis Pigmentosa Associated With the C.4120c>t Eys Variant

Natural History of Retinitis Pigmentosa Associated With the C.4120c>t Eys Variant | 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 Natural History of Retinitis Pigmentosa Associated With the C.4120c>t Eys Variant Maria Franca, Anabela Pereira, Ana Luísa Carvalho, Henrique Alves, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8495428/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Eyes shut homolog ( EYS ) is the gene most frequently associated with autosomal recessive retinitis pigmentosa (RP) in Portugal. This study describes the progression of RP associated with the EYS (NM_001142800.2):c.4120C>T(p.Arg1374*) variant by correlating functional and structural measures with patient-reported outcomes (PRO). Methods Study conducted at a Portuguese reference center for inherited retinal diseases. Patients with EYS-associated disease, with at least one c.4120C>T variant were identified using the IRD-PT registry (retina.com.pt). Other inclusion criteria were: at least 36 months of follow-up and baseline/last visit best-corrected visual acuity (BCVA), spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence phenotype and PRO (Michigan Retinal Degeneration Questionnaire (MRDQ); Michigan Vision-Related Anxiety Questionnaire (MVAQ)) data. Baseline and follow-up parameters were compared. Results Eleven patients (9 families; 72.7% men; mean age of 43.8 ± 11.29 years) were included. Among the 11 patients carrying the variant, 3 (27.3%) were homozygous and 8 (72.7%) compound heterozygous. Mean follow-up was 43.2 ± 1.2 months. In the better-seeing eye, BCVA deteriorated significantly ( p =0.007). There was a significant worsening in MRDQ (central vision, p =0.006; photopic peripheral function, p =0.033) and a significant increase in cone-related anxiety on the MVAQ ( p =0.008). Structural parameters, including EZ area, showed no statistically significant change ( p= 0.130). Changes in rod/cone anxiety correlated moderately ( r =0.692; p =0.018) and scotopic deterioration was strongly associated with mesopic peripheral limitation ( r= 0.873; p <0.001). Conclusion Disease progression was characterized by functional decline and increased psychosocial burden without significant structural deterioration. Integrating PRO with clinical and structural measures supports the design of therapeutic trials and clinical monitoring. Eye Diseases Hereditary Retinal Dystrophies EYS Retinitis Pigmentosa Patient Reported Outcome Measures Genetic Therapy Figures Figure 1 Figure 2 Figure 3 Key message Retinitis pigmentosa associated with the EYS gene, particularly the c.4120C>T variant, is one of the most frequent forms of autosomal recessive retinitis pigmentosa in Portugal and is characterized by relatively early onset, slow progression and marked interindividual clinical variability. Over the analyzed period, significant variations in functional measures and PRO were identified, including changes in best-corrected visual acuity and in PRO domains related to central vision and photopic peripheral function. No statistically significant structural changes were detected in SD-OCT biomarkers (ellipsoid zone area, PROS, FOSPET and FOSPET/PROS ratio), suggesting a dissociation between functional decline and measurable microstructural changes in this cohort. PRO, including increased cone-related anxiety, captured clinically meaningful aspects of disease progression that were not fully reflected by traditional structural measures, supporting their integration as key endpoints in clinical monitoring and therapeutic trial design. INTRODUCTION Retinitis pigmentosa (RP) is the most prevalent inherited retinal disease (IRD) globally and is characterized by the progressive degeneration of photoreceptors [ 1 ]. In 2025, Orphanet data reported a prevalence of approximately 1 in 33,333 individuals in Europe, with marked regional variations across the continent [ 1 , 2 ]. The Eyes shut homolog ( EYS , MIM *612424) gene was identified in 2008 as a causal gene for RP25, displaying an autosomal recessive inheritance pattern [ 3 ]. It is the third most frequently implicated gene in IRDs worldwide,[ 4 , 5 ] accounting for approximately 4.4% of all cases [ 6 ]. In Portugal, EYS is the second most commonly associated gene with IRDs [ 7 , 8 ]. Based on current knowledge, EYS is the largest gene expressed in the human eye [ 4 , 9 ]. The precise localization of EYS has not been fully resolved and it remains uncertain whether it is predominantly intracellular, intercellular and/or extracellular [ 3 , 10 ]. Existing data indicate that EYS may localize to the photoreceptor ciliary transition zone, near the basal region marked by acetylated α-tubulin, in both rods and cones. These observations have led to the hypothesis that EYS plays a role in maintaining photoreceptor architecture and structural stability [ 3 ]. Currently, 934 unique EYS gene variants have been documented [ 11 ]. Deep phenotyping has been crucial for expanding the clinical spectrum of disorders associated with this gene and identifying atypical phenotypes. The intra- and interfamilial variability observed among carriers of the same variants suggests an important contribution of genetic, epigenetic and environmental modifiers [ 7 , 12 ]. In the Portuguese population, the variants EYS (NM_001142800.1): c.(2023 + 1_2024-1)_(2259 + 1_2260-1)del p.?, EYS (NM_001142800.2): c.5928-2A > G p.? and EYS (NM_001142800.2): c.4120C > T p.(Arg1374*), are the most frequent, suggesting a possible European origin [ 7 , 8 ]. Recent assessments highlight the possibility that the c.4120C > T p.(Arg1374*) variant may be linked to a founder effect in the Leiria region [ 8 ]. However, this variant has also been reported in Dutch, Spanish and American cohorts [ 10 ]. Current therapeutic options for these patients are primarily supportive, highlighting the urgent need for emerging targeted therapies that could halt or prevent disease progression [ 3 ]. It is essential to define specific and measurable outcomes for evaluating the efficacy of potential treatments [ 13 , 14 ]. Patient-reported outcomes (PRO) are widely recognized as valid and meaningful endpoints in clinical trials [ 9 , 15 ]. These instruments provide valuable information on functional impact and quality of life, and validated tools such as the Michigan Retinal Degeneration Questionnaire (MRDQ)[ 16 ] and the Michigan Vision-Related Anxiety Questionnaire (MVAQ)[ 17 ] have recently been adapted for Portuguese-speaking populations [ 18 ]. Traditional functional metrics, particularly best-corrected visual acuity (BCVA), may not adequately capture disease progression in conditions that initially spare the macula [ 14 , 19 ]. Structural biomarkers such as ellipsoid zone (EZ) area on spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) patterns have therefore gained importance for disease staging and monitoring [ 14 , 20 , 21 ]. The aim of this study was to report the longitudinal natural history of EYS -related RP associated with the c.4120C > T variant, correlating clinician-reported outcomes (CRO) with patient-reported outcomes (PRO). MATERIALS AND METHODS Population and study design A retrospective cohort study was conducted at the reference center for IRDs within the ophthalmology and medical genetics departments of Unidade Local de Saúde (ULS) Coimbra . All data were collected and analyzed between June 2025 and October 2025. Medical records from patients with confirmed carrier status (homozygous or compound heterozygous genotype) of the c.4120C > T (p.Arg1374*) variant in the EYS gene were reviewed. These patients were identified through the Portuguese national registry of inherited retinal dystrophies (IRD-PT), integrated into the retina.com.pt platform (retina.com.pt) [ 22 ]. Only patients with at least 36 months of follow-up were included in the study. Baseline and last visit functional (BCVA), structural (SD-OCT) and PRO (MRDQ and MVAQ) data were recorded. Patients were excluded if clinical records were incomplete or lacked required assessments, if coexisting ocular or systemic conditions could affect vision, if prior retinal surgery or trauma could have altered retinal structure, or if they were unable to reliably complete the MRDQ or MVAQ. Ethics statement The study, included in the project “O papel da EYS na retina” , approved by the ethics committee of ULS Coimbra (175/24 CE, process number OBS.SF.107–2022), was conducted in accordance with the principles of the Declaration of Helsinki for biomedical research, and fully complied with the general data protection regulation and applicable national legislation. All patients provided written informed consent. All clinical data were anonymized to ensure confidentiality and prevent individual identification. Procedure Clinical records, including demographic information (age, sex, Portuguese region of residence), year, type and results of genetic testing, identified patients sharing a familial relationship and personal medical history, were collect from each individual patient file. Medical history included age at diagnosis, consanguinity, symptoms and age at symptom onset. To minimize the potential impact of recall bias, age at symptom onset was grouped into predefined timeframes: childhood (6–10 years), adolescence (11–20 years), early adulthood (21–30 years), adulthood (31–50 years) and elderly (> 51 years). Genetic variants were classified according to the guidelines of the American College of Medical Genetics and Genomics [ 23 ]. Self-assessment of visual function and psychosocial impact of vision loss The MRDQ evaluates the impact of visual impairment on daily tasks across five dimensions: reading; color and contrast; dark adaptation; mobility and peripheral vision; and light sensitivity. It comprises 59 items covering central vision (n = 11), color vision (n = 4), contrast sensitivity (n = 7), scotopic function (n = 12), photopic peripheral vision (n = 9), mesopic peripheral vision (n = 9) and photosensitivity (n = 7) [ 16 ]. The MVAQ is a 14-item instrument with two domains: rod-related functional anxiety (6 items) and cone-related anxiety (8 items) [ 17 ]. Neither questionnaire provides a composite score. Instead, based on item response theory, each domain generates a latent trait value ranging from − 3 to + 3 theta, where higher scores indicate greater functional difficulty (in the MRDQ) or higher levels of anxiety (in the MVAQ). The complete item lists are available in the original publications [ 16 , 17 ]. The questionnaires were clinician administered right after the clinic visit, with questions read aloud by the interviewer following predefined guidelines. Functional parameter: BCVA The Early Treatment of Diabetic Retinopathy Study (ETDRS) letter score was used to quantify BCVA. The ETDRS chart consists of 14 lines of five Sloan letters, arranged in logarithmic progression with proportional interline and interletter spacing to ensure uniform contour interaction. Visual acuity can be directly read from the same chart. For repeated testing, alternate charts were used to present different letter sequences. The standard testing distance is 4 m, although shorter distances may be used in cases of severe vision loss [ 23 ]. The eye with better EDTRS letter score was used as an indicator of visual function and was used as a functional parameter. Structural parameter: SD-OCT The optical coherence tomography (OCT) scans were acquired using the Spectralis HRA + OCT system (Heidelberg Engineering, Heidelberg, Germany) in both eyes. The images were independently analyzed by two masked medical graders (M.F. and J.P.M.), without access to clinical data or MRDQ/MVAQ scores. Disagreement was resolved by a senior grader (J.P.M.). Measurements included EZ width, photoreceptor outer segment length (PROS) and foveal outer segment pigment epithelial thickness (FOSPET). Using a previously reported methodology, the distance between the inner border of the EZ and the inner border of the retinal pigment epithelium, as well as the distance between the EZ and the outer border of the retinal pigment epithelium, were measured at the thinnest point of the fovea, thereby allowing the assessment of PROS and FOSPET, respectively (Fig. 1 ).[ 24 ] The foveal outer segment pigment epithelial thickness-photoreceptor outer segment length ratio (FPR), was also calculated (FOSPET/PROS ratio) [ 24 ]. The EZ width was quantified within the central 3 mm using horizontal and vertical line scans passing through the foveal center (Fig. 1 ). The EZ area was subsequently estimated using the ellipse formula, defined as π × (horizontal EZ/2) × (vertical EZ/2).[ 25 , 26 ] Structural parameter: ultra-widefield fundus autofluorescence (UW-FAF) patterns Retinal phenotype classification was based on UW-FAF imaging acquired with the Optos ® (Optos California, Optos GmbH, Germany) system. As no standardized classification exists for RP, criteria from prior studies describing abnormal FAF patterns in RP were applied [ 21 , 27 – 29 ]. Typical patterns of autofluorescence (AF) include the presence of a parafoveal ring of high-density AF, central hyperAF and central hypoAF. Other patterns were considered atypical. Phenotypes were categorized as typical or atypical by two medical graders (M.F. and J.P.M.), masked in patient identity, genetic testing results, visual acuity and MRDQ/MVAQ scores. Disagreement was resolved by a senior grader (J.P.M.). Statistical analysis The data were analyzed using IBM SPSS Statistics, version 30 (IBM, Armonk, NY, USA). Latent trait (theta) scores for each MRDQ and MVAQ domain were estimated using a graded response model with the expected-a-posteriori method. The normality of continuous variables was assessed with the Shapiro-Wilk test. Normally distributed data are reported as mean ± standard deviation (SD), whereas non-normally distributed variables are presented as median ± interquartile range (IQR). Categorical variables are summarized as frequencies and percentages. Descriptive statistics were used to characterize the study population and summarize variable distributions. Comparisons between homozygous and compound heterozygous patients were performed using Mann-Whitney U tests with exact p -values, due to small sample size. Paired comparisons between baseline and follow-up assessments were performed using paired-samples t-tests for normally distributed variables and the Wilcoxon signed-rank test otherwise. When comparing MRDQ domain scores treated as repeated measures, the Friedman test was applied. Associations between change scores (Δ = final - baseline) across domains were examined using Spearman’s rank correlation coefficient. Statistical significance was set at p < 0.05. RESULTS Eleven patients from 9 families (72.7% male), with a mean age of 43.82 ± 11.29 years (range 27–64) were included. All patients had a diagnosis of RP. The mean age at diagnosis was 35.73 ± 11.02 years (19–58). There was no history of consanguinity. Family history of the disease was reported in 54.5% of patients (n = 6). The cohort characterization, functional parameters and retinal structural measurements are summarized in Table 1 . In 9.1% of patients, symptoms began between 6 and 10 years. The most common age onset was 11–20 years (45%), followed by 21–30 years (36.4%), with 31–50 years accounting for the remaining 9.1%. Table 1 Clinical characteristics, functional parameters and retinal structural measurements of the cohort. DEMOGRAPHICS Number of patients, n 11 Age, years (mean ± SD) 43.82 ± 11.29 Age at diagnosis, years (mean ± SD) 35.73 ± 11.02 INITIAL BCVA (mean ± SD) Better seeing eye, ETDRS letters 67.55 ± 15.93 FINAL BCVA (mean ± SD) Better seeing eye, ETDRS letters 60.82 ± 17.34 INITIAL OCT (mean ± SD) EZ area (mm 2 ) 1.97 ± 1.85 PROS (µm) 43.64 ± 6.44 FOSPET (µm) 69.82 ± 10.51 FOSPET/PROS ratio 1.61 ± 0.13 FINAL OCT (mean ± SD) EZ area (mm 2 ) 1.49 ± 1.15 PROS (µm) 41.36 ± 9.89 FOSPET (µm) 67.73 ± 14.19 FOSPET/PROS ratio 1.68 ± 0.31 BCVA, best-corrected visual acuity; ETDRS, Early Treatment of Diabetic Retinopathy Study; EZ, ellipsoid zone; FOSPET, foveal outer segment pigment epithelial thickness; MRDQ, Michigan retinal degeneration questionnaire; MVAQ, Michigan vision-related anxiety questionnaire; OCT, optical coherence tomography; PROS, photoreceptor outer segment length; SD, standard deviation. For PRO, the progression of MRDQ and MVAQ scores across the evaluated domains are shown in Fig. 2 . All patients reported visual field constriction (100%) and nyctalopia (100%). Decreased visual acuity was reported by 72.73% of patients, whereas photophobia was reported by 9.09%. Regarding UW-FAF, 8 patients (72.7%) had typical findings, while the remaining 27.3% had atypical presentation (Fig. 3 ). No hypoAF pattern were observed in any of the patients. Among the 11 patients carrying the c.4120C > T variant, 3 (27.3%) were homozygous and 8 (72.7%) were compound heterozygous (Table 2 ). No statistically significant differences were observed between zygosity groups in age at symptom onset, Δ BCVA, Δ EZ area, Δ MRDQ or MVAQ domains (all p > 0.05). Table 2 Cohort’s genetic landscape of EYS variants Patient ID Family ID Nucleotide change Protein Change ACMG Classification Genetic test Year of genetic test Portuguese region 1 1 c.4120C > T p.(Arg1374*) Pathogenic MLPA NGS panel 2015 Coimbra c.2024-?_c.2259+?del p.(?) Pathogenic 2 2 c.4120C > T p.(Arg1374*) Pathogenic NGS panel 2020 Leiria c.9182_9185del p.(Asn3061Thrfs*3) Likely pathogenic 3 3 c.4120C > T p.(Arg1374*) Pathogenic Familial variant testing 2019 Lisboa c.9337A > T p.(Lys3113*) Likely pathogenic 4 4 c.4120C > T p.(Arg1374*) Pathogenic NGS panel 2016 Porto c.4120C > T p.(Arg1374*) Pathogenic 5 5 c.4120C > T p.(Arg1374*) Pathogenic MLPA WES 2019 Leiria c.(862 + 1_863-1)_(1056 + 1_1184 + 407)del p.(?) Likely pathogenic 6 6 c.4120C > T p.(Arg1374*) Pathogenic MLPA NGS panel 2020 Aveiro c.4120C > T p.(Arg1374*) Pathogenic 7 7 c.5928-2A > G p.? Pathogenic Familial variant testing 2019 Coimbra c.4120C > T p.(Arg1374*) Pathogenic 8 8 c.4120C > T p.(Arg1374*) Pathogenic NGS panel 2019 Leiria c.4120C > T p.(Arg1374*) Pathogenic 9 9 c.4120C > T p.(Arg1374*) Pathogenic NGS panel 2021 Coimbra c.(2023 + 1_2024-1)_(2259 + 1_2260-1)del p.(?) Pathogenic 10 3 c.4120C > T p.(Arg1374*) Pathogenic NGS panel 2019 Coimbra c.9337A > T p.(Lys3113*) Likely pathogenic 11 7 c.5928-2A > G p.? Pathogenic NGS panel 2018 Coimbra c.4120C > T p.(Arg1374*) Pathogenic ACMG, American College of Medical Genetics; ID, Identifier; MLPA, multiplex ligation-dependent probe amplification; NGS, next-generation sequencing; WES, whole exome sequencing. Baseline vs final assessment of CRO and PRO All patients had an initial and a final visit, during which they completed the questionnaires, with a mean interval of 43.18 ± 1.17 months between assessments. Functional and structural parameters were collected at both time points to enable comparison with the questionnaire responses. During follow-up, patients reported significant worsening in MRDQ domains related to central vision and photopic peripheral function, along with a significant increase in cone-related anxiety on the MVAQ, reflecting both progressive functional limitation in daily visual tasks and its associated psychosocial impact. These parameters were compared between the initial and final evaluations (Table 3 ). Longitudinal theta score changes in MRDQ domains did not differ in magnitude across dimensions overall (Friedman test: χ ²(6) = 1.870, p = 0.931), indicating no dominant domain-specific worsening pattern, despite significant decline in selected individual domains over time. Table 3 Comparison of CRO and PRO between the initial and final evaluations. INITIAL FINAL SIGNIFICANCE BCVA best eye, ETDRS letters (mean ± SD) 67.55 ± 15.93 60.82 ± 17.34 p = 0.007* OCT (mean ± SD) ) EZ area (mm 2 ) 1.97 ± 1.85 1.49 ± 1.15 p = 0.130 PROS (µm) 43.64 ± 6.44 41.36 ± 9.89 p = 0.537 FOSPET (µm) 69.82 ± 10.51 67.73 ± 14.19 p = 0.700 FOSPET-PROS ratio 1.61 ± 0.13 1.68 ± 0.31 p = 0.531 MRDQ scores (median, IQR) Central vision 0.276 (-0.568–0.567) 0.757 (0.255–0.918) Z = 2.756; p = 0.006* Color vision 0.479 (-0.086–0.887) 0.648 (0.135–0.774) Z = 1.067; p = 0.286 Contrast sensitivity 0.002 (-0.526–1.171) 0.962 (0.348–1.312) Z = 1.956; p = 0,050 Scotopic function 0.760 (0.142–1.173) 1.204 (0.629–1.337) Z = 1.689; p = 0.091 Photopic peripheral function 0.438 (0.221–1.015) 0.947 (0.349–1.445) Z = 2.134; p = 0.033* Mesopic peripheral function 0.916 (-0.041–1.309) 1.158 (0.655–1.495) Z = 1.334; p = 0.182 Photosensitivity 0.548 (0.120–0.961) 1.348 (0.189–1.798) Z = 1.600; p = 0.110 MVAQ scores (median, IQR) Rod function anxiety 0.171 (-0.270–1.630) 0.271 (-0.003–1.630) Z = 0.770; p = 0.441 Cone function anxiety -0.563 (-0.794–0.335) 0.953 (0.312–1.700) Z = 2.667; p = 0.008* BCVA, best-corrected visual acuity; ETDRS, Early Treatment of Diabetic Retinopathy Study; EZ, ellipsoid zone; FOSPET, foveal outer segment pigment epithelial thickness; IQR, interquartile range; MRDQ, Michigan retinal degeneration questionnaire; MVAQ, Michigan vision-related anxiety questionnaire; OCT, optical coherence tomography; PROS, photoreceptor outer segment length; SD, standard deviation. Asterisk (*) indicates a significant value. Correlation analysis of change scores (Δ) Spearman correlation analyses were performed on the changes (Δ) between baseline and final assessments for each domain. Moderate correlations were observed between changes in rod-related and cone-related functional anxiety (MVAQ Rod Δ ↔ Cone Δ, r = 0.692, p = 0.018), indicating that individuals with greater increases in rod-related anxiety also experienced larger increases in cone-related anxiety. Declines in central vision (MRDQ Central Vision Δ) were moderately associated with reductions in photopic peripheral function ( r = 0.673, p = 0.023) and mesopic peripheral function ( r = 0.664, p = 0.026), reflecting linked deterioration in core visual tasks and peripheral function under low or mixed lighting. Rod-mediated scotopic dysfunction (MRDQ Scotopic Function Δ) showed a very strong association with mesopic peripheral function impairment ( r = 0.873, p < 0.001) and a moderate correlation with photopic peripheral decline ( r = 0.682, p = 0.021), while photopic peripheral deficits were also moderately related to mesopic peripheral function limitations ( r = 0.645, p = 0.032). No statistically significant correlation was observed between the change in cone-related MVAQ scores and the change in BCVA over follow-up ( r = 0.009, p = 0.979). Additionally, age at symptom onset did not demonstrate a significant association with changes in MVAQ (rod or cone) or MRDQ domain scores, nor with longitudinal changes in BCVA, EZ area, FOSPET, PROS or the FOSPET/PROS ratio (all p > 0.05). DISCUSSION This longitudinal study provides a multidimensional characterization of EYS -associated RP linked to the c.4120C > T (p.Arg1374*) variant by integrating PRO, functional measures and structural biomarkers. By overcoming the limitations of previous cross-sectional and genetically heterogeneous cohorts, it offers new insights into natural history disease trajectories and structure-function correlations, informing clinical decision-making and trial design [ 9 , 26 , 30 – 33 ]. Symptom onset peaked between ages 11 and 30, aligning with established data for EYS -associated RP [ 7 , 10 , 34 ]. This window coincides with major educational, vocational and psychosocial transitions, likely influencing patient-reported functional difficulties and anxiety beyond traditional clinical metrics. Consistent with reported allelic heterogeneity and phenotypic variability in EYS mutations [ 34 ], no statistically significant association was observed between zygosity and age at symptom onset or longitudinal progression in BCVA, EZ area and PRO. These results suggest that zygosity alone does not dictate disease trajectories in this cohort, with genetic modifiers, environmental factors or recall bias in reporting onset, likely contributing to the observed variability. Consistent with rod-cone degeneration, patients reported early nyctalopia and peripheral field loss, while photophobia remained rare, aligning with its typical emergence in later disease stages [ 1 , 7 , 10 , 34 , 35 ]. A mean decline of 1.87 ETDRS letters per year was observed in BCVA. This rate, while slightly higher than some EYS -specific reports [ 7 , 35 ], remains lower than that observed in broader RP populations [ 36 ], supporting the characterization of EYS -associated RP as a relatively milder phenotype, albeit with notable inter-individual variability [ 3 ]. Despite initially preserved central acuity, progressive concentric field loss and night blindness significantly compromise mobility and independence, leading to activity restriction and reduced social participation [ 37 – 39 ]. As the disease advances, central involvement increasingly impairs high-acuity tasks, impacting vocational productivity. These findings underscore the need for early referral to low-vision rehabilitation and psychosocial support to mitigate the socioeconomic burden [ 40 ], even in the absence of curative therapies. Beyond functional limitations, many individuals face emotional, psychological and social difficulties that reduce quality of life [ 41 ]. For these reasons, incorporating patients’ perceptions of their visual function, rather than relying solely on traditional clinical tests, is increasingly important as patients frequently notice subtle changes in their vision before they become measurable. The PRO captured meaningful aspects of functional decline that were not always reflected in structural measures. Significant worsening in MRDQ domains related to central vision and photopic peripheral function, as well as increased cone-related anxiety on the MVAQ, reflects heightened awareness of difficulties in tasks relying on photopic and central vision. While previous cross-sectional work found no link between BCVA and rod or cone-related anxiety [ 9 ], our longitudinal data revealed that cone-related anxiety increases over time even if it does not correlate with BCVA at a single time point. However, changes in cone-related MVAQ scores were not significantly correlated with changes in BCVA, suggesting that anxiety trajectories may be influenced by factors not fully captured by visual acuity alone, including day-to-day functional limitations, expectations regarding disease progression and individual coping mechanisms. Furthermore, age at symptom onset did not predict longitudinal changes in PRO or CRO, likely due to symptom normalization, varied coping mechanisms and heterogeneity in contextual factors, such as regional disparities in healthcare access and sociodemographic resources [ 42 , 43 ]. Other longitudinal studies are needed to clarify how these factors influence psychiatric morbidity in this population and to identify targets for timely intervention. While previous cross-sectional studies[ 9 , 26 ] from our team on EYS and RPGR cohorts established correlations between SD-OCT biomarkers (EZ area, PROS, FOSPET) and patient-perceived disability, longitudinal results remain less clear. In our study, EZ area reduction was statistically non-significant and foveal outer retinal metrics remained stable. This suggests that central microstructural changes in this EYS cohort may be too slow for detection within the analyzed timeframe, potentially indicating a structure–function dissociation where functional decline precedes measurable structural loss. Although limited by a small sample size, these findings suggest that central macular architecture is relatively preserved in early or intermediate stages. Previous studies have suggesting that structure–function relationships vary by genotype and disease stage [ 9 , 24 , 26 , 44 ]. Correlation analysis of Δ-scores suggests that patient-perceived progression occurs in clusters rather than in isolation. Moderate correlations between rod- and cone-related anxiety indicate a shared psychosocial trajectory linked to worsening visual limitations, while central vision decline co-evolved with photopic and mesopic peripheral impairment, implying that difficulties in central tasks often co-evolve with increasing mobility and orientation challenges under varying illumination. The strongest association, between scotopic dysfunction and mesopic peripheral limitation, reflects expected rod-mediated mechanisms underlying mesopic performance. Overall, these patterns support the internal coherence of the MRDQ/MVAQ and reflect the expected progression of rod–cone dystrophies. Furthermore, the selective worsening in specific domains, alongside high structural variability, underscores the significant inter-individual heterogeneity of EYS -associated RP, likely driven by genetic, epigenetic or environmental modifiers. Emerging RP therapies require standardized assessment frameworks that integrate structural and functional metrics with the patient perspective [ 14 ]. While SD-OCT remains a cornerstone for quantifying photoreceptor integrity (EZ area, FOSPET, PROS) [ 14 ], our findings suggest these metrics may lack sensitivity over a longer follow-up window, particularly in subphenotypes with slow structural progression. Although quantitative measures of UW-FAF were not included in our study, hyperAF ring measurements, may serve as a surrogate marker and act as a structural indicator of RP progression, supporting longitudinal monitoring and characterization of perifoveal involvement [ 13 , 27 ]. Notably, a previous report demonstrated that mean retinal sensitivity measured by microperimetry was significantly more strongly associated with the diameter of the hyperAF ring than with the EZ line, suggesting that AF ring development is linked to declining visual function independently of, and more strongly than, EZ changes [ 29 ]. This study has limitations, including a small sample size, which reduces statistical power and may overestimate associations; the retrospective alignment of clinical and PRO data; the lack of complementary functional testing; and the single-center design, which may limit generalizability. Nevertheless, integrating longitudinal PRO and CRO data within a genetically defined cohort provides valuable insight into the natural history of EYS -related RP. CONCLUSION In conclusion, this study establishes a significant dissociation between patient-perceived functional decline and objective microstructural stability. The worsening of central vision and increased psychosocial anxiety, occurring even as structural parameters remained stable, suggests that current structural biomarkers are insufficient surrogates for disease progression in this specific cohort. These findings advocate for a shift in clinical trial design toward a multimodal, function-centric approach that prioritizes microperimetry, quantification of the hyper autofluorescence ring and validated patient-reported outcomes instruments as primary endpoints. Ultimately, integrating the patient's lived experience with functional clinical metrics is essential to accurately quantify disease trajectories and define meaningful outcomes for emerging therapeutic interventions targeting EYS -related retinal degeneration. Abbreviations ACMG American College of Medical Genetics AF Autofluorescence BCVA Best-corrected visual acuity CRO Clinician-reported outcomes ETDRS Early Treatment of Diabetic Retinopathy Study EYS Eyes shut homolog EZ Ellipsoid zone FAF Fundus autofluorescence FOSPET Foveal outer segment pigment epithelial thickness FPR Foveal outer segment pigment epithelial thickness-photoreceptor outer segment length ratio IQR Interquartile range IRD Inherited retinal disease IRD-PT Portuguese national registry of inherited retinal dystrophies MLPA Multiplex ligation-dependent probe amplification MRDQ Michigan Retinal Degeneration Questionnaire MVAQ Michigan Vision-Related Anxiety Questionnaire NGS Next-generation sequencing OCT Optical coherence tomography PRO Patient-reported outcomes PROS Photoreceptor outer segment length RP Retinitis pigmentosa SD Standard deviation SD-OCT Spectral-domain optical coherence tomography ULS Unidade Local de Saúde UW-FAF Ultra-widefield fundus autofluorescence WES Whole exome sequencing Declarations Clinical trial number not applicable. Ethics approval The study was approved by the local Ethics Committee and followed the tenets of the Declaration of Helsinki for biomedical research. All procedures involving human participants were in accordance with the ethical standards of the Human Research Ethics Committee (HREC) of Unidade Local de Saúde de Coimbra (175/24 CE, process number OBS.SF.107–2022) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Consent to participate Informed consent was obtained from all individual participants included in the study. Funding or Competing interests No funding was received to assist with the preparation of this manuscript. The authors have no relevant financial or non-financial interests to disclose. Author Contribution All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by M.F. and A.P.. The first draft of the manuscript was written by M.F. and A.P. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. References Cross N, van Steen C, Zegaoui Y, Satherley A, Angelillo L (2022) Retinitis Pigmentosa: Burden of Disease and Current Unmet Needs. Clin Ophthalmol 16:1993–2010 Orphanet Prevalence and incidence of rare diseases: Bibliographic data [Internet]. 2025 [cited 2025 Oct 21]. Available from: https://www.orpha.net/pdfs/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_decreasing_prevalence_or_cases.pdf Marques JP, Santos Sousa I, Patrício D, Simões BF, Chukwunalu O, Zeitz C et al (2025) Eyes shut homolog (EYS): Connecting molecule to disease. Progress in Retinal and Eye Research, vol 108. Elsevier Ltd Abd El-Aziz MM, Barragan I, O’Driscoll CA, Goodstadt L, Prigmore E, Borrego S et al (2008) EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa. Nat Genet 40(11):1285–1287 Collin RWJ, Littink KW, Klevering BJ, van den Born LI, Koenekoop RK, Zonneveld MN et al (2008) Identification of a 2 Mb Human Ortholog of Drosophila eyes shut/spacemaker that Is Mutated in Patients with Retinitis Pigmentosa. Am J Hum Genet 83(5):594–603 Schneider N, Sundaresan Y, Gopalakrishnan P, Beryozkin A, Hanany M, Levanon EY et al (2022) Inherited retinal diseases: Linking genes, disease-causing variants, and relevant therapeutic modalities. Progress in Retinal and Eye Research, vol 89. Elsevier Ltd Soares RM, Carvalho AL, Simão S, Soares CA, Raimundo M, Alves CH et al (2023) Eyes Shut Homolog-Associated Retinal Degeneration: Natural History, Genetic Landscape, and Phenotypic Spectrum. Ophthalmol Retina 7(7):628–638 Marta A, Marques-Couto P, Vaz-Pereira S, Costa J, Cabral D, Estrela-Silva S et al (2025) Clinical and genetic landscape of IRD in Portugal: pooled data from the nationwide IRD-PT registry. NPJ Genom Med. ;10(1) Marques JP, Machado Soares R, Simão S, Abuzaitoun R, Andrews C, Alves CH et al (2023) Self-reported visual function and psychosocial impact of visual loss in EYS-associated retinal degeneration in a Portuguese population. Ophthalmic Genet 44(4):334–340 Littink KW, Van Den Born LI, Koenekoop RK, Collin RWJ, Zonneveld MN, Blokland EAW et al (2010) Mutations in the EYS gene account for approximately 5% of autosomal recessive retinitis pigmentosa and cause a fairly homogeneous phenotype. Ophthalmology. ;117(10) Leiden Open Variation Database The EYS gene homepage [Internet]. 2012 [cited 2025 Nov 21]. Available from: https://databases.lovd.nl/shared/genes/EYS Marques JP, Porto FBO, Carvalho AL, Neves E, Chen R, Sampaio SAM et al (2022) EYS-Associated Sector Retinitis Pigmentosa. Graefe’s Archive Clin Experimental Ophthalmol 260(4):1405–1413 Yan Alvin Liu T, Ling C, Hahn L, Jones CK, Boon CJ, Singh MS (2023) Prediction of visual impairment in retinitis pigmentosa using deep learning and multimodal fundus images. Br J Ophthalmol [Internet] 107:1484–1489 Available from: www.clinicaltrials.gov Schmetterer L, Scholl H, Garhöfer G, Janeschitz-Kriegl L, Corvi F, Sadda SVR et al (2023) Endpoints for clinical trials in ophthalmology. Progress in Retinal and Eye Research, vol 97. Elsevier Ltd Rausch–Koster TP, van der Ham AJ, Terwee CB, Verbraak FD, van Rens GHMB, van Nispen RMA (2021) Translation and content validity of the Dutch Impact of Vision Impairment questionnaire assessed by Three-Step Test-Interviewing. J Patient Rep Outcomes. ;5(1) Lacy GD, Abalem MF, Andrews CA, Popova LT, Santos EP, Yu G et al (2021) The Michigan Retinal Degeneration Questionnaire: A Patient-Reported Outcome Instrument for Inherited Retinal Degenerations. Am J Ophthalmol 222:60–68 Lacy GD, Abalem MF, Andrews CA, Abuzaitoun R, Popova LT, Santos EP et al (2021) The Michigan Vision-Related Anxiety Questionnaire: A Psychosocial Outcomes Measure for Inherited Retinal Degenerations. Am J Ophthalmol 225:137–146 Marques JP, Bernardes L, Oliveira C, Fonseca G, Quadrado Gil J, Sotero L et al (2022) Portuguese translation and linguistic validation of the Michigan Retinal Degeneration Questionnaire and the Michigan Vision-Related Anxiety Questionnaire in a cohort with inherited retinal degenerations. Ophthalmic Genetics, vol 43. Taylor and Francis Ltd., pp 137–139 Thirunavukarasu AJ, Hassan R, Limonard A, Savant SV (2023) Accuracy and reliability of self-administered visual acuity tests: Systematic review of pragmatic trials. PLoS ONE. ;18(6 June). Smith TB, Parker MA, Steinkamp PN, Romo A, Erker LR, Lujan BJ et al (2019) Reliability of spectral-domain OCT ellipsoid zone area and shape measurements in retinitis pigmentosa. Transl Vis Sci Technol. ;8(3) Nagasato D, Sogawa T, Tanabe M, Tabuchi H, Numa S, Oishi A et al (2023) Estimation of Visual Function Using Deep Learning from Ultra-Widefield Fundus Images of Eyes with Retinitis Pigmentosa. JAMA Ophthalmol 141(4):305–313 Marques JP, Carvalho AL, Henriques J, Murta JN, Saraiva J, Silva R (2020) Design, development and deployment of a web-based interoperable registry for inherited retinal dystrophies in Portugal: the IRD-PT. Orphanet J Rare Dis. ;15(1) Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J et al (2015) Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Sci 17(5):405–424 Bühren J (2018) ETDRS visual acuity chart. In: Schmidt-Erfurth U, Kohnen T (eds) Encyclopedia of Ophthalmology. Springer Berlin Heidelberg, Berlin (Heidelberg), pp 741–742 Poornachandra B, Khurana AK, Sridharan P, Chatterjee P, Jayadev C, Yadav NK et al (2019) Quantifying microstructural changes in retinitis pigmentosa using spectral domain – optical coherence tomography. Eye Vis. ;6(1) Huang YH, Huang YS, Lin CY, Lai YJ, Yang CH, Ho TC et al (2025) The Exponential Constriction Model of the Ellipsoid Zone in Taiwanese Individuals With RPGR-Related X-Linked Retinitis Pigmentosa. Invest Ophthalmol Vis Sci. ;66(4) Gouveia N, Karuntu J, Almushattat H, Silva R, Boon C, Marques JP (2026) Retinitis Pigmentosa GTPase regulator–Associated Retinal Degeneration: Integrating Patient-Reported Outcomes, Genetic, and Structural Biomarkers. Ophthalmol Sci. ;6(1) Vittoria Cicinelli Alessandro Marchese Alessandro Bordato Maria Pia Manitto Francesco Bandello Maurizio Battaglia Parodi M Reviewing the Role of Ultra-Widefield Imaging in Inherited Retinal Dystrophies. Available from: https://doi.org/10.6084/ Varela MD, Esener B, Hashem SA, De Guimaraes TAC, Georgiou M, Michaelides M (2021) Structural evaluation in inherited retinal diseases. British Journal of Ophthalmology, vol 105. BMJ Publishing Group, pp 1623–1631 Lee J, Asano S, Inoue T, Fujino Y, Matsuura M, Kitamoto K et al (2018) Investigating the Usefulness of Fundus Autofluorescence in Retinitis Pigmentosa. Ophthalmol Retina 2(10):1062–1070 Gouveia N, Chukwunalu O, Oliveira C, Alves CH, Silva R, Murta J et al (2024) Exploring self-reported visual function and vision-related anxiety in patients with RPGR-associated retinal degeneration. Sci Rep. ;14(1) Parekh B, Duncan JL, Samarakoon L, Melia M, Abalem MF, Andrews CA et al (2024) Self-Reported Functional Vision in USH2A-Associated Retinal Degeneration as Measured by the Michigan Retinal Degeneration Questionnaire. Invest Ophthalmol Vis Sci. ;65(6) Karuntu JS, Nguyen XT, Boon CJF (2024) Correlations between the Michigan Retinal Degeneration Questionnaire and visual function parameters in patients with retinitis pigmentosa. Acta Ophthalmol 102(5):555–563 Leroy BP, Daly A, Héon E, Sahel JA, Dollfus H (2024) Therapies for Inherited Retinal Dystrophies: What is Enough? Drug Discovery Today, vol 29. Elsevier Ltd Gao FJ, Wang DD, Hu FY, Xu P, Chang Q, Li JK et al (2022) Genotypic spectrum and phenotype correlations of EYS-associated disease in a Chinese cohort. Eye (Basingstoke) 36(11):2122–2129 Pierrache LHM, Messchaert M, Thiadens AAHJ, Haer-Wigman L, de Jong-Hesse Y, van Zelst-Stams WAG et al (2019) Extending the spectrum of EYS-associated retinal disease to macular dystrophy. Invest Ophthalmol Vis Sci 60(6):2049–2063 Iftikhar M, Usmani B, Sanyal A, Kherani S, Sodhi S, Bagheri S et al (2019) Progression of retinitis pigmentosa on multimodal imaging: The PREP-1 study. Clin Exp Ophthalmol 47(5):605–613 Lange R, Kumagai A, Weiss S, Zaffke KB, Day S, Wicker D et al (2021) Vision-related quality of life in adults with severe peripheral vision loss: a qualitative interview study. J Patient Rep Outcomes. ;5(1) Prem Senthil M, Khadka J, Pesudovs K (2017) Seeing through their eyes: Lived experiences of people with retinitis pigmentosa. Eye (Basingstoke) 31(5):741–748 Sugawara T, Pak K, Miura G, Baba T (2024) Visual activities of daily living survey for retinitis pigmentosa. Jpn J Ophthalmol 68(6):717–721 Garip G, Kamal A (2019) Systematic review and meta-synthesis of coping with retinitis pigmentosa: Implications for improving quality of life. BMC Ophthalmol. ;19(1) Assi L, Chamseddine F, Ibrahim P, Sabbagh H, Rosman L, Congdon N et al (2021) A global assessment of eye health and quality of life a systematic review of systematic reviews. JAMA Ophthalmology, vol 139. American Medical Association, pp 526–541 Bittner AK, Edwards L, George M (2010) Coping strategies to manage stress related to vision loss and fluctuations in retinitis pigmentosa. Optometry 81(9):461–468 Marta A, Marques JP, Santos C, Coutinho-Santos L, Vaz-Pereira S, Costa J et al (2024) The socioeconomic epidemiology of inherited retinal diseases in Portugal. Orphanet J Rare Dis. ;19(1) Teixeira S, Franca M, Gouveia N, Teixeira B, Silva R, Murta J et al (2025) Structural and functional clinician-reported outcomes show strong correlations with patient-reported outcomes in Retinitis Pigmentosa. AJO Int. ;2(1) Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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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-8495428","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":569409479,"identity":"3f017139-99e3-4413-b509-81c113718c89","order_by":0,"name":"Maria Franca","email":"","orcid":"","institution":"Unidade Local de Saúde (ULS) Coimbra","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"","lastName":"Franca","suffix":""},{"id":569409480,"identity":"aedfd489-7c86-4c3c-a269-7a0c91a3a949","order_by":1,"name":"Anabela Pereira","email":"","orcid":"","institution":"Faculty of Medicine, University of Coimbra","correspondingAuthor":false,"prefix":"","firstName":"Anabela","middleName":"","lastName":"Pereira","suffix":""},{"id":569409486,"identity":"a6be4e5f-7c80-4186-b27a-de2b04e257f1","order_by":2,"name":"Ana Luísa Carvalho","email":"","orcid":"","institution":"Unidade Local de Saúde (ULS) de Coimbra","correspondingAuthor":false,"prefix":"","firstName":"Ana","middleName":"Luísa","lastName":"Carvalho","suffix":""},{"id":569409488,"identity":"c3b46618-84db-458c-a0df-ca7168629478","order_by":3,"name":"Henrique Alves","email":"","orcid":"","institution":"Coimbra Institute for Clinical and Biomedical Research (iCBR)","correspondingAuthor":false,"prefix":"","firstName":"Henrique","middleName":"","lastName":"Alves","suffix":""},{"id":569409493,"identity":"458448bd-c79a-40ff-b8cd-e404d4cc67e1","order_by":4,"name":"João Pedro Marques","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEklEQVRIiWNgGAWjYBADZgjFxsDAD6ITCkjRItkA0mJAtGVALQYHQAw8WnTbzz68zVNRx87PfvjYgw9l9+SMz69O/PDAgEGeX+wAVi1mZ9KNrXnOHGaW7ElLN5xxrtjY7MbbzRJAhxnOnJ2AXcuBNDZp3rYDzAYHcsyAjITEbTfObgBpSTC4jUPL+WdALf/qmA3OvzGT/gvUsnnG2c0/8Gq5AbKlgZnZ4AbQFkaglg38vdvw23LjGbPlnGNAv8x4lm7Ycy7BWOIG7zaLBAMJ3H45n8Z4401NXTI/f/KxBz/KEuT4+89uvvmjwkaeXxq7FhCQAOJkBnCkgLkJMEHcACRrh9DCfwCv6lEwCkbBKBh5AAA9Zl3fSu+UDQAAAABJRU5ErkJggg==","orcid":"","institution":"Unidade Local de Saúde (ULS) Coimbra","correspondingAuthor":true,"prefix":"","firstName":"João","middleName":"Pedro","lastName":"Marques","suffix":""}],"badges":[],"createdAt":"2026-01-01 13:38:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8495428/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8495428/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":100857652,"identity":"df535fca-4a6a-410b-bcc2-07f33572442d","added_by":"auto","created_at":"2026-01-22 07:16:07","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":352989,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative SD-OCT of the fovea illustrating the measurements used in the analysis.\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8495428/v1/f8fe85f9cb62d639a7c01302.jpg"},{"id":102294768,"identity":"f7da374f-f968-4b39-8520-b259f2e57b27","added_by":"auto","created_at":"2026-02-10 09:56:01","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":260532,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of theta (θ) scores for MRDQ and MVAQ domains at initial and final assessments, with boxplots representing the median and IQR.\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8495428/v1/849ccc85160293c50c1966dd.jpg"},{"id":100857654,"identity":"a8fa0292-9760-488b-90d6-fd65c9bfc0c6","added_by":"auto","created_at":"2026-01-22 07:16:07","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":507997,"visible":true,"origin":"","legend":"\u003cp\u003eUltra-widefield fundus autofluorescence patterns.\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8495428/v1/90604b6363cb6ff5b074ede0.jpg"},{"id":102299516,"identity":"ecf2abe7-bd0f-4f73-b145-d7aed0795321","added_by":"auto","created_at":"2026-02-10 11:06:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2013862,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8495428/v1/3c28a3b1-888d-42a8-9043-fa118da9039d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eNatural History of Retinitis Pigmentosa Associated With the C.4120c\u0026gt;t Eys Variant\u003c/p\u003e","fulltext":[{"header":"Key message","content":"\u003cul\u003e\n \u003cli\u003eRetinitis pigmentosa associated with the \u003cem\u003eEYS\u003c/em\u003e gene, particularly the c.4120C\u0026gt;T variant, is one of the most frequent forms of autosomal recessive retinitis pigmentosa in Portugal and is characterized by relatively early onset, slow progression and marked interindividual clinical variability.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cul\u003e\n \u003cli\u003eOver the analyzed period, significant variations in functional measures and PRO were identified, including changes in best-corrected visual acuity and in PRO domains related to central vision and photopic peripheral function.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cul\u003e\n \u003cli\u003eNo statistically significant structural changes were detected in SD-OCT biomarkers (ellipsoid zone area, PROS, FOSPET and FOSPET/PROS ratio), suggesting a dissociation between functional decline and measurable microstructural changes in this cohort.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cul\u003e\n \u003cli\u003ePRO, including increased cone-related anxiety, captured clinically meaningful aspects of disease progression that were not fully reflected by traditional structural measures, supporting their integration as key endpoints in clinical monitoring and therapeutic trial design.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"INTRODUCTION","content":"\u003cp\u003eRetinitis pigmentosa (RP) is the most prevalent inherited retinal disease (IRD) globally and is characterized by the progressive degeneration of photoreceptors [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In 2025, Orphanet data reported a prevalence of approximately 1 in 33,333 individuals in Europe, with marked regional variations across the continent [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe Eyes shut homolog (\u003cem\u003eEYS\u003c/em\u003e, MIM *612424) gene was identified in 2008 as a causal gene for RP25, displaying an autosomal recessive inheritance pattern [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. It is the third most frequently implicated gene in IRDs worldwide,[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] accounting for approximately 4.4% of all cases [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In Portugal, \u003cem\u003eEYS\u003c/em\u003e is the second most commonly associated gene with IRDs [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBased on current knowledge, \u003cem\u003eEYS\u003c/em\u003e is the largest gene expressed in the human eye [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The precise localization of \u003cem\u003eEYS\u003c/em\u003e has not been fully resolved and it remains uncertain whether it is predominantly intracellular, intercellular and/or extracellular [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Existing data indicate that \u003cem\u003eEYS\u003c/em\u003e may localize to the photoreceptor ciliary transition zone, near the basal region marked by acetylated α-tubulin, in both rods and cones. These observations have led to the hypothesis that \u003cem\u003eEYS\u003c/em\u003e plays a role in maintaining photoreceptor architecture and structural stability [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Currently, 934 unique \u003cem\u003eEYS\u003c/em\u003e gene variants have been documented [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Deep phenotyping has been crucial for expanding the clinical spectrum of disorders associated with this gene and identifying atypical phenotypes. The intra- and interfamilial variability observed among carriers of the same variants suggests an important contribution of genetic, epigenetic and environmental modifiers [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the Portuguese population, the variants \u003cem\u003eEYS\u003c/em\u003e (NM_001142800.1): c.(2023\u0026thinsp;+\u0026thinsp;1_2024-1)_(2259\u0026thinsp;+\u0026thinsp;1_2260-1)del p.?, \u003cem\u003eEYS\u003c/em\u003e (NM_001142800.2): c.5928-2A\u0026thinsp;\u0026gt;\u0026thinsp;G p.? and \u003cem\u003eEYS\u003c/em\u003e (NM_001142800.2): c.4120C\u0026thinsp;\u0026gt;\u0026thinsp;T p.(Arg1374*), are the most frequent, suggesting a possible European origin [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Recent assessments highlight the possibility that the c.4120C\u0026thinsp;\u0026gt;\u0026thinsp;T p.(Arg1374*) variant may be linked to a founder effect in the Leiria region [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, this variant has also been reported in Dutch, Spanish and American cohorts [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCurrent therapeutic options for these patients are primarily supportive, highlighting the urgent need for emerging targeted therapies that could halt or prevent disease progression [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. It is essential to define specific and measurable outcomes for evaluating the efficacy of potential treatments [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePatient-reported outcomes (PRO) are widely recognized as valid and meaningful endpoints in clinical trials [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. These instruments provide valuable information on functional impact and quality of life, and validated tools such as the Michigan Retinal Degeneration Questionnaire (MRDQ)[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] and the Michigan Vision-Related Anxiety Questionnaire (MVAQ)[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] have recently been adapted for Portuguese-speaking populations [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTraditional functional metrics, particularly best-corrected visual acuity (BCVA), may not adequately capture disease progression in conditions that initially spare the macula [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Structural biomarkers such as ellipsoid zone (EZ) area on spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) patterns have therefore gained importance for disease staging and monitoring [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe aim of this study was to report the longitudinal natural history of \u003cem\u003eEYS\u003c/em\u003e-related RP associated with the c.4120C\u0026thinsp;\u0026gt;\u0026thinsp;T variant, correlating clinician-reported outcomes (CRO) with patient-reported outcomes (PRO).\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePopulation and study design\u003c/h2\u003e \u003cp\u003eA retrospective cohort study was conducted at the reference center for IRDs within the ophthalmology and medical genetics departments of \u003cem\u003eUnidade Local de Sa\u0026uacute;de\u003c/em\u003e (ULS) \u003cem\u003eCoimbra\u003c/em\u003e. All data were collected and analyzed between June 2025 and October 2025. Medical records from patients with confirmed carrier status (homozygous or compound heterozygous genotype) of the c.4120C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg1374*) variant in the \u003cem\u003eEYS\u003c/em\u003e gene were reviewed. These patients were identified through the Portuguese national registry of inherited retinal dystrophies (IRD-PT), integrated into the retina.com.pt platform (retina.com.pt) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOnly patients with at least 36 months of follow-up were included in the study. Baseline and last visit functional (BCVA), structural (SD-OCT) and PRO (MRDQ and MVAQ) data were recorded. Patients were excluded if clinical records were incomplete or lacked required assessments, if coexisting ocular or systemic conditions could affect vision, if prior retinal surgery or trauma could have altered retinal structure, or if they were unable to reliably complete the MRDQ or MVAQ.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthics statement\u003c/h3\u003e\n\u003cp\u003eThe study, included in the project \u003cem\u003e\u0026ldquo;O papel da EYS na retina\u0026rdquo;\u003c/em\u003e, approved by the ethics committee of ULS \u003cem\u003eCoimbra\u003c/em\u003e (175/24 CE, process number OBS.SF.107\u0026ndash;2022), was conducted in accordance with the principles of the Declaration of Helsinki for biomedical research, and fully complied with the general data protection regulation and applicable national legislation. All patients provided written informed consent. All clinical data were anonymized to ensure confidentiality and prevent individual identification.\u003c/p\u003e\n\u003ch3\u003eProcedure\u003c/h3\u003e\n\u003cp\u003eClinical records, including demographic information (age, sex, Portuguese region of residence), year, type and results of genetic testing, identified patients sharing a familial relationship and personal medical history, were collect from each individual patient file. Medical history included age at diagnosis, consanguinity, symptoms and age at symptom onset. To minimize the potential impact of recall bias, age at symptom onset was grouped into predefined timeframes: childhood (6\u0026ndash;10 years), adolescence (11\u0026ndash;20 years), early adulthood (21\u0026ndash;30 years), adulthood (31\u0026ndash;50 years) and elderly (\u0026gt;\u0026thinsp;51 years). Genetic variants were classified according to the guidelines of the American College of Medical Genetics and Genomics [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eSelf-assessment of visual function and psychosocial impact of vision loss\u003c/h3\u003e\n\u003cp\u003eThe MRDQ evaluates the impact of visual impairment on daily tasks across five dimensions: reading; color and contrast; dark adaptation; mobility and peripheral vision; and light sensitivity. It comprises 59 items covering central vision (n\u0026thinsp;=\u0026thinsp;11), color vision (n\u0026thinsp;=\u0026thinsp;4), contrast sensitivity (n\u0026thinsp;=\u0026thinsp;7), scotopic function (n\u0026thinsp;=\u0026thinsp;12), photopic peripheral vision (n\u0026thinsp;=\u0026thinsp;9), mesopic peripheral vision (n\u0026thinsp;=\u0026thinsp;9) and photosensitivity (n\u0026thinsp;=\u0026thinsp;7) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The MVAQ is a 14-item instrument with two domains: rod-related functional anxiety (6 items) and cone-related anxiety (8 items) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Neither questionnaire provides a composite score. Instead, based on item response theory, each domain generates a latent trait value ranging from \u0026minus;\u0026thinsp;3 to +\u0026thinsp;3 theta, where higher scores indicate greater functional difficulty (in the MRDQ) or higher levels of anxiety (in the MVAQ). The complete item lists are available in the original publications [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The questionnaires were clinician administered right after the clinic visit, with questions read aloud by the interviewer following predefined guidelines.\u003c/p\u003e\n\u003ch3\u003eFunctional parameter: BCVA\u003c/h3\u003e\n\u003cp\u003eThe Early Treatment of Diabetic Retinopathy Study (ETDRS) letter score was used to quantify BCVA. The ETDRS chart consists of 14 lines of five Sloan letters, arranged in logarithmic progression with proportional interline and interletter spacing to ensure uniform contour interaction. Visual acuity can be directly read from the same chart. For repeated testing, alternate charts were used to present different letter sequences. The standard testing distance is 4 m, although shorter distances may be used in cases of severe vision loss [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The eye with better EDTRS letter score was used as an indicator of visual function and was used as a functional parameter.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStructural parameter: SD-OCT\u003c/h2\u003e \u003cp\u003eThe optical coherence tomography (OCT) scans were acquired using the Spectralis HRA\u0026thinsp;+\u0026thinsp;OCT system (Heidelberg Engineering, Heidelberg, Germany) in both eyes. The images were independently analyzed by two masked medical graders (M.F. and J.P.M.), without access to clinical data or MRDQ/MVAQ scores. Disagreement was resolved by a senior grader (J.P.M.). Measurements included EZ width, photoreceptor outer segment length (PROS) and foveal outer segment pigment epithelial thickness (FOSPET). Using a previously reported methodology, the distance between the inner border of the EZ and the inner border of the retinal pigment epithelium, as well as the distance between the EZ and the outer border of the retinal pigment epithelium, were measured at the thinnest point of the fovea, thereby allowing the assessment of PROS and FOSPET, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] The foveal outer segment pigment epithelial thickness-photoreceptor outer segment length ratio (FPR), was also calculated (FOSPET/PROS ratio) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The EZ width was quantified within the central 3 mm using horizontal and vertical line scans passing through the foveal center (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The EZ area was subsequently estimated using the ellipse formula, defined as π \u0026times; (horizontal EZ/2) \u0026times; (vertical EZ/2).[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStructural parameter: ultra-widefield fundus autofluorescence (UW-FAF) patterns\u003c/h3\u003e\n\u003cp\u003eRetinal phenotype classification was based on UW-FAF imaging acquired with the Optos\u003csup\u003e\u0026reg;\u003c/sup\u003e (Optos California, Optos GmbH, Germany) system. As no standardized classification exists for RP, criteria from prior studies describing abnormal FAF patterns in RP were applied [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Typical patterns of autofluorescence (AF) include the presence of a parafoveal ring of high-density AF, central hyperAF and central hypoAF. Other patterns were considered atypical. Phenotypes were categorized as typical or atypical by two medical graders (M.F. and J.P.M.), masked in patient identity, genetic testing results, visual acuity and MRDQ/MVAQ scores. Disagreement was resolved by a senior grader (J.P.M.).\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe data were analyzed using IBM SPSS Statistics, version 30 (IBM, Armonk, NY, USA). Latent trait (theta) scores for each MRDQ and MVAQ domain were estimated using a graded response model with the expected-a-posteriori method. The normality of continuous variables was assessed with the Shapiro-Wilk test. Normally distributed data are reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD), whereas non-normally distributed variables are presented as median\u0026thinsp;\u0026plusmn;\u0026thinsp;interquartile range (IQR). Categorical variables are summarized as frequencies and percentages. Descriptive statistics were used to characterize the study population and summarize variable distributions. Comparisons between homozygous and compound heterozygous patients were performed using Mann-Whitney U tests with exact \u003cem\u003ep\u003c/em\u003e-values, due to small sample size. Paired comparisons between baseline and follow-up assessments were performed using paired-samples t-tests for normally distributed variables and the Wilcoxon signed-rank test otherwise. When comparing MRDQ domain scores treated as repeated measures, the Friedman test was applied. Associations between change scores (Δ\u0026thinsp;=\u0026thinsp;final - baseline) across domains were examined using Spearman\u0026rsquo;s rank correlation coefficient. Statistical significance was set at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eEleven patients from 9 families (72.7% male), with a mean age of 43.82\u0026thinsp;\u0026plusmn;\u0026thinsp;11.29 years (range 27\u0026ndash;64) were included. All patients had a diagnosis of RP. The mean age at diagnosis was 35.73\u0026thinsp;\u0026plusmn;\u0026thinsp;11.02 years (19\u0026ndash;58). There was no history of consanguinity. Family history of the disease was reported in 54.5% of patients (n\u0026thinsp;=\u0026thinsp;6).\u003c/p\u003e \u003cp\u003eThe cohort characterization, functional parameters and retinal structural measurements are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. In 9.1% of patients, symptoms began between 6 and 10 years. The most common age onset was 11\u0026ndash;20 years (45%), followed by 21\u0026ndash;30 years (36.4%), with 31\u0026ndash;50 years accounting for the remaining 9.1%.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical characteristics, functional parameters and retinal structural measurements of the cohort.\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\u003eDEMOGRAPHICS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of patients, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43.82\u0026thinsp;\u0026plusmn;\u0026thinsp;11.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at diagnosis, years (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35.73\u0026thinsp;\u0026plusmn;\u0026thinsp;11.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eINITIAL BCVA (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\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\u003eBetter seeing eye, ETDRS letters\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67.55\u0026thinsp;\u0026plusmn;\u0026thinsp;15.93\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFINAL BCVA (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\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\u003eBetter seeing eye, ETDRS letters\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60.82\u0026thinsp;\u0026plusmn;\u0026thinsp;17.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eINITIAL OCT (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\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\u003eEZ area (mm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.97\u0026thinsp;\u0026plusmn;\u0026thinsp;1.85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePROS (\u0026micro;m)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43.64\u0026thinsp;\u0026plusmn;\u0026thinsp;6.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFOSPET (\u0026micro;m)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69.82\u0026thinsp;\u0026plusmn;\u0026thinsp;10.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFOSPET/PROS ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.61\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eFINAL OCT (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEZ area (mm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.49\u0026thinsp;\u0026plusmn;\u0026thinsp;1.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePROS (\u0026micro;m)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41.36\u0026thinsp;\u0026plusmn;\u0026thinsp;9.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFOSPET (\u0026micro;m)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67.73\u0026thinsp;\u0026plusmn;\u0026thinsp;14.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFOSPET/PROS ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.68\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eBCVA, best-corrected visual acuity; ETDRS, Early Treatment of Diabetic Retinopathy Study; EZ, ellipsoid zone; FOSPET, foveal outer segment pigment epithelial thickness; MRDQ, Michigan retinal degeneration questionnaire; MVAQ, Michigan vision-related anxiety questionnaire; OCT, optical coherence tomography; PROS, photoreceptor outer segment length; SD, standard deviation.\u003c/p\u003e \u003cp\u003eFor PRO, the progression of MRDQ and MVAQ scores across the evaluated domains are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. All patients reported visual field constriction (100%) and nyctalopia (100%). Decreased visual acuity was reported by 72.73% of patients, whereas photophobia was reported by 9.09%.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eRegarding UW-FAF, 8 patients (72.7%) had typical findings, while the remaining 27.3% had atypical presentation (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). No hypoAF pattern were observed in any of the patients.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAmong the 11 patients carrying the c.4120C\u0026thinsp;\u0026gt;\u0026thinsp;T variant, 3 (27.3%) were homozygous and 8 (72.7%) were compound heterozygous (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). No statistically significant differences were observed between zygosity groups in age at symptom onset, Δ BCVA, Δ EZ area, Δ MRDQ or MVAQ domains (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\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\u003eCohort\u0026rsquo;s genetic landscape of \u003cem\u003eEYS\u003c/em\u003e variants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient ID\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eFamily ID\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNucleotide change\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eProtein Change\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eACMG Classification\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eGenetic test\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYear of genetic test\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePortuguese region\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.4120C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.(Arg1374*)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMLPA\u003c/p\u003e \u003cp\u003eNGS panel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCoimbra\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.2024-?_c.2259+?del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.(?)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.4120C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.(Arg1374*)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNGS panel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eLeiria\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.9182_9185del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.(Asn3061Thrfs*3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLikely pathogenic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.4120C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.(Arg1374*)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFamilial variant testing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eLisboa\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.9337A\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.(Lys3113*)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLikely pathogenic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.4120C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.(Arg1374*)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNGS panel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePorto\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.4120C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.(Arg1374*)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.4120C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.(Arg1374*)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMLPA\u003c/p\u003e \u003cp\u003eWES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eLeiria\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.(862\u0026thinsp;+\u0026thinsp;1_863-1)_(1056\u0026thinsp;+\u0026thinsp;1_1184\u0026thinsp;+\u0026thinsp;407)del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.(?)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLikely pathogenic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e6\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.4120C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.(Arg1374*)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMLPA\u003c/p\u003e \u003cp\u003eNGS panel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAveiro\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.4120C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.(Arg1374*)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e7\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.5928-2A\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFamilial variant testing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCoimbra\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.4120C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.(Arg1374*)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e8\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.4120C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.(Arg1374*)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNGS panel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eLeiria\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.4120C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.(Arg1374*)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e9\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.4120C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.(Arg1374*)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNGS panel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCoimbra\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.(2023\u0026thinsp;+\u0026thinsp;1_2024-1)_(2259\u0026thinsp;+\u0026thinsp;1_2260-1)del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.(?)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.4120C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.(Arg1374*)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNGS panel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCoimbra\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.9337A\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.(Lys3113*)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLikely pathogenic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e11\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.5928-2A\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNGS panel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCoimbra\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ec.4120C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep.(Arg1374*)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eACMG, American College of Medical Genetics; ID, Identifier; MLPA, multiplex ligation-dependent probe amplification; NGS, next-generation sequencing; WES, whole exome sequencing.\u003c/p\u003e \u003cp\u003e \u003cb\u003eBaseline vs final assessment of CRO and PRO\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAll patients had an initial and a final visit, during which they completed the questionnaires, with a mean interval of 43.18\u0026thinsp;\u0026plusmn;\u0026thinsp;1.17 months between assessments. Functional and structural parameters were collected at both time points to enable comparison with the questionnaire responses. During follow-up, patients reported significant worsening in MRDQ domains related to central vision and photopic peripheral function, along with a significant increase in cone-related anxiety on the MVAQ, reflecting both progressive functional limitation in daily visual tasks and its associated psychosocial impact. These parameters were compared between the initial and final evaluations (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Longitudinal theta score changes in MRDQ domains did not differ in magnitude across dimensions overall (Friedman test: \u003cem\u003eχ\u003c/em\u003e\u0026sup2;(6)\u0026thinsp;=\u0026thinsp;1.870, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.931), indicating no dominant domain-specific worsening pattern, despite significant decline in selected individual domains over time.\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\u003eComparison of CRO and PRO between the initial and final evaluations.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eINITIAL\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFINAL\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSIGNIFICANCE\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 best eye, ETDRS letters (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67.55\u0026thinsp;\u0026plusmn;\u0026thinsp;15.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60.82\u0026thinsp;\u0026plusmn;\u0026thinsp;17.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;0.007*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOCT\u003c/b\u003e (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEZ area (mm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.97\u0026thinsp;\u0026plusmn;\u0026thinsp;1.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.49\u0026thinsp;\u0026plusmn;\u0026thinsp;1.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.130\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePROS (\u0026micro;m)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43.64\u0026thinsp;\u0026plusmn;\u0026thinsp;6.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41.36\u0026thinsp;\u0026plusmn;\u0026thinsp;9.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.537\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFOSPET (\u0026micro;m)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69.82\u0026thinsp;\u0026plusmn;\u0026thinsp;10.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67.73\u0026thinsp;\u0026plusmn;\u0026thinsp;14.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.700\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFOSPET-PROS ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.61\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.68\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.531\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMRDQ scores\u003c/b\u003e (median, IQR)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCentral vision\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.276 (-0.568\u0026ndash;0.567)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.757 (0.255\u0026ndash;0.918)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eZ\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;2.756;\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003ep\u0026thinsp;=\u003c/b\u003e\u0026thinsp;\u003cb\u003e0.006*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eColor vision\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.479 (-0.086\u0026ndash;0.887)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.648 (0.135\u0026ndash;0.774)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eZ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.067;\u003c/p\u003e \u003cp\u003e\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.286\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eContrast sensitivity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.002 (-0.526\u0026ndash;1.171)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.962 (0.348\u0026ndash;1.312)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eZ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.956;\u003c/p\u003e \u003cp\u003e\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0,050\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eScotopic function\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.760 (0.142\u0026ndash;1.173)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.204 (0.629\u0026ndash;1.337)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eZ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.689;\u003c/p\u003e \u003cp\u003e\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.091\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhotopic peripheral function\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.438 (0.221\u0026ndash;1.015)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.947 (0.349\u0026ndash;1.445)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eZ\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;2.134;\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003ep\u0026thinsp;=\u003c/b\u003e\u0026thinsp;\u003cb\u003e0.033*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMesopic peripheral function\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.916 (-0.041\u0026ndash;1.309)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.158 (0.655\u0026ndash;1.495)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eZ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.334;\u003c/p\u003e \u003cp\u003e\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.182\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhotosensitivity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.548 (0.120\u0026ndash;0.961)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.348 (0.189\u0026ndash;1.798)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eZ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.600;\u003c/p\u003e \u003cp\u003e\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.110\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMVAQ scores\u003c/b\u003e (median, IQR)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRod function anxiety\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.171 (-0.270\u0026ndash;1.630)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.271 (-0.003\u0026ndash;1.630)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eZ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.770;\u003c/p\u003e \u003cp\u003e\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.441\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCone function anxiety\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.563 (-0.794\u0026ndash;0.335)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.953 (0.312\u0026ndash;1.700)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eZ\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;2.667;\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003ep\u0026thinsp;=\u003c/b\u003e\u0026thinsp;\u003cb\u003e0.008*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eBCVA, best-corrected visual acuity; ETDRS, Early Treatment of Diabetic Retinopathy Study; EZ, ellipsoid zone; FOSPET, foveal outer segment pigment epithelial thickness; IQR, interquartile range; MRDQ, Michigan retinal degeneration questionnaire; MVAQ, Michigan vision-related anxiety questionnaire; OCT, optical coherence tomography; PROS, photoreceptor outer segment length; SD, standard deviation.\u003c/p\u003e \u003cp\u003eAsterisk (*) indicates a significant value.\u003c/p\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation analysis of change scores (Δ)\u003c/h2\u003e \u003cp\u003eSpearman correlation analyses were performed on the changes (Δ) between baseline and final assessments for each domain. Moderate correlations were observed between changes in rod-related and cone-related functional anxiety (MVAQ Rod Δ \u0026harr; Cone Δ, \u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.692, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.018), indicating that individuals with greater increases in rod-related anxiety also experienced larger increases in cone-related anxiety. Declines in central vision (MRDQ Central Vision Δ) were moderately associated with reductions in photopic peripheral function (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.673, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023) and mesopic peripheral function (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.664, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.026), reflecting linked deterioration in core visual tasks and peripheral function under low or mixed lighting. Rod-mediated scotopic dysfunction (MRDQ Scotopic Function Δ) showed a very strong association with mesopic peripheral function impairment (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.873, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and a moderate correlation with photopic peripheral decline (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.682, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021), while photopic peripheral deficits were also moderately related to mesopic peripheral function limitations (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.645, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.032).\u003c/p\u003e \u003cp\u003eNo statistically significant correlation was observed between the change in cone-related MVAQ scores and the change in BCVA over follow-up (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.979). Additionally, age at symptom onset did not demonstrate a significant association with changes in MVAQ (rod or cone) or MRDQ domain scores, nor with longitudinal changes in BCVA, EZ area, FOSPET, PROS or the FOSPET/PROS ratio (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis longitudinal study provides a multidimensional characterization of \u003cem\u003eEYS\u003c/em\u003e-associated RP linked to the c.4120C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg1374*) variant by integrating PRO, functional measures and structural biomarkers. By overcoming the limitations of previous cross-sectional and genetically heterogeneous cohorts, it offers new insights into natural history disease trajectories and structure-function correlations, informing clinical decision-making and trial design [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan additionalcitationids=\"CR31 CR32\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSymptom onset peaked between ages 11 and 30, aligning with established data for \u003cem\u003eEYS\u003c/em\u003e-associated RP [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. This window coincides with major educational, vocational and psychosocial transitions, likely influencing patient-reported functional difficulties and anxiety beyond traditional clinical metrics. Consistent with reported allelic heterogeneity and phenotypic variability in \u003cem\u003eEYS\u003c/em\u003e mutations [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], no statistically significant association was observed between zygosity and age at symptom onset or longitudinal progression in BCVA, EZ area and PRO. These results suggest that zygosity alone does not dictate disease trajectories in this cohort, with genetic modifiers, environmental factors or recall bias in reporting onset, likely contributing to the observed variability.\u003c/p\u003e \u003cp\u003eConsistent with rod-cone degeneration, patients reported early nyctalopia and peripheral field loss, while photophobia remained rare, aligning with its typical emergence in later disease stages [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. A mean decline of 1.87 ETDRS letters per year was observed in BCVA. This rate, while slightly higher than some \u003cem\u003eEYS\u003c/em\u003e-specific reports [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], remains lower than that observed in broader RP populations [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], supporting the characterization of \u003cem\u003eEYS\u003c/em\u003e-associated RP as a relatively milder phenotype, albeit with notable inter-individual variability [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Despite initially preserved central acuity, progressive concentric field loss and night blindness significantly compromise mobility and independence, leading to activity restriction and reduced social participation [\u003cspan additionalcitationids=\"CR38\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. As the disease advances, central involvement increasingly impairs high-acuity tasks, impacting vocational productivity. These findings underscore the need for early referral to low-vision rehabilitation and psychosocial support to mitigate the socioeconomic burden [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e], even in the absence of curative therapies.\u003c/p\u003e \u003cp\u003eBeyond functional limitations, many individuals face emotional, psychological and social difficulties that reduce quality of life [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. For these reasons, incorporating patients\u0026rsquo; perceptions of their visual function, rather than relying solely on traditional clinical tests, is increasingly important as patients frequently notice subtle changes in their vision before they become measurable. The PRO captured meaningful aspects of functional decline that were not always reflected in structural measures. Significant worsening in MRDQ domains related to central vision and photopic peripheral function, as well as increased cone-related anxiety on the MVAQ, reflects heightened awareness of difficulties in tasks relying on photopic and central vision. While previous cross-sectional work found no link between BCVA and rod or cone-related anxiety [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], our longitudinal data revealed that cone-related anxiety increases over time even if it does not correlate with BCVA at a single time point. However, changes in cone-related MVAQ scores were not significantly correlated with changes in BCVA, suggesting that anxiety trajectories may be influenced by factors not fully captured by visual acuity alone, including day-to-day functional limitations, expectations regarding disease progression and individual coping mechanisms. Furthermore, age at symptom onset did not predict longitudinal changes in PRO or CRO, likely due to symptom normalization, varied coping mechanisms and heterogeneity in contextual factors, such as regional disparities in healthcare access and sociodemographic resources [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Other longitudinal studies are needed to clarify how these factors influence psychiatric morbidity in this population and to identify targets for timely intervention.\u003c/p\u003e \u003cp\u003eWhile previous cross-sectional studies[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] from our team on \u003cem\u003eEYS\u003c/em\u003e and \u003cem\u003eRPGR\u003c/em\u003e cohorts established correlations between SD-OCT biomarkers (EZ area, PROS, FOSPET) and patient-perceived disability, longitudinal results remain less clear. In our study, EZ area reduction was statistically non-significant and foveal outer retinal metrics remained stable. This suggests that central microstructural changes in this \u003cem\u003eEYS\u003c/em\u003e cohort may be too slow for detection within the analyzed timeframe, potentially indicating a structure\u0026ndash;function dissociation where functional decline precedes measurable structural loss. Although limited by a small sample size, these findings suggest that central macular architecture is relatively preserved in early or intermediate stages. Previous studies have suggesting that structure\u0026ndash;function relationships vary by genotype and disease stage [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCorrelation analysis of Δ-scores suggests that patient-perceived progression occurs in clusters rather than in isolation. Moderate correlations between rod- and cone-related anxiety indicate a shared psychosocial trajectory linked to worsening visual limitations, while central vision decline co-evolved with photopic and mesopic peripheral impairment, implying that difficulties in central tasks often co-evolve with increasing mobility and orientation challenges under varying illumination. The strongest association, between scotopic dysfunction and mesopic peripheral limitation, reflects expected rod-mediated mechanisms underlying mesopic performance. Overall, these patterns support the internal coherence of the MRDQ/MVAQ and reflect the expected progression of rod\u0026ndash;cone dystrophies. Furthermore, the selective worsening in specific domains, alongside high structural variability, underscores the significant inter-individual heterogeneity of \u003cem\u003eEYS\u003c/em\u003e-associated RP, likely driven by genetic, epigenetic or environmental modifiers.\u003c/p\u003e \u003cp\u003eEmerging RP therapies require standardized assessment frameworks that integrate structural and functional metrics with the patient perspective [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. While SD-OCT remains a cornerstone for quantifying photoreceptor integrity (EZ area, FOSPET, PROS) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], our findings suggest these metrics may lack sensitivity over a longer follow-up window, particularly in subphenotypes with slow structural progression. Although quantitative measures of UW-FAF were not included in our study, hyperAF ring measurements, may serve as a surrogate marker and act as a structural indicator of RP progression, supporting longitudinal monitoring and characterization of perifoveal involvement [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Notably, a previous report demonstrated that mean retinal sensitivity measured by microperimetry was significantly more strongly associated with the diameter of the hyperAF ring than with the EZ line, suggesting that AF ring development is linked to declining visual function independently of, and more strongly than, EZ changes [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study has limitations, including a small sample size, which reduces statistical power and may overestimate associations; the retrospective alignment of clinical and PRO data; the lack of complementary functional testing; and the single-center design, which may limit generalizability. Nevertheless, integrating longitudinal PRO and CRO data within a genetically defined cohort provides valuable insight into the natural history of \u003cem\u003eEYS\u003c/em\u003e-related RP.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn conclusion, this study establishes a significant dissociation between patient-perceived functional decline and objective microstructural stability. The worsening of central vision and increased psychosocial anxiety, occurring even as structural parameters remained stable, suggests that current structural biomarkers are insufficient surrogates for disease progression in this specific cohort. These findings advocate for a shift in clinical trial design toward a multimodal, function-centric approach that prioritizes microperimetry, quantification of the hyper autofluorescence ring and validated patient-reported outcomes instruments as primary endpoints. Ultimately, integrating the patient's lived experience with functional clinical metrics is essential to accurately quantify disease trajectories and define meaningful outcomes for emerging therapeutic interventions targeting \u003cem\u003eEYS\u003c/em\u003e-related retinal degeneration.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eACMG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAmerican College of Medical Genetics\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAutofluorescence\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBCVA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBest-corrected visual acuity\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCRO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eClinician-reported outcomes\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eETDRS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEarly Treatment of Diabetic Retinopathy Study\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEYS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEyes shut homolog\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEZ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEllipsoid zone\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFAF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFundus autofluorescence\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFOSPET\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFoveal outer segment pigment epithelial thickness\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFPR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFoveal outer segment pigment epithelial thickness-photoreceptor outer segment length ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInterquartile range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIRD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInherited retinal disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIRD-PT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePortuguese national registry of inherited retinal dystrophies\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMLPA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMultiplex ligation-dependent probe amplification\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMRDQ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMichigan Retinal Degeneration Questionnaire\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMVAQ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMichigan Vision-Related Anxiety Questionnaire\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNGS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNext-generation sequencing\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOptical coherence tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePRO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePatient-reported outcomes\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePROS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePhotoreceptor outer segment length\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRetinitis pigmentosa\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStandard deviation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD-OCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSpectral-domain optical coherence tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eULS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cem\u003eUnidade Local de Sa\u0026uacute;de\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUW-FAF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eUltra-widefield fundus autofluorescence\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWES\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWhole exome sequencing\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eClinical trial number\u003c/h2\u003e \u003cp\u003enot applicable.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEthics approval\u003c/strong\u003e \u003cp\u003e The study was approved by the local Ethics Committee and followed the tenets of the Declaration of Helsinki for biomedical research. All procedures involving human participants were in accordance with the ethical standards of the Human Research Ethics Committee (HREC) of \u003cem\u003eUnidade Local de Sa\u0026uacute;de de Coimbra\u003c/em\u003e (175/24 CE, process number OBS.SF.107\u0026ndash;2022) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent to participate\u003c/strong\u003e \u003cp\u003e Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eor Competing interests\u003c/p\u003e \u003cp\u003eNo funding was received to assist with the preparation of this manuscript. The authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by M.F. and A.P.. The first draft of the manuscript was written by M.F. and A.P. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCross N, van Steen C, Zegaoui Y, Satherley A, Angelillo L (2022) Retinitis Pigmentosa: Burden of Disease and Current Unmet Needs. Clin Ophthalmol 16:1993\u0026ndash;2010\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOrphanet Prevalence and incidence of rare diseases: Bibliographic data [Internet]. 2025 [cited 2025 Oct 21]. 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Acta Ophthalmol 102(5):555\u0026ndash;563\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeroy BP, Daly A, H\u0026eacute;on E, Sahel JA, Dollfus H (2024) Therapies for Inherited Retinal Dystrophies: What is Enough? Drug Discovery Today, vol 29. Elsevier Ltd\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGao FJ, Wang DD, Hu FY, Xu P, Chang Q, Li JK et al (2022) Genotypic spectrum and phenotype correlations of EYS-associated disease in a Chinese cohort. Eye (Basingstoke) 36(11):2122\u0026ndash;2129\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePierrache LHM, Messchaert M, Thiadens AAHJ, Haer-Wigman L, de Jong-Hesse Y, van Zelst-Stams WAG et al (2019) Extending the spectrum of EYS-associated retinal disease to macular dystrophy. 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Optometry 81(9):461\u0026ndash;468\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarta A, Marques JP, Santos C, Coutinho-Santos L, Vaz-Pereira S, Costa J et al (2024) The socioeconomic epidemiology of inherited retinal diseases in Portugal. Orphanet J Rare Dis. ;19(1)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTeixeira S, Franca M, Gouveia N, Teixeira B, Silva R, Murta J et al (2025) Structural and functional clinician-reported outcomes show strong correlations with patient-reported outcomes in Retinitis Pigmentosa. AJO Int. ;2(1)\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Eye Diseases, Hereditary, Retinal Dystrophies, EYS, Retinitis Pigmentosa, Patient Reported Outcome Measures, Genetic Therapy","lastPublishedDoi":"10.21203/rs.3.rs-8495428/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8495428/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEyes shut homolog \u003c/em\u003e(\u003cem\u003eEYS\u003c/em\u003e) is the gene most frequently associated with autosomal recessive retinitis pigmentosa (RP) in Portugal. This study describes the progression of RP associated with the \u003cem\u003eEYS \u003c/em\u003e(NM_001142800.2):c.4120C\u0026gt;T(p.Arg1374*) variant by correlating functional and structural measures with patient-reported outcomes (PRO).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy conducted at a Portuguese reference center for inherited retinal diseases. Patients with EYS-associated disease, with at least one c.4120C\u0026gt;T variant were identified using the IRD-PT registry (retina.com.pt). Other inclusion criteria were: at least 36 months of follow-up and baseline/last visit best-corrected visual acuity (BCVA), spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence phenotype and PRO (Michigan Retinal Degeneration Questionnaire (MRDQ); Michigan Vision-Related Anxiety Questionnaire (MVAQ)) data. Baseline and follow-up parameters were compared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEleven patients (9 families; 72.7% men; mean age of 43.8 ± 11.29 years) were included. Among the 11 patients carrying the variant, 3 (27.3%) were homozygous and 8 (72.7%) compound heterozygous. Mean follow-up was 43.2 ± 1.2 months. In the better-seeing eye, BCVA deteriorated significantly (\u003cem\u003ep\u003c/em\u003e=0.007). There was a significant worsening in MRDQ (central vision, \u003cem\u003ep\u003c/em\u003e=0.006; photopic peripheral function,\u003cem\u003e p\u003c/em\u003e=0.033) and a significant increase in cone-related anxiety on the MVAQ (\u003cem\u003ep\u003c/em\u003e=0.008). Structural parameters, including EZ area, showed no statistically significant change (\u003cem\u003ep=\u003c/em\u003e0.130). Changes in rod/cone anxiety correlated moderately (\u003cem\u003er\u003c/em\u003e=0.692; \u003cem\u003ep\u003c/em\u003e=0.018) and scotopic deterioration was strongly associated with mesopic peripheral limitation (\u003cem\u003er=\u003c/em\u003e0.873; \u003cem\u003ep\u003c/em\u003e\u0026lt;0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDisease progression was characterized by functional decline and increased psychosocial burden without significant structural deterioration. Integrating PRO with clinical and structural measures supports the design of therapeutic trials and clinical monitoring.\u003c/p\u003e","manuscriptTitle":"Natural History of Retinitis Pigmentosa Associated With the C.4120c\u0026gt;t Eys Variant","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-22 07:16:03","doi":"10.21203/rs.3.rs-8495428/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5bf95fb5-2553-4784-8670-37e2b7077a29","owner":[],"postedDate":"January 22nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-22T07:16:03+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-22 07:16:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8495428","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8495428","identity":"rs-8495428","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}