# paper.pdf ## Metadata - PDFFormatVersion=1.6 - IsLinearized=true - IsAcroFormPresent=false - IsXFAPresent=false - IsCollectionPresent=false - IsSignaturesPresent=false - CreationDate=D:20260601094005+05'30' - ModDate=D:20260601094035+05'30' - Producer=Acrobat Distiller 10.0.0 (Windows) - pdf:keywords="X-linked retinitis pigmentosa"; "choroideremia"; "inherited retinal disease"; "female carriers" - dc:format=application/pdf - dc:title=Comparative Analysis of Retinal Structure and Function in Female Carriers of Choroideremia and X-Linked Retinitis Pigmentosa - dc:identifier=doi:10.1167/tvst.15.6.4 - dc:description=Translational Vision Science and Technology, 2026. doi:10.1167/tvst.15.6.4 - prism:doi=10.1167/tvst.15.6.4 - prism:url=https://doi.org/10.1167/tvst.15.6.4 - prism:aggregationtype=journal - prism:publicationname=Translational Vision Science and Technology - prism:issn=2164-2591 - dc:creator=Jedrzej P. Golebka,Maximilian D. Kong,Jin Kyun Oh,Jimmy Duong,Aykut Demirkol,Royce W. S. Chen,Stephen H. Tsang - dc:subject=X-linked retinitis pigmentosa,choroideremia,inherited retinal disease,female carriers - xmpmm:documentid=uuid:53dbadde-b2bb-3dca-880e-669bcb6ca19b - xmpmm:instanceid=uuid:efd53884-610f-3c9e-9b80-5a31be17f715 ## Contents ### Page 1 RetinaComparative Analysis of Retinal Structure and Function in Female Carriers of Choroideremia and X-Linked Retinitis Pigmentosa Jedrzej P. Golebka 1,2 , Maximilian D. Kong1,3 , Jin Kyun Oh1,2 , Jimmy Duong4 , Aykut Demirkol1 , Royce W. S. Chen1,2 , and Stephen H. Tsang 1,2,4,51 Harkness Coordinating Center, Jonas Children’s Vision Care, Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, New York-Presbyterian Hospital, New York, NY, USA 2 Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA 3 State University of New York at Downstate Medical Center, Brooklyn, NY, USA 4 Department of Biostatistics, Columbia University, New York, NY, USA 5 Department of Pathology & Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USACorrespondence: Stephen H. Tsang, Edward S. Harkness Eye Institute, Columbia University Medical Center, 701 W. 168th Street, HHSC205b, New York, NY 10032, USA. e-mail: sht2@cumc.columbia.eduReceived: January 15, 2026Accepted: April 14, 2026Published: June 2, 2026Keywords: X-linked retinitis pigmentosa; choroideremia; inherited retinal disease; female carriersCitation: Golebka JP, Kong MD, Oh JK, Duong J, Demirkol A, Chen RWS, Tsang SH. Comparative analysis of retinal structure and function in female carriers of choroideremia and X-linked retinitis pigmentosa. Transl Vis Sci Technol. 2026;15(6):4, https://doi.org/10.1167/tvst.15.6.4Purpose: To characterize and compare structural and functional outcomes in female carriers of choroideremia (CHM) and RPGR-associated X-linked retinitis pigmentosa (XLRP), focusing on differences in disease severity and progression.Methods: Carriers of CHM (n = 20) and XLRP (n = 27) were identified retrospectively from a database of a single tertiary center. Visual acuity (best-corrected visual acuity [BCVA]), multimodal imaging including color fundus photography, short-wavelength autofluorescence, optical coherence tomography (OCT), and full-field electroretinogra- phy (ERG) were analyzed. Eyes were classified into severity phenotypes using previously published grading systems. Macular retinal thicknesses were measured, and progression was assessed over follow-up. Age-matched analyses were conducted to compare CHM and XLRP carriers.Results: CHM and XLRP carriers exhibited a broad spectrum of phenotypes from subclin- ical changes to severe, male-like disease. In both groups, greater disease severity corre- lated with younger age at symptom onset, worse baseline BCVA, thinner retinochoroidal layers, and diminished light-adapted 30-Hz flicker ERG amplitudes. CHM carriers demon- strated significantly faster retinal thinning in the outer macula (3–6 mm Early Treatment Diabetic Retinopathy Study [ETDRS]) and exhibited faster BCVA decline compared to XLRP carriers (P < 0.05). Although phenotypic progression based on grading scales was infrequent, quantitative OCT measurements revealed continuous structural thinning over time.Conclusions: Compared to XLRP, CHM carriers experience accelerated retinal thinning. Severe phenotypes are associated with faster structural and functional decline. These findings underscore the need for careful monitoring and highlight female carriers as potential candidates for future gene therapy and therapeutic trials.Translational Relevance: This study translates genetic and structural disease mecha- nisms in X-linked retinal degeneration into clinically relevant prognostic tools that may inform counseling, surveillance, and future gene therapy strategies for female carriers. Copyright 2026 The Authors tvst.arvojournals.org | ISSN: 2164-2591 1 This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. ### Page 2 Analysis of Choroideremia and X-Linked RP Carriers TVST | June 2026 | Vol. 15 | No. 6 | Article 4 | 2IntroductionChoroideremia (CHM) and X-linked retinitis pigmentosa (XLRP) are X-linked inherited retinal degenerations that share overlapping patterns of photoreceptor and outer retinal involvement yet arise from distinct molecular mechanisms and exhibit differing trajectories of disease progression. 1–3 CHM results from pathogenic variants in the CHM gene, leading to REP1 deficiency and dysfunction of the retinal pigment epithelium and choroid, whereasRPGR-associated XLRP is driven by disruption of photoreceptor ciliary transport, which predominantly affects photoreceptor cells. 4 Although both condi- tions are classically considered severe in affected males and variably expressed in female carriers, emerg- ing evidence suggests that female carriers are not uniformly asymptomatic and may experience clinically meaningful structural and functional impairment.5,6 Despite this, the natural history and prognosis of female carriers remain poorly defined, particularly when considered across different X-linked retinal diseases. In the current era of gene-based therapies, where treatment paradigms are rapidly advancing for affected males, 7,8 there is a critical unmet need to better characterize disease burden in female carriers. Comparison of CHM and XLRP carriers offers a unique opportunity to determine whether lyonization- driven disease expression results in comparable or divergent structural and functional outcomes and to identify clinical features that best predict progression. Despite increasing awareness of carrier involve- ment, no large study has directly compared female carriers of CHM and XLRP or assessed differ- ences in disease severity and prognosis between these conditions.9 This gap is particularly relevant as gene therapy trials in affected males have shown only modest benefit, especially in advanced disease, 7,8 shift- ing attention toward patients with milder phenotypes and preserved retinal structure.10 Female carriers, who often exhibit milder, heterogeneous phenotypes, may therefore represent a clinically important and previ- ously underexplored population for future therapeu- tic strategies. Comparative evaluation of CHM and XLRP carriers has the potential to inform prognos- tic counseling, refine surveillance strategies, and guide prioritization for emerging interventions. In this study, we characterize the clinical, structural, and functional features of female carriers of CHM and XLRP using best-corrected visual acuity (BCVA), multimodal retinal imaging, and electrophysiologic testing. We then perform an age-matched compari- son to evaluate disease progression and identify clini- cal factors associated with prognosis, with the aim of advancing both patient care and research priorities in X-linked retinal disease.Methods Patients and GroupsThis is a retrospective observational study of female carriers of CHM and RPGR-associated XLRP identi- fied from a database at a single electrodiagnostic center, Jonas Children’s Vision Care in New York City. Inclu- sion criteria included a diagnosis confirmed by identi- fication of a pathogenic or likely pathogenic CHMor RPGR variant or obligate carrier status supported by examination conducted by the senior author of this project (SHT). In a small number of XLRP carriers (n = 4), genotype confirmation was unavail- able, but these individuals demonstrated characteris- tic multimodal imaging and electrophysiologic findings consistent with RPGR-associated carrier status, had a positive family history, and were examined and diagnosed by an expert in the field (SHT) and there- fore included in the analysis. Informed consent was waived due to the minimal risk conferred to the patients and the retrospective nature of the study design as per the Institutional Review Board at Columbia University (protocol AAAR8743). All procedures were reviewed and in accordance with the tenets of the Declaration of Helsinki. The identified cases of each condition were subdi- vided into phenotype severity categories based on previously published grading systems. 10,11 For CHM, the patients were divided into mild, intermediate, and severe CHM phenotype groups. For RPGR-associated XLRP, the patients were divided into normal, radial, focal, and male-pattern XLRP phenotype groups. No eyes in the present cohort met criteria for the normal XLRP phenotype, defined as the absence of charac- teristic radial or pigmentary retinal abnormalities. The images for the respective groups are presented in Figure 1. The collected data included age at initial presen- tation, age of symptom onset, gender, ophthal- mologic history, follow-up duration, visual acuity (in logarithm of the minimum angle of resolu- tion), electroretinography (ERG) tracings, and results. Patients were considered symptomatic if they reported nyctalopia or peripheral vision loss. Genotype infor- mation was collected from previous genetic testing results conducted on peripheral venous samples. Full- field ERG was performed using Dawson, Trick, and Litzkow electrodes and Ganzfeld stimulation ### Page 3 Analysis of Choroideremia and X-Linked RP Carriers TVST | June 2026 | Vol. 15 | No. 6 | Article 4 | 3Figure 1. Color fundus and short-wavelength autofluorescence images for CHM and XLRP phenotype groups. The images are organized from mildest severity (A; mild CHM mottling and radial XLRP with tapetal-like reflex) through intermediate (B; intermediate CHM, focal XLRP) to severe (C; severe CHM, male-pattern XLRP). Although the original RGPR-associated XLRP grading system includes a “normal” category, no eyes in our cohort met criteria for this phenotype, and it is therefore not shown.on a Diagnosys Espion Electrophysiology System (Diagnosys LLC, Littleton, MA, USA) in accordance with international standards.12 Testing was performed following international society for clinical electorphys- iology of vision (ISCEV) protocols for light- and dark-adapted responses. For functional analysis, light- adapted 30-Hz flicker amplitude and implicit time and dark-adapted 0.01 ERG b-wave amplitude were evaluated due to their sensitivity to photoreceptor decline.13–15Image AnalysisHigh-resolution optical coherence tomography (OCT) volume scans and short-wave autofluorescence (SW-AF) (488-nm excitation, 500-nm barrier filter, both 30° × 30° and 50° × 50° field) were collected. All images were obtained using a Spectralis HRA +OCT machine (Heidelberg Engineering, Heidelberg, Germany). Widefield pseudocolor fundus images (lasers: red, 633 nm; green, 532 nm; with red and green false color display) were obtained using an Optos 200Tx (Optos plc, Dunfermline, Scotland, UK). To assess the anatomic impact of each disease on the choroid and retina, we measured macular retinal thicknesses based upon the built-in Heidel- berg Spectralis OCT segmentation software. Single subfoveal choroidal thickness (SFCT) measurements were obtained in the choroid. Total retinal thick- ness (TRT; from inner limiting membrane to retinal pigment epithelium/Bruch’s membrane complex), the inner retinal thickness (IRT; from the inner limiting membrane to the external limiting membrane), and the photoreceptor complex thickness (PCT; from exter- nal limiting membrane to Bruch’s membrane) were obtained in the central foveal 1-mm zone, inner macular ring (1–3 mm), and outer macular ring (3–6 mm). For each OCT scan, the software-generated segmentation layers were manually corroborated, and in cases of mis-segmentation, the lines were refitted by one of the authors (JPG) from this study. In cases of uncertainty, the segmentation was confirmed by the senior author (SHT).Analysis and StatisticsData analysis and statistics were performed using the IBM SPSS Statistics software (version 30.0.0.0; SPSS, Inc., Chicago, IL, USA). Analysis of differ- ences in age at presentation and age at symptoms onset was done using one-way analysis of variance with pairwise comparisons (Tukey test) using the worse- eye severity. For all other variables, linear mixed- effects models (LMMs) were used to account for within-patient correlation (i.e., two eyes per patient) using patient ID as a random effect. The analy- ### Page 4 Analysis of Choroideremia and X-Linked RP Carriers TVST | June 2026 | Vol. 15 | No. 6 | Article 4 | 4sis was additionally repeated using age at diagnosis as a covariate. For comparison involving more than two severity groups, post hoc pairwise testing was conducted using the least significant difference method for multiple comparisons. A two-sided P value of<0.05 was considered statistically significant. Disease progression was assessed using longitudinal follow- up data where available, including repeated measure- ments of visual acuity, and OCT-derived retinal thickness parameters. Age-matched cross-sectional comparisons were additionally performed to evalu- ate differences in disease severity between groups at baseline. Additional analysis using age at diagnosis as a covariate was performed to enable age-adjusted comparison of the CHM and XLRP cohorts and to assess differences in disease severity independent of age distribution.Results DemographicsA total of 40 eyes from 20 female CHM carri- ers and 54 eyes from 27 female XLRP carriers satis- fied the study’s inclusion criteria. Follow-up data were available for 11 CHM carriers (mean [SD] duration of 3 [2.63] years; range, 1–9 years) and 13 XLRP carriers (mean [SD] duration 6 [2.9] years; range, 1– 12 years). Results of genetic testing are presented in Supplementary Figure S1 and Supplementary Table S1 for CHM and Supplementary Figure S2 and Supplementary Table S2 for XLRP. For CHM, no apparent genotype–phenotype correlation was identi- fied within this cohort, whereas in RPGR-associated XLRP, the more severely affected patients tended to harbor mutations within ORF15, consistent with prior reports. 16 For CHM, disease severity was graded using a previ- ously published scale 10 ; 18 eyes of 10 patients were classified as “mild,” 9 eyes of 6 patients were classi- fied as “intermediate,” and 13 eyes of 7 patients were classified as “severe.” Three patients demonstrated intereye differences in disease severity at presenta- tion: two with mild versus intermediate and one inter- mediate versus severe classification. During follow- up, only one CHM eye showed progression, from mild to intermediate, at year 9. Representative multi- modal images from patients with CHM are shown in Figure 2. For RPGR-associated XLRP, phenotypic classifica- tion using a corresponding grading system11 identified 35 eyes of 20 patients with the radial phenotype, 13 eyes of 10 patients with the focal phenotype, and 6 eyes of 4 patients with the male-pattern phenotype of XLRP. No eyes within this cohort met the criteria for the normalRPGR-associated XLRP phenotype (defined as the absence of characteristic radial or pigmentary retinal abnormalities). Seven patients had intereye differences in the XLRP phenotype: five radial versus focal and two focal versus male-pattern. Phenotypic progression was observed in four eyes of two patients: in one case, both eyes progressed from focal to male-pattern, and in the other, both eyes progressed from radial to focal. In both patients, progression was noted at year 12 of follow- up. Multimodal imaging examples from patients with XLRP are shown in Figure 3. Demographics and visual acuity data for both CHM and XLRP cohorts are presented in Table 1. For both CHM and XLRP, patients with mild disease phenotypes tended to be younger and more frequently asymptomatic, whereas progression was generally associated with older age and symptom devel- opment. However, in both CHM and XLRP, patients with severe, male-pattern phenotypes often reported symptom onset at an early age, similar to those with mild, radial disease, indicating that progression is not solely age-driven. In CHM, age at diagnosis differed significantly between the mild and intermediate groups (P = 0.033, Tukey test) but not between the mild and severe groups. Similarly, in XLRP, a significant difference was observed between the radial and focal phenotypes (P =0.001, Tukey test) but not between the radial and male- pattern groups. BCVA did not differ significantly between CHM severity groups, although the mild versus severe comparison approached significance (P = 0.070, LMM). In contrast, XLRP groups showed significant differences in BCVA across all phenotypes (P < 0.05, LMM). Analysis of change in BCVA per year revealed a difference between radial and focal XLRP pheno- types (P = 0.025, LMM), while other comparisons for both CHM and XLRP were nonsignificant (P >0.05, LMM). Taken together, these findings indicate that baseline BCVA may vary with disease severity, but the rate of decline over time is less clearly dependent on phenotype.OCT Retinal Thickness AnalysisThe results for OCT retinal thickness analysis are summarized in Table 2 for CHM and Table 3 for XLRP, with individual measurements included in Supplemen- tary Tables S3 and S4. In both CHM and XLRP, increasing disease severity was associated with progres- sive thinning of the retina and choroid across the Early Treatment Diabetic Retinopathy Study (ETDRS) ### Page 5 Analysis of Choroideremia and X-Linked RP Carriers TVST | June 2026 | Vol. 15 | No. 6 | Article 4 | 5Figure 2. Representative retinal fundus photographs and OCT images in CHM carriers. Optos fundus photographs are shown in A and B, demonstrating peripapillary atrophy (A) and chorioretinal atrophy with retinal pigment epithelium mottling and vascular attenuation (B). OCT images are shown in C and D, illustrating drusenoid deposits (C) and chorioretinal atrophy with outer retinal tubulations (D). Features such as peripapillary atrophy, drusenoid deposits, or outer retinal tubulations have been reported in CHM but are not disease-specific and were not used for phenotypic classification in this study.zones, with the most consistent effects in the TRT and PCT. In CHM, SFCT was significantly reduced in inter- mediate and severe groups compared with mild (P =0.011 and P = 0.002, LMM), but no difference was observed between intermediate and severe disease (P =0.224, LMM). Within the retina, TRT was significantly reduced across all severity groups and ETDRS zones (P< 0.05, LMM), except between intermediate and severe groups in both inner (0–1 mm) and outer (3–6 mm) macula, where the difference approached significance (P = 0.052 and P = 0.055, LMM). PCT was signifi- cantly reduced across all severity groups and ETDRS zones (P < 0.05, LMM). For IRT, no differences were observed at the fovea (0–1 mm), whereas significant reductions were present at the inner macula (1–3 mm) between all groups (P < 0.05, LMM) and at the outer macula (3–6 mm) between mild versus intermediate (P = 0.003, LMM) and mild versus severe (P < 0.001, LMM), with the intermediate versus severe difference approaching significance (P = 0.074, LMM). In XLRP, SFCT was significantly reduced in male-pattern eyes compared with radial (P = 0.024, LMM), while the difference between radial and focal approached significance (P = 0.057, LMM); no differ- ence was observed between male-pattern and focal groups (P = 0.278, LMM). Across ETDRS zones and retinal layers, retinal thickness was significantly reduced between severity groups (P < 0.05, LMM). Longitudinal analysis reinforced these findings. In CHM, severe eyes showed significantly faster thinning in TRT 1 to 3 mm, TRT 3 to 6 mm, PCT 1 to 3 mm, and PCT 3 to 6 mm compared with intermediate and mild groups (P < 0.05, LMM). In XLRP, male- pattern eyes demonstrated significantly faster thinning at the fovea, specifically TRT1 and IRT1 (P < 0.05), ### Page 6 Analysis of Choroideremia and X-Linked RP Carriers TVST | June 2026 | Vol. 15 | No. 6 | Article 4 | 6Figure 3. Representative fundus photographs, short-wave autofluorescence (SW-AF), and OCT images showing characteristic XLRP features. (A) Optic disc pallor, vascular attenuation, and bony spicules in the fundus. (B) Retinal pigment epithelium atrophy around the optic nerve, with the macula present on the fundus photograph. Tapetal reflex is present in C and D. SW-AF hypoautofluorescent lesions and hyperautofluorescent macular ring are present in E. A foveal OCT scan (F) shows outer retinal atrophy on both sides of the fovea.compared with focal and radial phenotypes. No group differences in the rate of SFCT or PCT decline were observed. Although phenotypic progression based on grading scales was observed in only a small number of eyes, these categorical classifications capture relatively coarse structural changes. Quantitative OCT measure- ments therefore provide a more sensitive indicator of progressive retinal thinning over time. ### Page 7 Analysis of Choroideremia and X-Linked RP Carriers TVST | June 2026 | Vol. 15 | No. 6 | Article 4 | 7Table 1. Demographics and Visual Acuity Data for Both CHM and XLRP Cohorts and Corresponding Phenotypic Severity Subgroups Age BCVA (LogMAR) Characteristic Diagnosis Symptoms Symptomatic Eyes [ASx/Sx] First Visit Per Year CHM 43 ± 16.6 (10–76) 46 ± 15.8 (22–76) 7/13 0.34 ± 0.13 0.19 Mild 36 ± 15.3 (10–56) 40 ± 11.8 (28–55) 7/3 0.04 ± 0.21 0.00 Intermediate 60 ± 11.7 (46–76) 61 ± 11.7 (46–76) 1/5 0.40 ± 0.24 0.12 Severe 39 ± 12.9 (22–66) 39 ± 12.9 (22–66) 0/7 0.59 ± 0.19 0.34 XLRP 36 ± 20.8 (3–74) 37 ± 21.4 (7–69) 18/9 0.61 ± 0.08 0.011 Radial 30 ± 18.3 (3–74) 36 ± 20.9 (10–69) 15/5 0.12 ± 0.08 0.014 Focal 52 ± 19.8 (15–74) 44 ± 21.3 (15–69) 5/5 0.50 ± 0.13 0.003 Male-pattern 34 ± 21.3 (7–50) 29 ± 24.8 (7–50) 0/4 1.21 ± 0.19 0.012 ASx, asymptomatic; logMAR, logarithm of the minimum angle of resolution; Sx, symptomatic. Mean ± standard deviation (range) are included for age at diagnosis and symptom onset. For BCVA, at first visit, the mean and standard error values are included, alongside mean change () per year.Table 2. OCT Retinal Thickness Measurements in CHM Female Carriers Mild vs. Intermediate Mild vs. Severe Intermediate vs. Severe Characteristic Initial Per Year Initial Per Year Initial Per Year SFCT, μm 78.74 16.85 122.19 17.00 43.45 0.15 TRT, μm Fovea 22.52 1.10 46.14 4.35 22.63 3.26 Inner macula 33.91 −0.62 28.56 15.70 34.80 16.32 Outer macula 25.75 0.44 45.67 4.23 19.92 3.79 IRT, μm Fovea 10.59 1.15 14.19 3.59 3.60 2.44 Inner macula 26.10 1.26 54.52 2.23 28.425 0.97 Outer macula 18.77 1.43 32.61 −0.55 13.85 −1.98 PCT, μm Fovea 12.02 −0.33 31.46 1.44 19.44 1.76 Inner macula 6.72 −1.73 17.69 2.33 10.96 4.06 Outer macula 6.84 −0.53 12.48 3.58 5.65 4.10 The table includes mean difference values between the groups for initial thickness measurements as well as the mean differences in rates of thickness change per year. Positive values of change per year suggest greater thinning in the more severe group.ERGERG results for both CHM and XLRP cohorts, focusing on the light-adapted 30-Hz flicker and dark- adapted 0.01 b-wave, are summarized in Table 4. In the CHM cohort, significant differences in 30-Hz flicker amplitudes were observed between patients with severe versus mild disease (P = 0.009, LMM) and inter- mediate versus mild disease (P = 0.049, LMM). Flicker peak times differed significantly only between the mild and severe groups (P = 0.005, LMM). No significant difference was found between the severe and interme- diate groups (P = 0.197, LMM), suggesting a plateau in ERG amplitude reduction between these later stages of disease. In XLRP, mean amplitudes progressively declined with severity, with male-pattern eyes demonstrating extinguished responses (0 μV). For 30-Hz flicker ampli- tudes, a significant difference was observed between focal and radial groups (P = 0.013, LMM); the male- pattern versus radial comparison approached signifi- cance (P = 0.058, LMM), while male-pattern versus focal was nonsignificant (P = 0.240, LMM). Flicker peak times were significantly prolonged in male-pattern eyes compared with both radial and focal groups (P <0.001, LMM) but not between radial and focal cohorts ### Page 8 Analysis of Choroideremia and X-Linked RP Carriers TVST | June 2026 | Vol. 15 | No. 6 | Article 4 | 8Table 3. OCT Retinal Thickness Measurements in XLRP Female Carriers Radial vs. Focal Radial vs. Male-Pattern Focal vs. Male-Pattern Characteristic Initial Per Year Initial Per Year Initial Per Year SFCT, μm 54.69 −5.71 99.30 −6.93 44.61 −1.22 TRT, μm Fovea 27.42 1.33 79.34 5.63 51.92 4.31 Inner macula 35.62 2.55 84.96 3.03 49.24 0.48 Outer macula 27.14 −0.10 71.16 0.523 44.02 0.62 IRT, μm Fovea 17.64 0.53 50.59 5.36 32.95 4.83 Inner macula 26.11 1.82 60.11 1.56 34.00 −0.26 Outer macula 20.41 −0.10 40.58 1.70 20.17 1.80 PCT, μm Fovea 13.13 0.81 37.45 1.04 24.31 0.23 Inner macula 13.44 0.46 29.30 0.58 15.87 0.12 Outer macula 8.56 0.61 30.30 −0.01 21.74 −0.62 The table includes mean difference values between the groups for initial thickness measurements as well as the mean differences in rates of thickness change per year. Positive values of change per year suggest greater thinning in the more severe group.Table 4. Light-Adapted 30-Hz Flicker and Dark-Adapted 0.01 b-Wave Amplitude Results for CHM and XLRP Cohorts and Their Respective Phenotypic Severity Subgroups Light-Adapted 30-Hz Flicker Amplitude, μV Time, ms Dark-Adapted 0.01 b-Wave Amplitude, μV CHM 75.0 ± 12.7 29.3 ± 0.8 167.1 ± 16.4 Mild 123.3 ± 19.2 26.4 ± 0.5 306.7 ± 20.7 Intermediate 62.9 ± 19.9 28.4 ± 1.4 171.1 ± 35.9 Severe 38.9 ± 17.5 33.6 ± 1.2 23.4 ± 24.8 XLRP 54.0 ± 37.5 28.4 ± 1.0 94.6 ± 25.1 Radial 67.9 ± 34.0 28.5 ± 0.6 172.9 ± 16.1 Focal 26.0 ± 23.0 28.1 ± 3.4 111.0 ± 22.8 Male-pattern 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 For each group and the entire disease cohort, values for mean ± standard error are included.(P = 0.323, LMM). For the dark-adapted 0.01 b- wave, radial eyes had significantly larger amplitudes compared with focal (P = 0.012, LMM) and male- pattern groups (P = 0.026, LMM).Comparison of CHM and XLRPTo explore differences in prognosis between CHM and XLRP, we conducted an age-matched compara- tive analysis of female carriers. Visual function analy- sis revealed no significant difference in baseline BCVA between CHM and XLRP (P = 0.848, LMM), although the rate of BCVA decline was faster in CHM, approaching significance (P = 0.067, LMM). Baseline OCT measurements showed significantly thinner outer macular (3–6 mm) layers in CHM, with reduced TRT (P = 0.049, LMM) and IRT (P = 0.025, LMM) compared with XLRP. Longitudinally, CHM carriers demonstrated greater annual thinning in TRT (1–3 mm: P = 0.007; 3–6 mm: P = 0.009; LMM) and IRT (1–3 mm: P = 0.032; 3–6 mm: P = 0.002; LMM). PCT thinning also tended to be greater in CHM, with differences approaching significance at both 1 to 3 mm (P = 0.069, LMM) and 3 to 6 mm (P = 0.056, LMM). In contrast to results of visual acuity and retinal thickness analysis, ERG comparison revealed signifi- cantly worse 30-Hz flicker amplitudes in patients with XLRP (P = 0.047, LMM), with no differences noted in 30-Hz flicker time or b-wave amplitudes. However, ### Page 9 Analysis of Choroideremia and X-Linked RP Carriers TVST | June 2026 | Vol. 15 | No. 6 | Article 4 | 9CHM carriers more often exhibited combined light- and dark-adapted dysfunction, occurring in 36% of CHM carriers and only 14% of XLRP carriers.DiscussionTo our knowledge, this represents the largest, multimodal comparison of structural and functional outcomes in female carriers of CHM and RPGR- associated XLRP. 9 Across both cohorts, we observed two patterns of progression: an age-related transition from mild to moderate disease phenotypes and an age- independent, early-onset severe phenotype. Increas- ing severity in both conditions was characterized by progressive retinal thinning and combined light- and dark-adapted ERG impairment, with BCVA relatively preserved until late disease. When compared, CHM carriers demonstrated greater structural deterioration, including thinner retinas and faster rates of outer retinal thinning, and a trend toward worse BCVA, whereas XLRP carriers showed more pronounced electrophysiologic deficits, particularly in the 30-Hz flicker response. These differences are biologically plausible given the distinct pathogenic mechanisms of the two conditions. Choroideremia results from the loss of Rab escort protein 1 (REP1), which disrupts intracellular vesicular trafficking and affects multiple retinal tissues, including the retinal pigment epithelium, photoreceptors, and choroid.17 This broader involve- ment of supporting retinal structures may contribute to the greater structural thinning observed in our CHM cohort. In contrast, RPGR-associated XLRP primar- ily disrupts protein trafficking within the photore- ceptor connecting cilium, leading to photoreceptor dysfunction and degeneration, which may explain the more pronounced electrophysiologic impairment seen in XLRP carriers.18 These findings underscore the value of multimodal imaging and electroretinog- raphy in characterizing disease burden and will be important in the evaluation of future gene therapy interventions. Recent advances in CRISPR-based approaches and other gene editing strategies have shown promise in preclinical models of retinitis pigmentosa, including rescue of disease phenotypes through novel therapeutic targets. 19 Simultaneously, studies evaluating genotype–phenotype concordance across diverse X-linked retinal dystrophy variants highlight the need for personalized risk stratifica- tion in carriers, which our multimodal approach addresses.20,21 In CHM, severe phenotypes developed symptoms earlier and progressed more rapidly, yet age at presen- tation did not differ significantly between mild and severe groups, consistent with previously described work. 10 This contrasts with a prior retrospective series that did not find any phenotype–age association. 6 One possible explanation is that severely affected carriers may come to clinical attention at a similar age to mildly affected carriers despite having a more aggres- sive disease course, because referral is influenced not only by disease severity but also by family history, surveillance patterns, and timing of symptom recog- nition. The limited utility of BCVA as a progression biomarker aligns with CHM’s centripetal course and preserved foveal function until late stages 22,23 and with male trial data, emphasizing structure over acuity. 24 OCT analysis confirmed predominant outer retinal and choroidal thinning with relative IRT preservation, consistent with remodeling or neuronal reorganiza- tion of inner layers.25,26 Longitudinally, severe CHM thinned faster, challenging plateau models27 and align- ing with the NIGHT study’s observation that outer retinal metrics outperform BCVA for tracking progres- sion.24 XLRP carriers showed parallel trends with earlier diagnosis and worse baseline BCVA in severe pheno- types but similar intergroup rates of BCVA decline. This suggests that BCVA may capture early or subtle functional compromise even in carriers with less advanced structural disease, indicating that visual acuity may detect subtle functional impairment that may not be fully reflected by fundus-based severity grading. 28 Thickness analyses demonstrated signifi- cant loss across compartments, with most TRT reduc- tion reflecting PCT loss, matching classic RPGR- mediated outer retinal pathology. 29 IRT was relatively preserved in milder disease but thinned at the fovea in male-pattern eyes, suggesting inner retinal involve- ment emerges in advanced stages, again consistent with progressive remodeling. 29 Age-matched analyses showed a trend toward faster BCVA decline and significantly greater retinal thinning across multiple zones in CHM compared to XLRP, mirroring prior OCT follow-up where XLRP carri- ers exhibited relatively smaller mean changes, partic- ularly in the outer retina.6,30 Conversely, ERG ampli- tudes were lower in XLRP. CHM carriers often have normal or near-normal ERGs, 31 whereas a large XLRP carrier study reported mean 30-Hz flicker amplitudes at 50% of normal.28 Together, these data suggest more rapid structural loss in CHM but greater photore- ceptor dysfunction in XLRP. Importantly, this does not conflict with the relatively small number of eyes showing phenotypic progression on grading scales during follow-up, as these categorical systems capture only relatively coarse changes, whereas quantitative OCT measurements can detect more subtle and contin- uous structural progression over time. ### Page 10 Analysis of Choroideremia and X-Linked RP Carriers TVST | June 2026 | Vol. 15 | No. 6 | Article 4 | 10Our findings demonstrate that both CHM and XLRP carriers display a broad phenotypic spectrum, consistent with recent observations in other X-linked dystrophies where monoallelic and biallelic variants produce divergent clinical manifestations.20,21 Stratifi- cation by severity revealed two progression patterns. The more common was a slowly progressive course, with late-onset symptoms and relatively preserved retinal structure and ERG function. In contrast, a subset developed severe or male-pattern disease, marked by early symptom onset, rapid retinal thinning, reduced ERG amplitudes, and visual acuity loss. These severely affected carriers were diagnosed at similar ages to those with mild disease but progressed much faster. This variability is most likely explained by X- chromosome inactivation, or lyonization, in which one X chromosome is randomly silenced during embryo- genesis. 32 While the mutant allele is often preferen- tially inactivated, skewed inactivation of the normal allele has also been reported and may underlie the severe phenotypes seen in some carriers. 33 RPGR carri- ers with skewed inactivation of the wild-type allele measured in blood or saliva had significantly worse function. 34 Thus, the severe CHM and male-pattern XLRP carriers in our study likely represent individu- als with unfavorable lyonization, resulting in male-like disease expression. Sample size and enrichment for severe cases in longitudinal follow-up limit power and may bias progression estimates. Even so, the convergent struc- tural and functional signals, aligned with prior litera- ture, argue for earlier structural surveillance and for including carriers, especially CHM, in future gene therapy designs, where structure-based endpoints may be more sensitive than BCVA. Future work should prioritize multicenter collaborations to assemble larger carrier cohorts and validate these findings across diverse populations. Such efforts are essential to refine prognostic markers and improve power for subgroup analyses. Our results also have direct implications for therapy development. Both CHM and XLRP are strong candidates for gene replacement strategies, yet trials to date have largely excluded female carriers. Our data demonstrate that carriers, particularly of CHM, should be considered in the design of future gene therapy studies. Several limitations of our study should be acknowl- edged. The relatively small sample size, reflecting the rarity of both conditions, limited statistical power. Because clinical focus has historically centered on affected males, asymptomatic carriers are often under- diagnosed and underrepresented, and longitudinal data were more frequently available for severely affected patients, potentially biasing progression analy- ses toward worse outcomes. Full-field ERG followed ISCEV standards, assessing light-adapted 30-Hz flicker and dark-adapted 0.01 b-wave responses, both sensi- tive to cone and rod dysfunction in carrier states. Visual field data were not available consistently across the retrospective cohort and therefore could not be included, although they would have provided an additional functional measure for comparison. Never- theless, we acknowledge the need for broader pheno- typing. Future analysis of parameters such as dark- adapted 3.0/a-wave, light-adapted 3.0 amplitude, and peak times will offer additional information about photoreceptor and postreceptoral function. In this study, we were limited by the incomplete nature of the retrospective data capture.ConclusionsFemale carriers of both CHM and RPGR- associated XLRP demonstrate heterogeneous but clinically meaningful structural and functional disease expression. CHM carriers showed greater structural retinal thinning, whereas XLRP carriers exhibited more marked electrophysiologic dysfunction. These findings support the use of multimodal structural and functional biomarkers for prognostic assessment and reinforce the importance of considering affected female carriers in the design of future therapeutic trials.AcknowledgmentsHarkness Coordinating Center, Jonas Children’s Vision Care (JCVC) is supported by the National Institutes of Health (U01EY030580, U01EY034590, R24EY028758, R24EY027285, 5P30EY019007, R01EY033770, R01EY018213, R01EY024698), the Foundation Fighting Blindness (TA-GT-0321-0802- COLU-TRAP), Richard Jaffe, NYEE Foundation, the Rosenbaum Family Foundation, the Gebroe Family Foundation, Piyada Phanaphat Fund, the Research to Prevent Blindness (RPB) Physician-Scientist Award, and unrestricted funds from RPB.AI Statements: The original manuscript in its entirety was planned and written by one of the authors of this study (JG) and revised by all the other authors included in this manuscript. Follow- ing in-house revisions, AI technology (OpenAI [2024], ChatGPT 5.3 version, https://chatgpt.com/, accessed April–May 2025) was used to review grammar, punctu- ### Page 11 Analysis of Choroideremia and X-Linked RP Carriers TVST | June 2026 | Vol. 15 | No. 6 | Article 4 | 11ation, and syntax. Any changes suggested by AI have been reviewed by the authors of the study. Disclosure: J.P. Golebka, None; M.D. Kong, None;J.K. Oh, None; J. Duong, None; A. Demirkol, None;R.W.S. Chen, None; S.H. Tsang, NoneReferences1. Prokisch H, Hartig M, Hellinger R, Meitinger T, Rosenberg T. A population-based epidemiological and genetic study of X-linked retinitis pigmentosa.Invest Ophthalmol Vis Sci. 2007;48(9):4012. 2. Pennesi ME, Birch DG, Duncan JL, Ben- nett J, Girach A. Choroideremia. Retina. 2019;39(11):2059–2069. 3. Stone EM, Andorf JL, Whitmore SS, et al. 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