Phenotypic and Genetic Alterations in Adult-Onset Cone and Cone-Rod Dystrophy

Cone dystrophy (CD) is a progressive retinal disorder characterized by the gradual loss of cone photoreceptors, leading to symptoms such as progressive visual decline, color vision abnormalities, central scotoma, and photophobia [1, 2]. Patient with CD had a wide range of phenotypic spectrum, with affected macular appearance that can range from nearly normal or minor macular atrophy in early stages to a bull’s eye maculopathy and diffuse atrophy of outer retinal layers in advanced stage [3]. Some CDs only affect the cone system, while others develop rod dysfunction later, leading to cone-rod dystrophy (CRD). Full-field electroretinogram (ERG) demonstrated impaired cone function with or without rod dysfunction. While the clinical course of CD/CRD varies depending on genetic and environmental factors, typical clinical findings with visual impairment are usually observed before the age of 30 [4]. However, there are some patients whose visual symptoms first appear after the age of 40 or even 60 years and are diagnosed with CD/CRD, which is here referred to as adult-onset cone dystrophy (AOCD) or adult-onset cone-rod dystrophy (AOCRD).

Although the clinical features and genetic cause of typical CD/CRD have been already studied including causative genes such as RPGR, ABCA4, AIPL1, CRX, GUCY2D, and so on [1, 3, 5], only a few cases of AOCD/AOCRD have been reported, and its clinical and genetic features remain unestablished [4, 6]. The clinical features of AOCD/AOCRD occurring after middle age can be similar to that of other retinal disorders including atrophic age-related macular degeneration (AMD), autoimmune retinopathy, drug-induced retinopathy, and so on. These clinical similarities can make the diagnosis of AOCD/AOCRD more challenging [1, 7].

In this study, we investigated the clinical and genetic features of 22 individuals with genetically confirmed CD/CRD, whose symptoms began after 30 years of age. Comprehensive ophthalmic examinations, including fundus examination, spectral-domain optical coherence tomography (SD-OCT), and electrophysiological tests, were performed, and exome sequencing targeting 296 genes associated with inherited retinal diseases was performed. Based on the clinical and genetic features, the genotype-phenotype correlation was analyzed. Finally, we aimed to provide insight into the clinical manifestations and genetic variations of AOCD/AOCRD, highlighting the importance of considering this diagnosis in patients presenting visual impairment and macular abnormalities later in life.

This retrospective study included 22 individuals who visited Seoul National University Bundang Hospital between June 2009 and June 2022 and were diagnosed with AOCD/AOCRD by genetic testing. This study adhered to the Declaration of Helsinki and was approved by the Institutional Review Board of the Ethics Committee of Seoul National University Bundang Hospital (IRB no. B-2303-816-103). Informed consent was obtained from all individuals prior to genetic analysis. The inclusion criteria were as follows: (1) visual symptoms such as decreased visual acuity for the first time over the age of 30 years, (2) a clinical diagnosis of CD/CRD, and (3) genetically confirmed cases. Individuals with other vitreoretinal diseases including AMD, central serous retinopathy, and uveitis were excluded. CD/CRD was diagnosed based on the individual’s initial symptoms, fundus abnormalities, ERG findings, and the overall disease course, which included a decrease in central vision, presence of a central scotoma, mild or no constriction of the visual field, and reduced ERG responses consistent with cone involvement. Cases involving the entire retina outside the macula at disease onset, which were diagnosed as having retinitis pigmentosa, were excluded.

All patients underwent comprehensive ophthalmic examinations, including best corrected visual acuity (BCVA), intraocular pressure measurement, slit-lamp examination, and fundus examination. Spectral-domain OCT (SD-OCT, Spectralis; Heidelberg Engineering, Heidelberg, Germany) with eye-tracking and image-averaging systems and VX-10a (Kowa Inc., Nagoya, Japan) were used to acquire the retinal images at each visit. Standard automated perimetry was performed using a Humphrey field analyzer (Humphrey Field Analyzer II 750; 30-2 Swedish interactive threshold algorithm, Carl Zeiss Meditec). There were two types of visual defects: paracentral scotoma (which existed within 10 degrees of fixation, excluding the fixation point itself) and central scotoma (which encompassed the point of fixation). The Visual Evoked Response Imaging System (VERIS) ERG (VERIS II; Electro-Diagnostic Imaging Inc., San Francisco, CA, USA) was used as indicated by the International Society for Clinical Electrophysiology of Vision (ISCEV) [8]. To quantitatively analyze the ERG, the relative photopic ERG amplitude ratio was used. The relative photopic ERG amplitude ratio was defined as the patient’s photopic ERG b-wave/the photopic ERG b-wave amplitude from the normal standard reference. The normal ERG reference was derived from data collected from a cohort of 20 normal individuals from Seoul National University Bundang Hospital (SNUBH). The value of b-wave amplitude was automatically provided by the instrument. The central retinal thickness (CRT) was measured using Spectralis SD-OCT, where CRT is defined as the average retinal thickness within the central 1-mm diameter of the macula. To determine the extent of the lesions, the horizontal line was drawn from the nasal end to the temporal end of the affected photoreceptor which was characterized by abnormalities in any of the following: ellipsoid zone (EZ), IZ, ELM, and RPE. This horizontal line was measured on both vertical and horizontal scans. Finally, the extent of the lesions was represented as the average of two lengths of horizontal line. Additionally, AOCD/AOCRD was classified into five modified categories based on a previously published paper using the SD-OCT images [9]: category 0 indicates intact photoreceptor layers; category 1 indicates disorganization of the interdigitation zone (IZ); category 2 indicates disruption of the IZ and EZ; category 3 indicates disruption of the IZ, EZ, and external limiting membrane; and category 4 indicates loss of the outer retina and retinal pigment epithelium (RPE) layer. In the case of foveal involvement, the letter F was added next to each category (online suppl. Fig. 1; for all online suppl. material, see https://doi.org/10.1159/000535430).

In the present study, we used a customized exome panel comprising 296 known and potential candidate genes associated with inherited retinal diseases. The panel covered all the coding exons, 5′ and 3′ untranslated regions, and alternative splicing regions of each gene. To prepare DNA libraries, we used the Celemics Library Preparation Kit (Celemics, Korea), which involves several enzymatic steps, including end repair, dA-tailing, and ligation of Illumina sequence adapters, followed by pre-PCR amplification. Next-generation sequencing was performed using the prepared DNA library and capture probes, which were hybridized in a buffer to capture the retinal panel of interest, with a Celemics Target Enrichment Kit (Celemics, Korea). After the capture and washing processes, the captured library was amplified using post-PCR. Finally, the PCR products were sequenced using Illumina Inc.’s NextSeq platform. The average coverage depth of the panel was greater than 200x.

Single-nucleotide variations and small insertion-deletion variants were identified using the Genome Analysis Toolkit (GATK) 3.0 best practice, and annotation was performed using ANNOVAR. Variants with a variant allele fraction of less than 0.35 for heterozygous and 0.85 for homozygous were filtered out. Copy number variation analysis was also performed for all target genes using the Celemics pipeline.

We used several public databases, including the Genome Aggregation Database (gnomAD), the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project, and the Korean Reference Genome Database, to identify common variants. Variants in genes causing disease in an autosomal dominant manner were filtered using an allele frequency filter threshold of <0.01%. For autosomal-recessive variants, the filter threshold was set at <0.05% in East Asian population. Additionally, variants that were previously reported to be disease-causing were included as disease-causing variants, even if they had higher allele frequencies. Using the ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) and HGMD (https://www.hgmd.cf.ac.uk/ac/index.php) databases, we checked whether the variants were previously reported as disease-causing variants of CD. Only variants of genes previously reported to cause CD or CRD were analyzed. Variants were excluded if there was an insufficient clinical correlation with the identified genes. To classify the clinical importance of each variant, we followed the latest recommendations of the American College of Medical Genetics and Genomics (ACMG) standards for the interpretation and reporting of sequence variations: Variants were classified as pathogenic, likely pathogenic, variants of uncertain significance, benign, or likely benign. Cases with two causative variants containing more than one pathogenic or likely pathogenic variant in genes with recessive inheritance patterns were included. Cases with pathogenic or likely pathogenic variants were included in genes with a dominant inheritance pattern. To assess whether a pair of variants in a gene occurs in cis (same copy of the gene) or trans (different copies of the gene), we used the variant co-occurrence (phasing) information on the gnomAD browser (https://gnomad.broadinstitute.org/variant-cooccurrence).

All analyses were performed using SPSS Statistics (version 25.0; SPSS, Inc., Chicago, IL, USA) and GraphPad Prism software (version 6.0; GraphPad Software Inc., San Diego, CA, USA). Statistical significance was set at a p value <0.05. Prior to statistical analysis, the normality of data distribution was assessed using the Kolmogorov-Smirnov or Shapiro-Wilk test. Continuous data are presented as mean ± standard deviation, while categorical data are presented as frequencies (percentages). For non-parametric data, the Kruskal-Wallis and Mann-Whitney tests were used. The correlation between causative genes and demographic and ophthalmic parameters, including age, BCVA (logMAR), CRT, photopic ERG, flicker ERG, and the extent of the lesions, were calculated using the Spearman rank correlation coefficient.

In the genetic analysis of 22 unrelated individuals with AOCD/AOCRD, disease-causing variants were identified in six genes: RP1, CRX, CDHR1, PROM1, GUCY2D, and CRB1 (Table 1). All individuals in this study were of East Asian ethnicity. Pathogenic variants in RP1 and CRX were detected in eight and six individuals, respectively, accounting for 64% of the genes causing AOCD/AOCRD. Variants in CDHR1 were detected as the next ranking cause affecting three individuals. Pathogenic variants in PROM1, GUCY2D, and CRB1 were identified in the remaining patients. In one individual, known pathogenic variants of both CDHR1 and PROM1 and an extremely rare variant with uncertain significance in GUCY2D were detected. Biallelic variants were identified in RP1, CDHR1, and CRB1, which are associated with autosomal-recessive inheritance. Importantly, a hypomorphic variant, p.Arg1933Ter, was identified in 7 of 8 cases in which the RP1 gene was detected. In contrast, various variant types, such as non-synonymous, splicing, and stop-loss variants, have been found in the CRX gene rather than a specific variant type. A stop-loss variant p.Ter300Glnext118 and a splicing variant c.101-1G>A in CRX and the stop-gain variants p.Tyr634Ter and p.Tyr828Ter in PROM1 are newly detected in this study. The p.Ter300Glnext118 variant was predicted to extend 118 abnormal amino acids beyond the normal protein encoded by CRX. Alu insertion into RP1 and CRX was not detected in our pipeline, and thus, manual curation was performed using Integrative Genomics Viewer. The variants p.Cys1399LeufsTer5, p.Arg1933Ter, and p.Ile2061SerfsTer12 in the RP1 gene, p.Ter300GlnextTer118 in the CRX gene, and p.Glu201Lys and p.Val234Ile in the CDHR1 gene were repeatedly detected in individuals with AOCD/AOCRD. In individual H0340, pathogenic or reported variants were detected in all two genes, PROM1 and GUCY2D.

The demographic and clinical characteristics of the patients with AOCD/AOCRD are summarized in Table 2. The median age at the onset of symptoms and the first visit at SNUBH was 39 years (with an average of 38.5 ± 8.0, ranging from 30 to 50 years) and 52 years (with an average of 50.0 ± 10.9, ranging from 31 to 76 years), respectively. The discrepancy between the initial symptoms and the initial visit was 11.3 ± 10.0 years. Most individuals initially complained of decreased visual acuity (19/22, 86.4%). The second most frequent symptom was metamorphopsia (2/22, 9.1%), followed by visual field loss (1/22, 4.5%). The symptoms generally began after 40 years of age. The exact time of symptom onset could not be determined in four individuals because of the slowly progressive nature of AOCD/AOCRD. The average BCVA at the first visit was 0.48 ± 0.56 logMAR (20/60 in Snellen equivalents), and there was no difference in BCVA according to the genes detected (Fig. 1b). Fundus findings revealed a wide spectrum of CD, ranging from nearly normal to diffuse macular dystrophy. Six individuals (26.1%) showed nearly normal or mild perifoveal RPE changes, whereas 13 (56.5%) showed bull’s eye maculopathy or macular atrophy. Most individuals with AOCD/AOCRD had normal peripheral retina. On OCT, the average CRT was 199.84 ± 38.64 µm. There was no statistically significant difference in the CRT or lesion area according to the genes (Fig. 1c, f). Regardless of genotype, a highly correlation existed between the fundus examination and the OCT image in relation to macular atrophy.

The relative ratio of ERG amplitudes in the affected individuals compared to that in the normal subjects was 0.46 ± 0.18 (mean ± SD) and 0.49 ± 0.21 (mean ± SD) in the photopic 3.0 ERG and flicker ERG, respectively. Photopic and flicker ERGs were relatively similar in individuals with variants of RP1 or CDHR1 (Fig. 1d, e). In the visual field test, 12 of 13 individuals (92.3%) had a central scotoma, and one individual had a paracentral scotoma (7.7%). Figure 2 shows scatter plots illustrating the overall correlation between the initial BCVA (logMAR) and various ophthalmic parameters. The relationships between the initial BCVA and initial CRT (Rho = −0.283, p = 0.062) (Fig. 2a), the initial BCVA and initial extent of lesion (Rho = −0.242, p = 0.076) (Fig. 2b), the initial BCVA and photopic 3.0 ERG (Rho = −0.080, p = 0.643) (Fig. 2c), and the initial BCVA and initial flicker ERG (Rho = −0.051, p = 0.766) (Fig. 2d) all demonstrated negative correlations without any significance.

Eight individuals with pathogenic biallelic variants in RP1 were examined. Biallelic stop-gain variants (p.Arg1933Ter, p.Cys1399LeufsTer5, and p.Ile2061SerfsTer12) were identified in all AOCD/AOCRD cases related to the RP1 gene except in case H0563, which showed missense and frameshift variants. The mean age at the onset of symptoms and the first visit at SNUBH was 42.9 ± 9.5 (with a median of 50 years, ranging from 30 to 50 years) and 51.3 ± 7.5 (with a median of 54 years, ranging from 37 to 58 years), respectively, with a discrepancy of 13.8 ± 17.5 years between them. The primary reason for their visit was decreased visual acuity. Individuals with mutations in RP1 had a relatively later age of onset than in those with mutations in other genes (Fig. 1a). At the initial visit, the mean BCVA was 0.53 ± 0.50 logMAR, and a typical fundus finding, bull’s eye maculopathy, with corresponding disruption of the photoreceptor layers on OCT, were observed. However, the cone response on the ERG was relatively preserved even with severe photoreceptor loss in all macular areas (Fig. 1d, e, 3).

Considerable phenotypic heterogeneity was observed among individuals with CRX variants. Male patients were predominantly affected in this study (male:female ratio = 5:1). The average age when symptoms began and the initial visit at SNUBH was 35.0 ± 4.6 (with a median of 35 years, ranging from 30 to 40 years) and 47.0 ± 16.1 (with a median of 44 years, ranging from 31 to 76 years), respectively, showing a discrepancy of 12.0 ± 14.8 years between them. The mean BCVA was 0.60 ± 0.81 logMAR. Various fundus findings were observed, ranging from mild depigmentation of the macula to bull’s eye maculopathy. The OCT showed photoreceptor loss, consistent with the fundus examination (Fig. 4). The cone response was generally reduced, but it was relatively preserved compared to the normative reference line. All patients with CRX-related AOCD/AOCRD showed decreased amplitudes in both photopic and scotopic ERGs. Four of these individuals showed a severe reduction in both photopic and scotopic ERGs, whereas the remaining 2 had subnormal amplitudes in both photopic and scotopic ERGs (Fig. 4). The CRX variants consisted of two novel variants (c.101-1G>A, c.838T>C) and two previously reported variants (c.193G>C, c.128G>A). Mutations in the CDHR1 gene were detected in three individuals; all of them carried the previously reported missense variant c.601G>A (p.Glu201Lys). The median age at the initial visit was 52 years (56.7 ± 13.6, range 46–72 years). The mean BCVA was 0.37 ± 0.54 logMAR with complaints of decreased visual acuity or metamorphopsia. Fundus examination revealed bull eye maculopathy with or without foveal involvement (Fig. 5a, b). Even with marked photoreceptor loss on the OCT images, the cone response was reduced but relatively preserved. Three pathogenic variants of the PROM1 gene were identified in two males and one female. The median age at the initial visit was 45 years (46.0 ± 6.6, range 40–53 years). The mean BCVA was 0.39 ± 0.28 (mean ± SD) logMAR with complaints of decreased visual acuity. Fundus photographs of the two individuals showed round parafoveal atrophy with OCT categories 2–3. One affected individual had macular dystrophy with OCT category 4F (Fig. 5c). All 3 patients showed a bit cone response reduction sparing rod response. One male patient had a known pathogenic variant, c.2513G>A (p.Arg838His), in GUCY2D. The patient’s age at the initial visit was 40 years. The BCVA was 0.30 logMAR with complaints of decreased visual acuity, which began in their 40s. Mild RPE changes were observed with OCT category 1. The scotopic ERG was normal, but the photopic ERG was subnormal (Fig. 5d). A 56-year-old female (H1638) with CRB1 variants initially visited our hospital complaining of decreased visual acuity that began in her 40s. The BCVA was 0.10 logMAR, and severe macular atrophy with OCT category 4F was observed.

We conducted a thorough examination of 22 patients with AOCD/AOCRD and analyzed their clinical and genetic characteristics. The affected individuals typically had symptoms that appeared after 40 years of age (median age, 52 years; range, 31–76 years) and complained of visual decline. The BCVA at the initial visit was on average 0.48 ± 0.56 logMAR and was measured variably from 0 (Snellen equivalent, 20/20) to 1.4 logMAR (Snellen equivalent, 20/500). A diverse range of clinical manifestations can also be observed on the fundus and OCT. Either a nearly normal fundus or bull’s eye maculopathy of variable severity was observed on the fundus examination. Fundus examination and OCT images showed relatively symmetrical photoreceptors and RPE atrophy in both eyes. In the analysis of OCT categories, 75.0% were in category 3 or 4, and 61.4% had foveal involvement. OCT severity did not show a direct correlation with BCVA or cone amplitude on the ERG. For instance, while fundus photography and OCT revealed severe macular dystrophy, three individuals (H1028, H1508, H0563) exhibited a comparatively bit decrease in cone response.

Mutations in RP1, CRX, CDHR1, PROM1, CRB1, and GUCY2D were the underlying causes of AOCD/AOCRD, of which RP1, CRX, and CDHR1 accounted for 77% of the cases. Intriguingly, p.Cys1399LeufsTer5, p.Arg1933Ter, and p.Ile2061SerfsTer12 in RP1; p.Ter300GlnextTer118 in the CRX; and p.Glu201Lys and p.Val234Ile in CDHR1 were repeatedly detected in individuals with AOCD/AOCRD, suggesting that these variants may be mutational hotspots in AOCD/AOCRD in this cohort.

Similar to CD, AOCD/AOCRD exhibits a wide range of genetic and phenotypic heterogeneities. However, the biggest differences between CD and AOCD/AOCRD were the age of onset and rate of progression. On average, patients with CD showed onset within 20 years of age, followed by a visual decline, ultimately leading to legal blindness before reaching the middle age [21]. Several causative genes and loci have been identified in CD, including ABCA4, CNGA3, CNGB3, PDE6C, and RP1 for autosomal-recessive CD; GUCY2D, PRPH2, GUCA1A, CRX, and PROM1 for autosomal dominant CD; and RPGR, CACNA1F, and OPN1LW/OPN1MW for X-linked CD [1, 7, 22]. Compared to the rapid progressive visual decline seen in CD individuals with mutations in the ABCA4 gene, those with mutations in RP1 tend to have a later onset of symptoms [12, 22]. Even in cases of retinitis pigmentosa associated with RP1 mutations, symptoms commonly manifest after adolescence or adulthood [23]. In the eight individuals with RP1 mutations, three compound heterozygous variants (p.Cys1399LeufsTer5/p.Pro86Thr, p.Cys1399LeufsTer5/p.Arg1933Ter, and p.Arg1933Ter/p.Ile2061SerfsTer12) and one homozygous variant (p.Arg1933Ter) were identified. In other words, p.Arg1933Ter was detected in 87.5% (7/8) of the individuals with RP1-related AOCD/AOCRD. This hypomorphic variant is thus presumed to be the major variant associated with AOCD/AOCRD in South Korea. Previous studies have reported that homozygotes of p.Arg1933Ter exhibit a normal phenotype, even at 80 years of age [10]. However, p.Arg1933Ter can also be functional in combination with other pathogenic variants [12]. Three individuals with homozygous p.Arg1933Ter mutations had AOCD/AOCRD. This clinical heterogeneity might originate from the existence of other genetic modifier variants apart from those in RP1 or the existence of a variant within the noncoding regions of RP1, although there was no Alu insertion in its exon region. Two variants (p.Glu201Lys and p.Val234Ile) were identified in all individuals with CDHR1-associated AOCD/AOCRD. But, the variant co-occurrence (phasing) estimated that p.Glu201Lys and p.Val234Ile in CDHR1 occur in cis (same copy of the gene). In patient H1541, p.Val234Ile has been detected as a heterozygous variant, but given the consistent presence of the homozygous variant p.Glu201Lys, p.Glu201Lys is postulated as the causative mutation. The p.Glu201Lys variant distrupts the Ca²⁺-binding domain of CDHR1, leading to alteration in the junction between the inner and outer segments of rod and cone photoreceptor cells [24]. A previous study reported that one individual with the p.Glu201Lys variant had CRD that developed after 40 years of age. Thus, p.Glu201Lys appears to be a variant closely correlated with AOCD/AOCRD. CRX mutations are known to be associated with a wide range of phenotypic heterogeneity including CRD, Leber congenital amaurosis, retinitis pigmentosa, and CD [25‒27]. In the present study, individuals with CRX variants showed variable genotypic and phenotypic features. In the six individuals with CRX mutations, four variants (c.101-1G>A, pTer300GlnextTer118, p.Asp65His, and p.Arg43His) were identified. Fundus examination showed mild depigmentation at the macula to a bull’s eye, with an age range of 31–76 years. Heterozygous missense variants located within exon 3 are frequently associated with CRD [15]. Consistent with previous literature, this study found that 50.0% (3/6) of the individuals with AOCRD had heterozygous missense variants located within exon 3 (c.193G>C and c.128G>A). In addition to missense variants, a stop-loss variant, p.Ter300GlnextTer118, and a splicing variant, c.101-1G>A, were identified. The p.Ter300GlnextTer118 variant leads to elongation of 118 abnormal amino acids behind the normal stop codon of CRX protein, which results in an abnormal or non-functional protein. As PROM1 is expressed in rod and cone cells, mutations in PROM1 can cause retinal dystrophy specific to the affected cells. Recessive variants of PROM1 are associated with early-onset severe panretinal degeneration, whereas dominant variants are associated with a milder cone-driven phenotype [28, 29]. All three AOCD cases with PROM1 mutations were of the dominant missense type, presenting a milder, cone-driven phenotype.

Elderly patients also exhibit an increased incidence of other age-related disorders. Patients with AMD have several symptoms similar to those of patients with AOCD/AOCRD. Therefore, the diagnosis of AOCD/AOCRD may be challenging in cases where alterations in the macula are either absent or subtle, coupled with vague symptoms and signs. SD-OCT can be a valuable diagnostic tool for excluding exudative AMD, but it is insufficient to exclude atrophic AMD. Full-field ERG is an imperative diagnostic procedure that can establish the proper diagnosis. In the case of CD, the cone response was more reduced and delayed than the rod response. Finally, a genetic test serves as definitive confirmation of an inherited retinal disease. An interesting finding of this study was that there was no linear relationship between extent of lesions and cone response. The cone response decreased slightly to subnormal despite the deep and diffuse loss of photoreceptors in some cases (H0563, H1508), whereas in others, even a subtle change in the RPE resulted in a markedly decreased cone response (H1244, H0361).

This retrospective cross-sectional study of AOCD/AOCRD has some limitations, including potential selection bias, a small sample size, and a relatively short-term follow-up. Therefore, these are insufficient to establish the clinical characteristics of progressive disease. Long-term follow-up is necessary to establish whether the clinical course presents a different phenotype or different stages of the disease. We also analyzed the relationship between BCVA and other ophthalmic test results, including full-field ERG, CRT, and the extent of lesion. However, no remarkable factors were detected for visual predictors or associations. Further studies involving larger patient populations and multimodalities including fundus autofluorescence, multifocal ERG, color vision test, and so on are required to strengthen the evidence obtained from our clinical and genetic findings. All individuals presented with adult-onset disease, which limited the investigation of segregation, family history, and pedigree. Several affected individuals reported that their parents had low visual acuity due to AMD or unknown causes.

Overall, this study indicates that AOCD/AOCRD is a distinct subtype of CD with specific clinical characteristics and genetics. RP1, CRX, and CDHR1 were identified as the major genetic causes of AOCD/AOCRD in South Korea, and specific variants of these genes were identified as the major causative variants. Clinically, AOCD/AOCRD presents after the middle age with either a nearly normal fundus or bull’s eye maculopathy. All cases of AOCD/AOCRD showed a decrease in the cone response, which was independent of the severity of photoreceptor loss. Thus, improved knowledge of the relationship between the genotype and phenotype in AOCD/AOCRD can assist in providing clinical and genetic guidance to patients with cone and CRD.

This research followed the principles stated in the Declaration of Helsinki and received approval from the Institutional Review Board of the Ethics Committee of Seoul National University Bundang Hospital (IRB no. B-2303-816-103). Written informed consent was obtained from all individuals for publication of the details of their medical case and any accompanying images.

The authors have no proprietary interests in the materials presented herein. All the authors attest that they meet the current ICMJE criteria for authorship.

This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (Ministry of Science and ICT) (No. 2022R1A2C4002114). This study was also supported by the New Faculty Startup Fund from Seoul National University and by the Seoul National University Bundang Hospital (SNUBH) Research Fund (Grant No. 14-2018-0019). The funding organization had no role in the design or conduct of the study.

Dong Ju Kim: writing – original draft preparation, data collection, and analysis. Se Joon Woo: review and editing. Kwangsic Joo: conceptualization, review and editing, and funding acquisition.

The datasets generated and/or analyzed in the current study are available from the corresponding author upon reasonable request. Data are not publicly available due to ethical reasons. Further enquiries can be directed to the corresponding author.