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Purpose: Heterozygous variants of IMPDH1 are associated with autosomal dominant retinitis pigmentosa (adRP). The current study aims to investigate the characteristics of the adRP-associated variants., Methods: IMPDH1 variants from our exome sequencing dataset were retrieved and systemically evaluated through multiple online prediction tools, comparative genomics (in-house dataset, HGMD, and gnomAD), and phenotypic association. Potential pathogenic variants (PPVs) were further confirmed by Sanger sequencing and segregation analysis., Results: In total, seven heterozygous PPVs (six missenses and one inframe) were identified in 10 families with RP, in which six of the seven might be classified as pathogenic or likely pathogenic while one others as variants of uncertain significance. IMPDH1 variants contributed to 0.7% (10/1519) of RP families in our cohort, ranking the top four genes implicated in adRP. These adRP-associated variants were located in exons 8-10, a region within or downstream of the CBS domain. All these variants were predicted to be damaged by at least three of the six online prediction tools. Two truncation variants were considered non-pathogenic. Hitherto, 41 heterozygous variants of IMPDH1 were detected in 110 families in published literature, including 33 missenses, two inframes, and six truncations (including a synonymous variant affecting splicing). Of the 35 missense and inframe variants, most were clustered in exons 8-10 (77.1%, 27/35), including 18 (51.4%, 18/35) in exon 10 accounting for 70.9% (78/110) of the families. However, truncation variants were enriched in the general population with a pLI value of 0 (tolerated), and the reported variants in patients with RP did not cluster in specific region., Conclusions: Our data together with comprehensive analysis of existing datasets suggest that causative variants of IMPDH1 are usually missense and mostly clustered in exons 8-10. Conversely, most missense variants outside this region and truncation variants should be interpreted with great care in clinical gene test.

Introduction: Retinal degenerative or inflammatory changes may occur with hereditary immunological disorders (HID) due to variants in approximately 20 genes. This study aimed to investigate if such retinopathy may present as an initial sign of immunological disorders in eye clinic., Methods: The variants in the 20 genes were selected from in-house exome sequencing data from 10,530 individuals with different eye conditions. Potential pathogenic variants were assessed by multistep bioinformatic analysis. Pathogenic variants were defined according to the ACMG/AMP criteria and confirmed by Sanger sequencing, co-segregation analysis, and consistency with related phenotypes. Ocular clinical data were thoroughly reviewed, especially fundus changes., Results: A total of seven pathogenic variants in four of the 20 genes were detected in six probands from six families, including three with hemizygous nonsense variants p.(Q308*), p.(Q416*), and p.(R550*) in MSN , one with homozygous nonsense variants p.(R257*) in AIRE , one with compound heterozygous nonsense variants p.(R176*) and p.(T902*) in LAMB2 , and one with a known c.1222T>C (p.W408R) heterozygous variant in CBL . Ocular presentation, as the initial signs of the diseases, was mainly retinopathy mimicking other forms of hereditary retinal degeneration, including exudative vitreoretinopathy in the three patients with MSN variants or tapetoretinal degeneration in the other three patients. Neither extraocular symptoms nor extraocular manifestations were recorded at the time of visit to our eye clinic. However, of the 19 families in the literature with retinopathy caused by variants in these four genes, only one family with an AIRE homozygous variant had retinopathy as an initial symptom, while the other 18 families had systemic abnormalities that preceded retinopathy., Discussion: This study, for the first time, identified six unrelated patients with retinopathy as their initial and only presenting sign of HID, contrary to the previous reports where retinopathy was the accompanying sign of systemic HID. Recognizing such phenotype of HID may facilitate the clinical care of these patients. Follow-up visits to such patients and additional studies are expected to validate and confirm our findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Jiang, Wang, Li, Jia, Xiao, Sun, Wang and Zhang.)

Variants in PRPH2 are a common cause of inherited retinal dystrophies with high genetic and phenotypic heterogeneity. In this study, variants in PRPH2 were selected from in-house exome sequencing data, and all reported PRPH2 variants were evaluated with the assistance of online prediction tools and the comparative validation of large datasets. All variants were classified based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. Individuals with pathogenic or likely pathogenic variants of PRPH2 were confirmed by Sanger sequencing. Clinical characteristics were summarized. Ten pathogenic or likely pathogenic variants of PRPH2 were identified in 14 families. In our cohort, the most frequent variant was p.G305Afs*19, accounting for 33.3% (5/15) of alleles, in contrast to the literature, where p.R172G (11.6%, 119/1028) was the most common variant. Nine in-house families (63.8%) were diagnosed with retinitis pigmentosa (RP), distinct from the phenotypic spectrum in the literature, which shows that RP accounts for 27.9% (283/1013) and macular degeneration is more common (45.2%, 458/1013). Patients carrying missense variants predicted as damaging by all seven prediction tools and absent in the gnomAD database were more likely to develop RP compared to those carrying missense variants predicted as damaging with fewer tools or with more than one allele number in the gnomAD database ( p = 0.001). The population-specific genetic and phenotypic spectra of PRPH2 were explored, and novel insight into the genotype-phenotype correlation of PRPH2 was proposed. These findings demonstrated the importance of assessing PRPH2 variants in distinct populations and the value of providing practical suggestions for the genetic interpretation of PRPH2 variants.

Purpose: To evaluate the nature and association of different phenotypes associated with ABCA4 mutations in Chinese., Methods: All patients were recruited from our pediatric and genetic eye clinic. Detailed ocular phenotypes were characterized. The disease course was evaluated by long-term follow-up observation, with a focus on fundus changes. Cox regression was used to identify the factors associated with disease progression., Results: A systematic review of genetic and clinical data for 228 patients and follow-up data for 42 patients indicated specific features in patients with two ABCA4 variants. Of 185 patients with available fundus images, 107 (57.8%) showed focal lesions restricted to the central macula without flecks. Among these 107 patients, 30 patients (28.0%) initially presented with relatively preserved visual acuity and inconspicuous performance on routine fundus screening. A pigmentary change in the posterior pole was observed in 22 of 185 patients (11.9%), and this change mimicked retinitis pigmentosa in 10 cases (45.5%). Follow-up visits and sibling comparisons demonstrated disease progression from cone-rod dystrophy, Stargardt disease, to retinitis pigmentosa. An earlier age of onset was associated with a more rapid decrease in visual acuity (P = 0.03). Patients with two truncation variants had an earlier age of onset., Conclusion: Phenotypic variation in ABCA4-associated retinopathy may represent sequential changes in a single disease: early-stage Stargardt disease may resemble cone-rod dystrophy, whereas the presence of diffuse pigmentation in the late stage may mimic retinitis pigmentosa. Recognizing the natural progression of fundus changes, especially those visualized by wide-field fundus autofluorescence, is valuable for diagnostics and therapeutic decision-making.

Purpose: Heterozygous truncating variants of TOPORS have been reported to cause autosomal dominant retinitis pigmentosa (adRP). The purpose of this study was to investigate whether all heterozygous truncating variants, including copy number variants (CNVs), are pathogenic., Methods: TOPORS truncating variants were collected and reviewed through an in-house dataset and existing databases. Individuals with truncating variants underwent ophthalmological evaluation., Results: Six truncating variants were detected in seven families. Three N-terminus truncating variants were detected in three families without RP, and the other three were identified in four unrelated families with typical RP. Based on the in-house dataset and published literature, 17 truncating variants were identified in 47 families with RP. All RP-associated truncating alleles, except one, were distributed in the last exon of TOPORS and clustered in amino acid residues 807 to 867 (46/47, 97.9%). Conversely, in the gnomAD database, only one truncating allele (1/27, 3.7%) was in this region, and the others were outside (26/27, 96.3%), suggesting that the pathogenic truncating variants were significantly clustered in residues 807 to 867 (χ2 = 65.6, P = 1.1 × 10-17). Additionally, three CNVs involving the N-terminus of TOPORS were recorded in control populations but were absent in affected patients., Conclusions: This study suggests that all pathogenic truncating variants of TOPORS were clustered in residues 807 to 867, whereas the truncating variants outside this region and the CNVs involving the N-terminus were not associated with RP. A dominant-negative effect, rather than haploinsufficiency, is speculated to be the underlying pathogenesis. These findings provide valuable information for interpreting variation in TOPORS and other genes in similar situations, especially for CNVs.

Purpose: Variants in RCBTB1 have been reported in autosomal recessive inherited retinal dystrophies and autosomal dominant familial exudative vitreoretinopathy (FEVR). This study aims to verify the correlation between RCBTB1 variations and phenotypes., Methods: Variants in RCBTB1 were selected from 6303 unrelated families with different forms of eye conditions based on whole exome sequencing and targeted exome sequencing. Potential pathogenic truncation variants were filtered by multistep bioinformatics analysis and identified by Sanger sequencing. Segregation and enrichment analysis were used to evaluate the association of truncation variants in RCBTB1 with phenotypes., Results: Biallelic damaging variants in RCBTB1 were found in one family while heterozygous truncation variants were detected in 28 unrelated families based on our in-house data from 6303 unrelated families. Totally, 11 variants were present in the 29 families, including seven frameshift variants, three splicing variants, and one nonsense variant. The biallelic variants, c.170delG and c.905_906insTT, were identified in an isolated case with retinitis pigmentosa (RP). Heterozygous truncation variants were distributed in different forms of eye conditions (including normal) without significant enrichment in FEVR, suggesting unrelatedness to specific eye diseases. The frequency and location of truncation variants in the 6303 samples are comparable with the East Asian data from gnomAD. Segregation analysis of available family members further demonstrated the nonpathogenic nature of heterozygous truncation variants., Conclusions: Contrary to the previous report, heterozygous truncation variants in RCBTB1 are not associated with FEVR based on our data. The extreme rareness of biallelic truncation variants present in a singleton case with RP further suggests that variants in RCBTB1 are responsible for autosomal recessive RP. This result reminds us that variants of a gene with certain diseases should be thoroughly verified before the use of such information in clinical practice.

Purpose: The PROM1 p.Arg373Cys variant has been reported to cause dominant Stargardt disease, cone-rod dystrophy, and occasionally retinitis pigmentosa. This study aimed to evaluate the common phenotype associated with this variant in Chinese patients., Methods: Variants in PROM1 were collected from in-house exome data. Potential pathogenic variants were selected, verified, and then confirmed by Sanger sequencing and co-segregation analysis. Ocular phenotypes were reviewed and further clarified by ophthalmologic examinations., Results: The heterozygous c.1117C>T (p.Arg373Cys) variant was identified in four unrelated families, and biallelic variants were detected in three families. Of the 10 patients from four families with the p.Arg373Cys variant, six patients from three families who underwent full fundus examination demonstrated various degrees of macular dystrophy, as well as typical bone-spicule pigment deposits in the peripheral retina. The remaining four patients did not undergo a full dilated fundus examination. A relatively preserved zone was observed between the macular and peripheral lesions. Electroretinography results showed cone and rod involvement in three patients., Conclusions: Unlike Stargardt disease alone, which was considered to be the main phenotype of the p.Arg373Cys variant, all patients with full-field fundus examination in our study presented with macular dystrophy plus peripheral retinopathy resembling retinitis pigmentosa. Different phenotypes associated with the p.Arg373Cys variant may actually reflect different stages of the same disease: a predominant central cone phenotype at an early stage and peripheral rod involvement as degeneration progresses. Evaluation of the full fundus, especially the peripheral region in additional patients, is expected to confirm our findings.

Purpose: Mutations in 60 known genes were previously identified by exome sequencing in 79 of 157 families with retinitis pigmentosa (RP). This study analyzed variants in 129 genes associated with other forms of hereditary retinal dystrophy in the same cohort., Methods: Apart from the 73 genes previously analyzed, a further 129 genes responsible for other forms of hereditary retinal dystrophy were selected based on RetNet. Variants in the 129 genes determined by whole exome sequencing were selected and filtered by bioinformatics analysis. Candidate variants were confirmed by Sanger sequencing and validated by analysis of available family members and controls., Results: A total of 90 candidate variants were present in the 129 genes. Sanger sequencing confirmed 83 of the 90 variants. Analysis of family members and controls excluded 76 of these 83 variants. The remaining seven variants were considered to be potential pathogenic mutations; these were c.899A>G, c.1814C>G, and c.2107C>T in BBS2; c.1073C>T and c.1669C>T in INPP5E; and c.3582C>G and c.5704-5C>G in CACNA1F. Six of these seven mutations were novel. The mutations were detected in five unrelated patients without a family history, including three patients with homozygous or compound heterozygous mutations in BBS2 and INPP5E, and two patients with hemizygous mutations in CACNA1F. None of the patients had mutations in the genes associated with autosome dominant retinal dystrophy., Conclusions: Only a small portion of patients with RP, about 3% (5/157), had causative mutations in the 129 genes associated with other forms of hereditary retinal dystrophy.

Retinitis pigmentosa (RP) is the most common and highly heterogeneous form of hereditary retinal degeneration. This study was to identify mutations in the 60 genes that were known to be associated with RP in 157 unrelated Chinese families with RP. Genomic DNA from probands was initially analyzed by whole exome sequencing. Sanger sequencing was used to confirm potential candidate variants affecting the encoded residues in the 60 genes, including heterozygous variants from genes that are related to autosomal dominant RP, homozygous or compound heterozygous variants from genes that are related to autosomal recessive RP, and hemizygous variants from genes that are related to X-linked RP. Synonymous and intronic variants were also examined to confirm whether they could affect splicing. A total of 244 candidate variants were detected by exome sequencing. Sanger sequencing confirmed 240 variants out of the 244 candidates. Informatics and segregation analyses suggested 110 potential pathogenic mutations in 28 out of the 60 genes involving 79 of the 157 (50%) families, including 31 (39%, 31/79) families with heterozygous mutations in autosomal dominant genes, 37 (47%, 37/79) families with homozygous (9) or compound heterozygous (28) mutations in autosomal recessive genes, and 11 (14%, 11/79) families with hemizygous mutations in X-linked genes. Of the 110 identified variants, 74 (67%) were novel. The genetic defects in approximately half of the 157 studies families were detected by exome sequencing. A comprehensive analysis of the 60 known genes not only expanded the mutation spectrum and frequency of the 60 genes in Chinese patients with RP, but also provided an overview of the molecular etiology of RP in Chinese patients. The analysis of the known genes also supplied the foundation and clues for discovering novel causative RP genes.

Importance: Mutations in CNGA3 are the most common cause of achromatopsia and cone-rod dystrophies., Objective: To identify CNGA3 mutations in patients with cone dystrophies or Leber congenital amaurosis., Design, Setting, and Participants: Clinical data and genomic DNA in 267 Chinese probands from 138 families with cone dystrophies and 129 families with Leber congenital amaurosis collected at the Zhongshan Ophthalmic Center, Guangzhou, China., Main Outcomes and Measures: Variants in CNGA3 and associated phenotypes, assessed by Sanger sequencing of CNGA3, bioinformatics of variants, and segregation analysis., Results: Homozygous or compound heterozygous mutations in CNGA3, including 26 novel and 13 known mutations, were identified in 46 probands from 138 families with cone dystrophies, but none were found in any of the probands from 129 families with Leber congenital amaurosis. The 46 probands with CNGA3 mutations could be further classified as likely having achromatopsia (18 probands) and cone-rod dystrophies (28 probands) based on electroretinographic recordings. Analysis of family members in 17 of 46 families demonstrated good segregation of the disease with the CNGA3 mutations., Conclusions and Relevance: To our knowledge, this study is the first systemic analysis of CNGA3 in Chinese patients and expands the mutational spectrum and associated phenotypes. Our results suggest that CNGA3 mutations are a common cause of cone-rod dystrophies and achromatopsia in the Chinese population. These data indicate that CNGA3-associated cone dystrophies may be a common form of early-onset severe retinal dystrophies. Therapeutic potential such as gene therapy targeting this gene may benefit some children with early-onset severe retinal dystrophies.

Objective: The goal of this study was to identify mutations in 25 known causative genes in 47 unrelated Chinese families with cone-rod dystrophy (CORD)., Methods: Forty-seven probands from unrelated families with CORD were recruited. Genomic DNA prepared from leukocytes was analyzed by whole exome sequencing. Variants in the 25 genes were selected and then validated by Sanger sequencing., Results: Fourteen potential pathogenic mutations, including nine novel and five known, were identified in 10 of the 47 families (21.28%). Homozygous, compound heterozygous, and hemizygous mutations were detected in three, four, or three families, respectively. The 14 mutations in the 10 families were distributed among CNGB3 (three families), PDE6C (two families), ABCA4 (one family), RPGRIP1 (one family), RPGR (two families), and CACNA1F (one family)., Conclusions: This study provides a brief view on mutation spectrum of the 25 genes in a Chinese cohort with CORD. Identification of novel mutations enriched our understanding of variations in these genes and their associated phenotypes. To our knowledge, this is the first systemic exome-sequencing analysis of all of the 25 CORD-associated genes.

Cone-rod dystrophy (CORD) is a hereditary retinal disorder with primary cone impairment and subsequent rod involvement. To date, mutations responsible for CORD have been reported in 24 genes. However, the systemic evaluation of variants in these genes in a cohort of patients is rare, particularly in East Asia. In this study, 58 coding exons from 20 CORD genes, including 35 exons with previously identified mutations in 17 genes and all 23 coding exons for the other 3 genes (GUCY2D, PRPH2 and KCNV2), were analyzed by cycle sequencing on 130 unrelated probands with CORD. Four heterozygous mutations, 1 novel and 3 known, were detected in 4/130 patients, including c.259G>A (p.Asp87Asn) in UNC119, c.2512C>T (p.Arg838Cys) and c.2513G>A (p.Arg838His) in GUCY2D and c.946T>G (p.Trp316Gly) in PRPH2. The result implies a comparatively low rate of mutations in these exons in Chinese patients. These data suggest that in Chinese patients, CORD may be caused by mutations in exons that have not yet been screened or in genes that have yet to be identified. Further analysis of these patients may provide clarification.

Ten mutations in the guanylate cyclase activator 1A (GUCA1A) have been previously identified and reported in patients with retinal degeneration, including patients from 12 families with cone-rod dystrophy (CORD) and in an isolated patient with retinitis pigmentosa (RP). In this study, the coding exons and adjacent regions of GUCA1A were evaluated in 130 probands with CORD from 130 unrelated Chinese families using Sanger sequencing. A novel heterozygous c.464A>C (p.Glu155Ala) mutation was detected in a proband from a large family. The mutation presented in all nine patients examined in that family, but it was absent in six unaffected family members and 192 normal controls. All the nine patients in that family expressed typical CORD in eight cases and atypical CORD in one case. The results of this study suggested that the GUCA1A mutation only contributes to a small portion of CORD in people of Chinese descent., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Mutations in the cone-rod homeobox gene (CRX) are associated with cone-rod dystrophy (CORD), Leber congenital amaurosis (LCA), and, in rare cases, retinitis pigmentosa (RP). In this study, three variations were detected in 3 of 130 families with CORD, including two novel mutations, c.239A>G (p.Glu80Gly) and c.362C>T (p.Ala121Val). So far, 49 mutations in CRX were reported, affecting about 2.35% of LCA, 4.76% of CORD, and 0.80% of RP. These mutations can be classified as missense (38.78%), nonsense (4.08%), deletion (36.73%), insertion (16.33%), and indel (4.08%). They distributed in the three coding exons without mutation hot spots. No clear genotype-phenotype correlation could be established so far., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To identify the genetic locus and mutation responsible for autosomal dominant cone dystrophy (adCOD) in a large Chinese family and to describe the phenotypes of the patients., Methods: Genomic DNA and clinical data were collected from the family. Genome-wide linkage analysis was performed to map the disease locus, and Sanger dideoxy sequencing was used to detect the mutation in a candidate gene., Results: Initially, genome-wide linkage analysis mapped the disease to 17p13.1 between D17S831 and D17S799, with a maximum lod score of 2.71 for D17S938 and D17S1852 at theta=0. Sequence analysis of the guanylate cyclase 2D gene (GUCY2D) in the linkage interval detected a recurrent heterozygous mutation, c.2513G>A (p.Arg838His). This mutation was present in all eight patients with adCOD, but neither in any of the six unaffected family members nor in 192 control chromosomes., Conclusions: adCOD in this family is caused by a recurrent mutation in GUCY2D. adCOD can be detected in the first few years after birth in the family by fundus observation and electroretinogram recordings.

(1) Background: NR2E3 encodes a nuclear receptor transcription factor that is considered to promote cell differentiation, affect retinal development, and regulate phototransduction in rods and cones. This study aimed to analyze the clinical characteristics and observe the prognosis of autosomal dominant retinopathy (ADRP) and autosomal recessive retinopathy (ARRP) associated with NR2E3; (2) Methods: NR2E3 variants were collected from our exome sequencing data and identified per the American College of Medical Genetics and Genomics criteria. Data from our cohort and a systemic literature review were conducted to explore the NR2E3 variants spectrum and potential genotype-phenotype correlations; (3) Results: Nine pathogenic variants/likely pathogenic variants in NR2E3, including five novel variants, were detected in eight families (four each with ADRP and ARRP). Follow-up data showed schisis/atrophy in the macula and retinal degeneration initiation around the vascular arcades with differences in ADRP and ARRP. A systemic literature review indicated patients with ADRP presented better visual acuity (p < 0.01) and later onset age (p < 0.0001) than did those with ARRP; (4) Conclusions: Macular schisis and retinal degeneration around vascular arcades may present as the prognosis of NR2E3-retinopathy, dominant, or recessive. Our data might further enrich our understanding of NR2E3 variants and associated inherited retinopathy. [ABSTRACT FROM AUTHOR]