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Study of Inherited Retinal Diseases—Volume II
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Study of Inherited Retinal Diseases—Volume II

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (15 October 2024) | Viewed by 8912

Special Issue Editor

Prof. Dr. Se Joon Woo

E-Mail Website
Guest Editor
Department of Ophthalmology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si 13620, Gyeonggi-do, Republic of Korea
Interests: inherited retinal diseases; retinal artery occlusion; age-related macular degeneration; biosimilars; diabetic retinopathy; ocular drug delivery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Inherited retinal disease (IRD) is a major cause of bilateral visual decline and blindness worldwide. To date, there is no definitive treatment option for this condition. Recently, there have been advances in the field of genetic diagnosis, and new treatment methods have been introduced, including gene therapy and genome editing. Since the approval of gene therapy for RPE65-related IRD, the future of IRD treatment appears bright, and more patients with IRD may be saved from blindness as technology develops. To reach a better visual outcome for IRD patients, a greater understanding of IRD, including the genetics, mechanism, clinical features, and preclinical and clinical trial results related to the conditions, is needed by physicians, researchers, and patients alike, as well as pharmaceutical companies and governments.

In this Special Issue, we welcome reviews and original articles about the study of IRD. These include, but are not limited to, the genetic and molecular mechanisms of IRD, diagnosis, clinical features and imaging of IRD cases, epidemiology, ethnic variability, preclinical research, and clinical trials of new treatments. We look forward to your contributions.

Prof. Dr. Se Joon Woo
Guest Editor

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Keywords

  • inherited retinal diseases
  • retinitis pigmentosa
  • macular dystrophy
  • cone dystrophy
  • genotype
  • gene therapy
  • clinical trial
  • imaging
  • genetic mechanism
  • genome editing
  • phenotype

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Published Papers (6 papers)

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Research

15 pages, 5760 KiB  
Article
Retinal Dystrophy Associated with Homozygous Variants in NRL
by Jordi Maggi, James V. M. Hanson, Lisa Kurmann, Samuel Koller, Silke Feil, Christina Gerth-Kahlert and Wolfgang Berger
Genes 2024, 15(12), 1594; https://doi.org/10.3390/genes15121594 - 12 Dec 2024
Viewed by 1176
Abstract
Background/Objectives: Neural retina leucine zipper (NRL) is a transcription factor involved in the differentiation of rod photoreceptors. Pathogenic variants in the gene encoding NRL have been associated with autosomal dominant retinitis pigmentosa and autosomal recessive clumped pigmentary retinal degeneration. Only a dozen [...] Read more.
Background/Objectives: Neural retina leucine zipper (NRL) is a transcription factor involved in the differentiation of rod photoreceptors. Pathogenic variants in the gene encoding NRL have been associated with autosomal dominant retinitis pigmentosa and autosomal recessive clumped pigmentary retinal degeneration. Only a dozen unrelated families affected by recessive NRL-related retinal dystrophy have been described. The purpose of this study was to expand the genotypic spectrum of this disease by reporting clinical and genetic findings of two unrelated families. Methods: Index patients affected by retinal dystrophy were genetically tested by whole-exome sequencing (WES) and whole-genome sequencing (WGS). Segregation analysis within the families was performed for candidate variants. A minigene assay was performed to functionally characterize a variant suspected to affect splicing. Results: Variant filtering revealed homozygous NRL variants in both families. The variant in patient A was a small deletion encompassing the donor splice site of exon 1 of transcript NM_006177.3. The minigene assay revealed that this variant led to two aberrant transcripts that used alternative cryptic donor splice sites located in intron 1. In patient B, a stop-gain variant was identified in the last exon of NRL in a homozygous state due to maternal uniparental disomy of chromosome 14. Conclusions: Our study expands the genotypic spectrum of autosomal recessive NRL-related retinal dystrophy. Moreover, it underscores the importance of actively maintaining bioinformatic pipelines for variant detection and the utility of minigene assays in functionally characterizing candidate splicing variants. Full article
(This article belongs to the Special Issue Study of Inherited Retinal Diseases—Volume II)
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20 pages, 10024 KiB  
Article
Kir4.1 and Aqp4 Contribution to Schisis Cystic Water Accumulation and Clearance in the Rs1 Exon-1 Del XLRS Rat Model
by Zeljka Smit-McBride, Ning Sun, Serafina Thomas, In Hwan Cho, Robin G. Stricklin and Paul A. Sieving
Genes 2024, 15(12), 1583; https://doi.org/10.3390/genes15121583 - 9 Dec 2024
Cited by 1 | Viewed by 995
Abstract
Background/Objective: The Rs1 exon-1-del rat (Rs1KO) XLRS model shows normal retinal development until postnatal day 12 (P12) when small cystic spaces start to form in the inner nuclear layer. These spaces enlarge rapidly, peak at P15, and then collapse by P19. Methods: We [...] Read more.
Background/Objective: The Rs1 exon-1-del rat (Rs1KO) XLRS model shows normal retinal development until postnatal day 12 (P12) when small cystic spaces start to form in the inner nuclear layer. These spaces enlarge rapidly, peak at P15, and then collapse by P19. Methods: We explored the possible involvement of Kir4.1 and Aqp4, the principal retina channels for water movement and homeostasis, along with Muller glia cells (MGCs), using semi-quantitative fluorescent immunohistochemistry at P7, P9, P12, and P30, in Rs1KO and WT littermates. Results: Kir4.1 expression was reduced in Rs1KO retinas at all the early time points—P7, P9, and P12—as the schisis cavities began to form; downregulation would reduce water egress from the retina. Aqp4 was upregulated at P30 in Rs1KO retinas during schisis cavity closure but not as cavities formed at P12. When examined by GFAP expression, MGCs were not activated at the preschisis P12 age but showed considerable GFAP expression at P30 following retinal cystic structural damage at P15, indicating that MGCs were activated during the period of retina water removal and cavity closure. Conclusions: The study results implicate the downregulation of Kir4.1 in schisis formation and a role for both Kir4.1 and Aqp4 upregulation in subsequent schisis closure. Full article
(This article belongs to the Special Issue Study of Inherited Retinal Diseases—Volume II)
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10 pages, 3481 KiB  
Article
A Leaky Deep Intronic Splice Variant in CLRN1 Is Associated with Non-Syndromic Retinitis Pigmentosa
by Maria Abu Elasal, Samer Khateb, Daan M. Panneman, Susanne Roosing, Frans P. M. Cremers, Eyal Banin, Dror Sharon and Asodu Sandeep Sarma
Genes 2024, 15(11), 1363; https://doi.org/10.3390/genes15111363 - 24 Oct 2024
Viewed by 1271
Abstract
Background: Inherited retinal diseases (IRDs) are clinically complex and genetically heterogeneous visual impairment disorders with varying penetrance and severity. Disease-causing variants in at least 289 nuclear and mitochondrial genes have been implicated in their pathogenesis. Methods: Whole exome sequencing results were analyzed using [...] Read more.
Background: Inherited retinal diseases (IRDs) are clinically complex and genetically heterogeneous visual impairment disorders with varying penetrance and severity. Disease-causing variants in at least 289 nuclear and mitochondrial genes have been implicated in their pathogenesis. Methods: Whole exome sequencing results were analyzed using established pipelines and the results were further confirmed by Sanger sequencing and minigene splicing assay. Results: Exome sequencing in a 51-year-old Ashkenazi Jewish patient with non-syndromic retinitis pigmentosa (RP) identified compound heterozygous variants in the CLRN1 gene: a known pathogenic missense [p.(N48K)] and a novel deep intronic variant c.254-643G>T. A minigene splicing assay that was performed aiming to study the effect of the c.254-643G>T variant on CLRN1 pre-mRNA splicing revealed the inclusion of a pseudo-exon that was also reported to be included in the transcript due to an adjacent variant, c.254-649T>G. However, unlike the reported c.254-649T>G variant, c.254-643G>T showed aberrant splicing in a leaky manner, implying that the identified variant is not totally penetrant. Conclusion: We report on a novel deep intronic variant in CLRN1 causing non-syndromic RP. The non-syndromic phenotype observed in this index case may be attributed to the leaky nature of this variant, which is causing some normal transcripts to be produced. Full article
(This article belongs to the Special Issue Study of Inherited Retinal Diseases—Volume II)
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9 pages, 3210 KiB  
Article
Detecting Alu Element Insertion Variant in RP1 Gene Using Whole Genome Sequencing in Patients with Retinitis Pigmentosa
by Hye-Ji Kwon, Beom-Hee Lee and Joo-Yong Lee
Genes 2024, 15(10), 1290; https://doi.org/10.3390/genes15101290 - 30 Sep 2024
Cited by 1 | Viewed by 1070
Abstract
Background/Objectives: Alu element insertion in the exon 4 of the RP1 gene was newly identified through whole genome sequencing (WGS). This was not detected in previous next-generation sequencing (NGS) analysis. We report three cases of Korean retinitis pigmentosa (RP) patients with compound [...] Read more.
Background/Objectives: Alu element insertion in the exon 4 of the RP1 gene was newly identified through whole genome sequencing (WGS). This was not detected in previous next-generation sequencing (NGS) analysis. We report three cases of Korean retinitis pigmentosa (RP) patients with compound heterozygous variants including Alu element insertion in the RP1 gene, indicating that Alu element insertion could be a cause of RP; Methods: Among patients diagnosed with RP having variants in the RP1 gene in the Asan Medical Center, WGS was additionally performed for genetically unsolved cases in previous NGS analysis to detect any presence of Alu element insertion. For cases detected to have Alu element insertion in the exon 4 of the RP1 gene, genetic and clinical characteristics were analyzed; Results: Among 16 patients with RP, 3 patients were detected to have Alu element insertion in the RP1 gene. Alu element insertion in the RP1 gene was also detected using WGS. It was revealed to be a pathogenic variant. Therefore, RP1 gene mutation was the confirmed genetic cause of RP for these three cases and genetic counseling was enabled for them; Conclusions: Alu element insertion in the RP1 gene could be a genetic cause of autosomal recessive RP patients with compound heterozygous variants. Through WGS, the identification of this pathogenic variant was possible. Confirmation is needed to check the presence of Alu element insertion in patients with compound heterozygous variants in the RP1 gene. Full article
(This article belongs to the Special Issue Study of Inherited Retinal Diseases—Volume II)
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24 pages, 1264 KiB  
Article
The Clinical and Mutational Spectrum of Bardet–Biedl Syndrome in Saudi Arabia
by Doaa Milibari, Sawsan R. Nowilaty and Rola Ba-Abbad
Genes 2024, 15(6), 762; https://doi.org/10.3390/genes15060762 - 11 Jun 2024
Cited by 1 | Viewed by 1541
Abstract
The retinal features of Bardet–Biedl syndrome (BBS) are insufficiently characterized in Arab populations. This retrospective study investigated the retinal features and genotypes of BBS in Saudi patients managed at a single tertiary eye care center. Data analysis of the identified 46 individuals from [...] Read more.
The retinal features of Bardet–Biedl syndrome (BBS) are insufficiently characterized in Arab populations. This retrospective study investigated the retinal features and genotypes of BBS in Saudi patients managed at a single tertiary eye care center. Data analysis of the identified 46 individuals from 31 families included visual acuity (VA), systemic manifestations, multimodal retinal imaging, electroretinography (ERG), family pedigrees, and genotypes. Patients were classified to have cone–rod, rod–cone, or generalized photoreceptor dystrophy based on the pattern of macular involvement on the retinal imaging. Results showed that nyctalopia and subnormal VA were the most common symptoms with 76% having VA ≤ 20/200 at the last visit (age: 5–35). Systemic features included obesity 91%, polydactyly 56.5%, and severe cognitive impairment 33%. The predominant retinal phenotype was cone–rod dystrophy 75%, 10% had rod–cone dystrophy and 15% had generalized photoreceptor dystrophy. ERGs were undetectable in 95% of patients. Among the 31 probands, 61% had biallelic variants in BBSome complex genes, 32% in chaperonin complex genes, and 6% had biallelic variants in ARL6; including six previously unreported variants. Interfamilial and intrafamilial variabilities were noted, without a clear genotype–phenotype correlation. Most BBS patients had advanced retinopathy and were legally blind by early adulthood, indicating a narrow therapeutic window for rescue strategies. Full article
(This article belongs to the Special Issue Study of Inherited Retinal Diseases—Volume II)
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13 pages, 1377 KiB  
Article
In Silico CRISPR-Cas-Mediated Base Editing Strategies for Early-Onset, Severe Cone–Rod Retinal Degeneration in Three Crumbs homolog 1 Patients, including the Novel Variant c.2833G>A
by Hoda Shamsnajafabadi, Maria Kaukonen, Julia-Sophia Bellingrath, Robert E. MacLaren and Jasmina Cehajic-Kapetanovic
Genes 2024, 15(5), 625; https://doi.org/10.3390/genes15050625 - 15 May 2024
Cited by 4 | Viewed by 2072
Abstract
Pathogenic variants in the Crumbs homolog 1 (CRB1) gene lead to severe, childhood-onset retinal degeneration leading to blindness in early adulthood. There are no approved therapies, and traditional adeno-associated viral vector-based gene therapy approaches are challenged by the existence of multiple CRB1 isoforms. [...] Read more.
Pathogenic variants in the Crumbs homolog 1 (CRB1) gene lead to severe, childhood-onset retinal degeneration leading to blindness in early adulthood. There are no approved therapies, and traditional adeno-associated viral vector-based gene therapy approaches are challenged by the existence of multiple CRB1 isoforms. Here, we describe three CRB1 variants, including a novel, previously unreported variant that led to retinal degeneration. We offer a CRISPR-Cas-mediated DNA base editing strategy as a potential future therapeutic approach. This study is a retrospective case series. Clinical and genetic assessments were performed, including deep phenotyping by retinal imaging. In silico analyses were used to predict the pathogenicity of the novel variant and to determine whether the variants are amenable to DNA base editing strategies. Case 1 was a 24-year-old male with cone–rod dystrophy and retinal thickening typical of CRB1 retinopathy. He had a relatively preserved central outer retinal structure and a best corrected visual acuity (BCVA) of 60 ETDRS letters in both eyes. Genetic testing revealed compound heterozygous variants in exon 9: c.2843G>A, p.(Cys948Tyr) and a novel variant, c.2833G>A, p.(Gly945Arg), which was predicted to likely be pathogenic by an in silico analysis. Cases 2 and 3 were two brothers, aged 20 and 24, who presented with severe cone–rod dystrophy and a significant disruption of the outer nuclear layers. The BCVA was reduced to hand movements in both eyes in Case 2 and to 42 ETDRS letters in both eyes in Case 3. Case 2 was also affected with marked cystoid macular lesions, which are common in CRB1 retinopathy, but responded well to treatment with oral acetazolamide. Genetic testing revealed two c.2234C>T, p.(Thr745Met) variants in both brothers. As G-to-A and C-to-T variants, all three variants are amenable to adenine base editors (ABEs) targeting the forward strand in the Case 1 variants and the reverse strand in Cases 2 and 3. Available PAM sites were detected for KKH-nSaCas9-ABE8e for the c.2843G>A variant, nSaCas9-ABE8e and KKH-nSaCas9-ABE8e for the c.2833G>A variant, and nSpCas9-ABE8e for the c.2234C>T variant. In this case series, we report three pathogenic CRB1 variants, including a novel c.2833G>A variant associated with early-onset cone–rod dystrophy. We highlight the severity and rapid progression of the disease and offer ABEs as a potential future therapeutic approach for this devastating blinding condition. Full article
(This article belongs to the Special Issue Study of Inherited Retinal Diseases—Volume II)
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