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Molecular Diagnosis and Disease Mechanisms in Eye Disorders
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Molecular Diagnosis and Disease Mechanisms in Eye Disorders

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Genetic Diagnosis".

Deadline for manuscript submissions: 15 August 2024 | Viewed by 7766

Special Issue Editor

Dr. Shi Song Rong

E-Mail Website
Guest Editor
Mass Eye and Ear, Mass General Brigham, Harvard Medical School, Boston, MA, USA
Interests: ocular genomics; gene functions; disease models

Special Issue Information

Dear Colleagues,

Recent advances in understanding inherited eye diseases' genetic and molecular bases have enabled more accurate diagnoses and targeted treatments. By leveraging the power of high-throughput and precision methods, such as genome-wide association study, next-generation sequencing, multi-omics study, genome manipulation, and artificial intelligence/machine learning-based automation, researchers are accelerating the identification of novel biomarkers and therapeutic targets of human eye diseases. Genetic editing and stem cell techniques also enable scientists to create animal, organoid, or cellular models with specific genetic or molecular changes that mimic ocular conditions to test potential treatments. Moreover, through sophisticated imaging systems, researchers can now observe the cellular and molecular processes of eye disorders in unprecedented detail. These advances are giving us more actionable insights into the molecular mechanisms of various eye diseases and gradually transforming our approach to disease diagnosis, treatment, and prevention to be more effective and personalized.

This Special Issue aims to advance the knowledge of molecular diagnosis and mechanisms of various eye disorders and inform future genomic studies, functional testing, diagnostics and therapeutic development, and the broader field of ophthalmic research. To this end, we invite original research articles, reviews, and perspectives that discuss novel biomarkers, unique biological insights, new technologies, and improved methodologies.

Dr. Shi Song Rong
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • molecular diagnosis
  • disease mechanisms
  • eye diseases
  • ocular diseases
  • biomarker
  • precision medicine
  • personalized medicine
  • gene therapy
  • genetic testing
  • disease models

Published Papers (6 papers)

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16 pages, 1984 KiB  
Article
A Molecular Genetic Analysis of RPE65-Associated Forms of Inherited Retinal Degenerations in the Russian Federation
by Anna Stepanova, Natalya Ogorodova, Vitaly Kadyshev, Olga Shchagina, Sergei Kutsev and Aleksandr Polyakov
Genes 2023, 14(11), 2056; https://doi.org/10.3390/genes14112056 - 09 Nov 2023
Viewed by 1116
Abstract
Pathogenic variants in the RPE65 gene cause the only known form of inherited retinal degenerations (IRDs) that are prone to gene therapy. The current study is aimed at the evaluation of the prevalence of RPE65-associated retinopathy in the Russian Federation, the characterization of [...] Read more.
Pathogenic variants in the RPE65 gene cause the only known form of inherited retinal degenerations (IRDs) that are prone to gene therapy. The current study is aimed at the evaluation of the prevalence of RPE65-associated retinopathy in the Russian Federation, the characterization of known variants in the RPE65 gene, and the establishment of the specificities of the mutation spectrum in Russian patients. Methods: The analysis was carried out on blood samples obtained from 1053 non-related IRDs patients. The analysis, which consisted of 211 genes, was carried out based on the method of massive parallel sequencing (MPS) for all probands. Variant validation, as well as biallelic status verification, were carried out using direct automated Sanger sequencing. The number of copies of RPE65 exons 1–14 was analyzed with quantitative MLPA using an MRC-Holland SALSA MLPA probemix. Results: Out of 1053 non-related patients, a molecular genetic diagnosis of IRDs has been confirmed in 474 cases, including 25 (5.3%) patients with RPE65-associated retinopathy. We detected 26 variants in the RPE65 gene, nine of which have not been previously described in the literature. The most common mutations in the Russian population were c.304G>T/p.(Glu102*), c.370C>T/p.(Arg124*), and c.272G>A/p.(Arg91Gln), which comprised 41.8% of all affected chromosomes. Conclusions: The current study shows that pathogenic variants in the RPE65 gene contribute significantly to the pathogenesis of IRDs and comprise 5.3% of all patients with a confirmed molecular genetic diagnosis. This study allowed for the formation of a cohort for target therapy of the disorder; such therapy has already been carried out for some patients. Full article
(This article belongs to the Special Issue Molecular Diagnosis and Disease Mechanisms in Eye Disorders)
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14 pages, 1608 KiB  
Article
Combined Single Gene Testing and Genome Sequencing as an Effective Diagnostic Approach for Anophthalmia and Microphthalmia Patients
by Rabia Basharat, Kim Rodenburg, María Rodríguez-Hidalgo, Afeefa Jarral, Ehsan Ullah, Jordi Corominas, Christian Gilissen, Syeda Tatheer Zehra, Usman Hameed, Muhammad Ansar and Suzanne E. de Bruijn
Genes 2023, 14(8), 1573; https://doi.org/10.3390/genes14081573 - 01 Aug 2023
Cited by 1 | Viewed by 1340
Abstract
Anophthalmia and microphthalmia (A/M) are among the most severe congenital developmental eye disorders. Despite the advancements in genome screening technologies, more than half of A/M patients do not receive a molecular diagnosis. We included seven consanguineous families affected with A/M from Pakistani cohort [...] Read more.
Anophthalmia and microphthalmia (A/M) are among the most severe congenital developmental eye disorders. Despite the advancements in genome screening technologies, more than half of A/M patients do not receive a molecular diagnosis. We included seven consanguineous families affected with A/M from Pakistani cohort and an unknown molecular basis. Single gene testing of FOXE3 was performed, followed by genome sequencing for unsolved probands in order to establish a genetic diagnosis for these families. All seven families were provided with a genetic diagnosis. The identified variants were all homozygous, classified as (likely) pathogenic and present in an A/M-associated gene. Targeted FOXE3 sequencing revealed two previously reported pathogenic FOXE3 variants in four families. In the remaining families, genome sequencing revealed a known pathogenic PXDN variant, a novel 13bp deletion in VSX2, and one novel deep intronic splice variant in PXDN. An in vitro splice assay was performed for the PXDN splice variant which revealed a severe splicing defect. Our study confirmed the utility of genome sequencing as a diagnostic tool for A/M-affected individuals. Furthermore, the identification of a novel deep intronic pathogenic variant in PXDN highlights the role of non-coding variants in A/M-disorders and the value of genome sequencing for the identification of this type of variants. Full article
(This article belongs to the Special Issue Molecular Diagnosis and Disease Mechanisms in Eye Disorders)
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17 pages, 14527 KiB  
Article
Natural History of Stargardt Disease: The Longest Follow-Up Cohort Study
by Jana Sajovic, Andrej Meglič, Ana Fakin, Jelka Brecelj, Maja Šuštar Habjan, Marko Hawlina and Martina Jarc Vidmar
Genes 2023, 14(7), 1394; https://doi.org/10.3390/genes14071394 - 02 Jul 2023
Viewed by 1938
Abstract
Long-term natural history studies are important in rare disease research. This study aimed to assess electrophysiological and fundus autofluorescence (FAF) progression rate in 18 genetically confirmed Stargardt disease (STGD1) patients with a minimum follow-up of 10 years. Age at the first and last [...] Read more.
Long-term natural history studies are important in rare disease research. This study aimed to assess electrophysiological and fundus autofluorescence (FAF) progression rate in 18 genetically confirmed Stargardt disease (STGD1) patients with a minimum follow-up of 10 years. Age at the first and last exams, age at onset, Snellen decimal visual acuity (VA), electroretinography (ERG), and FAF images were evaluated. Patients were classified into four Fishman stages and three electroretinography groups, and areas of definitely decreased autofluorescence (DDAF) were measured. Patients were further substratified based on genotype, and phenotype-genotype correlations were performed. The median follow-up was 18 (range 10–26) years. The median yearly VA loss was 0.009 (range 0.002–0.071), while the median progression rate of the DDAF area was 0.354 (range 0.002–4.359) mm2 per year. Patients harbouring p.(Gly1961Glu) or p.(Asn1868Ile) allele had significantly slower DDAF area progression when compared to patients with other genotypes (0.07 mm2 vs. 1.03 mm2, respectively), as well as significantly later age at onset (20 years vs. 13 years, respectively). Results showed that structural and functional parameters, together with genotype, should be considered when counselling patients regarding prognosis and monitoring disease progression. Patients harbouring hypomorphic variants p.(Gly1961Glu) or p.(Asn1868Ile) presented with overall milder disease than patients with other genotypes. Full article
(This article belongs to the Special Issue Molecular Diagnosis and Disease Mechanisms in Eye Disorders)
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11 pages, 850 KiB  
Communication
The Role of Genetic Testing in Children Requiring Surgery for Ectopia Lentis
by Mohammud Musleh, Adam Bull, Emma Linton, Jingshu Liu, Sarah Waller, Claire Hardcastle, Jill Clayton-Smith, Vinod Sharma, Graeme C. Black, Susmito Biswas, Jane L. Ashworth and Panagiotis I. Sergouniotis
Genes 2023, 14(4), 791; https://doi.org/10.3390/genes14040791 - 25 Mar 2023
Viewed by 1337
Abstract
Non-traumatic ectopia lentis can be isolated or herald an underlying multisystemic disorder. Technological advances have revolutionized genetic testing for many ophthalmic disorders, and this study aims to provide insights into the clinical utility of genetic analysis in paediatric ectopia lentis. Children that underwent [...] Read more.
Non-traumatic ectopia lentis can be isolated or herald an underlying multisystemic disorder. Technological advances have revolutionized genetic testing for many ophthalmic disorders, and this study aims to provide insights into the clinical utility of genetic analysis in paediatric ectopia lentis. Children that underwent lens extraction for ectopia lentis between 2013 and 2017 were identified, and gene panel testing findings and surgical outcomes were collected. Overall, 10/11 cases received a probable molecular diagnosis. Genetic variants were identified in four genes: FBN1 (associated with Marfan syndrome and cardiovascular complications; n = 6), ADAMTSL4 (associated with non-syndromic ectopia lentis; n = 2), LTBP2 (n = 1) and ASPH (n = 1). Parents appeared unaffected in 6/11 cases; the initial presentation of all six of these children was to an ophthalmologist, and only 2/6 had FBN1 variants. Notably, 4/11 cases required surgery before the age of 4 years, and only one of these children carried an FBN1 variant. In summary, in this retrospective cohort study, panel-based genetic testing pointed to a molecular diagnosis in >90% of paediatric ectopia lentis cases requiring surgery. In a subset of study participants, genetic analysis revealed changes in genes that have not been linked to extraocular manifestations and highlighted that extensive systemic investigations were not required in these individuals. We propose the introduction of genetic testing early in the diagnostic pathway in children with ectopia lentis. Full article
(This article belongs to the Special Issue Molecular Diagnosis and Disease Mechanisms in Eye Disorders)
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13 pages, 1404 KiB  
Case Report
Syndromic Retinitis Pigmentosa: A 15-Patient Study
by Ianne Pessoa Holanda, Priscila Hae Hyun Rim, Rare Genomes Project Consortium, Mara Sanches Guaragna, Vera Lúcia Gil-da-Silva-Lopes and Carlos Eduardo Steiner
Genes 2024, 15(4), 516; https://doi.org/10.3390/genes15040516 - 20 Apr 2024
Viewed by 282
Abstract
Retinitis pigmentosa is a group of genetically determined retinal dystrophies characterized by primary photoreceptor apoptosis and can occur in isolated or syndromic conditions. This study reviewed the clinical data of 15 patients with syndromic retinitis pigmentosa from a Rare Disease Reference Center in [...] Read more.
Retinitis pigmentosa is a group of genetically determined retinal dystrophies characterized by primary photoreceptor apoptosis and can occur in isolated or syndromic conditions. This study reviewed the clinical data of 15 patients with syndromic retinitis pigmentosa from a Rare Disease Reference Center in Brazil and the results of their next-generation sequencing tests. Five males and ten females participated, with the mean ages for ocular disease onset, fundoscopic diagnosis, and molecular evaluation being 9, 19, and 29 years, respectively. Bardet–Biedl syndrome (n = 5) and Usher syndrome (n = 3) were the most frequent diagnoses, followed by other rare conditions. Among the patients, fourteen completed molecular studies, with three negative results and eleven revealing findings in known genes, including novel variants in MKKS (c.432_435del, p.Phe144Leufs*14), USH2A (c.(7301+1_7302-1)_(9369+1_9370-1)del), and CEP250 (c.5383dup, p.Glu1795Glyfs*13, and c.5050del, p.Asp1684Thrfs*9). Except for Kearn-Sayre, all presented an autosomal recessive inheritance pattern with 64% homozygosity results. The long gap between symptom onset and diagnosis highlights the diagnostic challenges faced by the patients. This study reaffirms the clinical heterogeneity of syndromic retinitis pigmentosa and underscores the pivotal role of molecular analysis in advancing our understanding of these diseases. Full article
(This article belongs to the Special Issue Molecular Diagnosis and Disease Mechanisms in Eye Disorders)
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23 pages, 1315 KiB  
Systematic Review
Association of Gene Polymorphisms with Normal Tension Glaucoma: A Systematic Review and Meta-Analysis
by Lijie Pan, Jian Wu and Ningli Wang
Genes 2024, 15(4), 491; https://doi.org/10.3390/genes15040491 - 14 Apr 2024
Viewed by 429
Abstract
Background: Normal tension glaucoma (NTG) is becoming a more and more serious problem, especially in Asia. But the pathological mechanisms are still not illustrated clearly. We carried out this research to uncover the gene polymorphisms with NTG. Methods: We searched in Web of [...] Read more.
Background: Normal tension glaucoma (NTG) is becoming a more and more serious problem, especially in Asia. But the pathological mechanisms are still not illustrated clearly. We carried out this research to uncover the gene polymorphisms with NTG. Methods: We searched in Web of Science, Embase, Pubmed and Cochrane databases for qualified case-control studies investigating the association between single nucleotide polymorphisms (SNPs) and NTG risk. Odds ratios (ORs) and 95% confidence intervals (CIs) for each SNP were estimated by fixed- or random-effect models. Sensitivity analysis was also performed to strengthen the reliability of the results. Results: Fifty-six studies involving 33 candidate SNPs in 14 genetic loci were verified to be eligible for our meta-analysis. Significant associations were found between 16 SNPs (rs166850 of OPA1; rs10451941 of OPA1; rs735860 of ELOVL5; rs678350 of HK2; c.603T>A/Met98Lys of OPTN; c.412G>A/Thr34Thr of OPTN; rs10759930 of TLR4; rs1927914 of TLR4; rs1927911 of TLR4; c.*70C>G of EDNRA; rs1042522/-Arg72Pro of P53; rs10483727 of SIX1-SIX6; rs33912345 of SIX1-SIX6; rs2033008 of NCK2; rs3213787 of SRBD1 and c.231G>A of EDNRA) with increased or decreased risk of NTG. Conclusions: In this study, we confirmed 16 genetic polymorphisms in 10 genes (OPA1, ELOVL5, HK2, OPTN, TLR4, EDNRA, P53, NCK2, SRBD1 and SIX1-SIX6) were associated with NTG. Full article
(This article belongs to the Special Issue Molecular Diagnosis and Disease Mechanisms in Eye Disorders)
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