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Genetics of Eye Development and Diseases
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Genetics of Eye Development and Diseases

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

Deadline for manuscript submissions: closed (25 December 2024) | Viewed by 6978

Special Issue Editors

Prof. Dr. Colin E. Willoughby

E-Mail Website
Guest Editor
Genomic Medicine Group, Biomedical Sciences Research Institute, Ulster University, Coleraine BT52 1SA, Northern Ireland, UK
Interests: microRNAs; ophthalmology; glaucoma; trabecular meshwork; fibrosis; oxidative stress; mitochondria; TGFβ; gene therapy
Special Issues, Collections and Topics in MDPI journals
Dr. Jing Chen

E-Mail Website
Guest Editor
Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Interests: microRNA; nuclear receptor; wnt signaling; angiogenesis; blood–retinal barrier; retinal pigment epithelium; retinopathy; age-related macular degeneration
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Genetics plays a key role in ocular development and diseases of the eye. Inherited eye diseases affect 1:1000 people, and as a group of genetic ocular disorders, they are a major cause of visual impairment in both children and adults. Understanding the genetic basis of Mendelian diseases is important for diagnosis, counseling, and prognosis. Discovering the molecular basis of genetic ocular development and diseases has been accelerated by advances in gene sequencing, yet challenges have been presented in the interpretation and modeling of genetic defects in silico and in vitro/vivo. GWAS has identified risk loci for common ocular diseases, and polygenic risk scores are being developed in order to stratify patient risk and improve clinical management pathways. Understanding the underlying genetic basis of ocular diseases not only improves our knowledge of disease pathogenesis and ocular physiology but also opens up the possibility of using gene-based therapies. In this Special Issue, we aim to encompass a range of approaches to understand, diagnose, and ultimately treat ocular genetic diseases from bench to bedside.

Prof. Dr. Colin E. Willoughby
Dr. Jing Chen
Guest Editors

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Keywords

  • eye
  • eye disease
  • retinal degeneration
  • age-related macular degeneration
  • glaucoma
  • retinitis pigmentosa
  • genetics
  • gene
  • genomics
  • mutation
  • inherited
  • developmental
  • vision
  • sequencing
  • SNP
  • GWAS
  • noncoding RNA
  • microRNA
  • bioinformatics
  • gene therapy

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Published Papers (4 papers)

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Research

17 pages, 3769 KiB  
Article
Atypical Leber Hereditary Optic Neuropathy (LHON) Associated with a Novel MT-CYB:m.15309T>C(Ile188Thr) Variant
by Sanja Petrovic Pajic, Ana Fakin, Martina Jarc-Vidmar, Maja Sustar Habjan, Lucija Malinar, Kasja Pavlovic, Nina Krako Jakovljevic, Andjelka Isakovic, Sonja Misirlic-Dencic, Marija Volk, Ales Maver, Gregor Jezernik, Damjan Glavac, Borut Peterlin, Ivanka Markovic, Nebojsa Lalic and Marko Hawlina
Genes 2025, 16(1), 108; https://doi.org/10.3390/genes16010108 - 20 Jan 2025
Viewed by 2978
Abstract
Background: The study presents a detailed examination and follow-up of a Slovenian patient with an Leber Hereditary Optic Neuropathy (LHON)-like phenotype and bilateral optic neuropathy in whom genetic analysis identified a novel variant MT-CYB:m.15309T>C (Ile188Thr). Methods: We provide detailed analysis of the [...] Read more.
Background: The study presents a detailed examination and follow-up of a Slovenian patient with an Leber Hereditary Optic Neuropathy (LHON)-like phenotype and bilateral optic neuropathy in whom genetic analysis identified a novel variant MT-CYB:m.15309T>C (Ile188Thr). Methods: We provide detailed analysis of the clinical examinations of a male patient with bilateral optic neuropathy from the acute stage to 8 years of follow-up. Complete ophthalmological exam, electrophysiology and optical coherence tomography (OCT) segmentation were performed. The genotype analysis was performed with a complete screening of the mitochondrial genome. Furthermore, proteomic analysis of the protein structure and function was performed to assess the pathogenicity of a novel variant of unknown significance. Mitochondrial function analysis of the patient’s peripheral blood mononuclear cells (PBMCs) was performed with the objective of evaluating the mutation effect on mitochondrial function using flow cytometry and high-resolution respirometry. Results: The patient had a profound consecutive bilateral visual loss at 19 years of age due to optic neuropathy with characteristics of LHON; however, unlike patients with typical LHON, the patient experienced a fluctuation in visual function and significant late recovery. He had a total of three visual acuity deteriorations and improvements in the left eye, with concomitant visual loss in the right eye and a final visual acuity drop reaching nadir 9 months after onset. The visual loss was characterized by centrocecal scotoma, abnormal color vision and abnormal VEP, while deterioration of PERG N95 followed with a lag of several months. The OCT examination showed retinal nerve fiber layer thinning matching disease progression. Following a two-year period of legal blindness, the patient’s visual function started to improve, and over the course of 5 years, it reached 0.5 and 0.7 Snellen (0.3 and 0.15 LogMAR) visual acuity (VA). Mitochondrial sequencing identified a presumably pathogenic variant m.15309T>C in the MT-CYB gene at 65% heteroplasmy, belonging to haplogroup K. Mitochondrial function assessment of the patient’s PBMCs showed a lower respiration rate, an increase in reactive oxygen species production and the presence of mitochondrial depolarization, compared to an age- and sex-matched healthy control’s PBMCs. Conclusions: A novel variant in the MT-CYB:m.15309T>C (Ile188Thr) gene was identified in a patient with optic nerve damage and the LHON phenotype without any additional systemic features and atypical presentation of the disease with late onset of visual function recovery. The pathogenicity of the variant is supported by proteomic analysis and the mitochondrial dysfunction observed in the patient’s PBMCs. Full article
(This article belongs to the Special Issue Genetics of Eye Development and Diseases)
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16 pages, 3571 KiB  
Article
Chromosome 4 Duplication Associated with Strabismus Leads to Gene Expression Changes in iPSC-Derived Cortical Neurons
by Mayra Martinez-Sanchez, William Skarnes, Ashish Jain, Sampath Vemula, Liang Sun, Shira Rockowitz and Mary C. Whitman
Genes 2025, 16(1), 80; https://doi.org/10.3390/genes16010080 - 12 Jan 2025
Viewed by 1074
Abstract
Background/Objectives: Strabismus is the most common ocular disorder of childhood. Three rare, recurrent genetic duplications have been associated with both esotropia and exotropia, but the mechanisms by which they contribute to strabismus are unknown. This work aims to investigate the mechanisms of the [...] Read more.
Background/Objectives: Strabismus is the most common ocular disorder of childhood. Three rare, recurrent genetic duplications have been associated with both esotropia and exotropia, but the mechanisms by which they contribute to strabismus are unknown. This work aims to investigate the mechanisms of the smallest of the three, a 23 kb duplication on chromosome 4 (hg38|4:25,554,985-25,578,843). Methods: Using CRISPR and bridging oligos, we introduced the duplication into the Kolf2.1J iPSC line. We differentiated the parent line and the line with the duplication into cortical neurons using a three-dimensional differentiation protocol, and performed bulk RNASeq on neural progenitors (day 14) and differentiated neurons (day 63). Results: We successfully introduced the duplication into Kolf2.1J iPSCs by nucleofecting a bridging oligo for the newly formed junction along with cas9 ribonucleoparticles. We confirmed that the cells had a tandem duplication without inversion or deletion. The parent line and the line with the duplication both differentiated into neurons reliably. There were a total of 37 differentially expressed genes (DEGs) at day 63, 25 downregulated and 12 upregulated. There were 55 DEGs at day 14, 18 of which were also DEGs at day 63. The DEGs included a number of protocadherins, several genes involved in neuronal development, including SLITRK2, CSMD1, and VGF, and several genes of unknown function. Conclusions: A copy number variant (CNV) that confers risk for strabismus affects gene expression of several genes involved in neural development, highlighting that strabismus most likely results from abnormal neural development, and identifying several new genes and pathways for further research into the pathophysiology of strabismus. Full article
(This article belongs to the Special Issue Genetics of Eye Development and Diseases)
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11 pages, 705 KiB  
Article
Novel Intragenic and Genomic Variants Highlight the Phenotypic Variability in HCCS-Related Disease
by Linda M. Reis, Donald Basel, Pierre Bitoun, David S. Walton, Tom Glaser and Elena V. Semina
Genes 2024, 15(12), 1636; https://doi.org/10.3390/genes15121636 - 20 Dec 2024
Viewed by 542
Abstract
Background: Disruption of HCCS results in microphthalmia with linear skin lesions (MLS) characterized by microphthalmia/anophthalmia, corneal opacity, aplastic skin lesions, variable central nervous system and cardiac anomalies, intellectual disability, and poor growth in heterozygous females. Structural variants consisting of chromosomal rearrangements or [...] Read more.
Background: Disruption of HCCS results in microphthalmia with linear skin lesions (MLS) characterized by microphthalmia/anophthalmia, corneal opacity, aplastic skin lesions, variable central nervous system and cardiac anomalies, intellectual disability, and poor growth in heterozygous females. Structural variants consisting of chromosomal rearrangements or deletions are the most common variant type, but a small number of intragenic variants have been reported. Methods: Exome sequencing identified variants affecting HCCS. Results: Three novel intragenic variants and two genomic deletions of HCCS were found in individuals with primarily ocular features of MLS. X-inactivation was highly skewed in affected individuals with all three intragenic variants. Corneal opacity was the most penetrant feature (100%). In addition, a duplication of uncertain significance including both HCCS and AMELX was identified in a male with corneal anomalies, glaucoma, an atrial septal defect, and enamel hypoplasia along with a family history of developmental ocular disorders consistent with X-linked inheritance. Conclusion: Although variable expressivity is a known feature of MLS, our findings provide additional support for including HCCS in testing for individuals with isolated ocular anomalies and provide further evidence for its association with congenital aphakia, aniridia/other iris defects, and corneal staphyloma/ectasia. Full article
(This article belongs to the Special Issue Genetics of Eye Development and Diseases)
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17 pages, 2958 KiB  
Article
Whole-Exome Analysis for Polish Caucasian Patients with Retinal Dystrophies and the Creation of a Reference Genomic Database for the Polish Population
by Ewa Matczyńska, Robert Szymańczak, Katarzyna Stradomska, Przemysław Łyszkiewicz, Maria Jędrzejowska, Karolina Kamińska, Marta Beć-Gajowniczek, Ewa Suchecka, Marek Zagulski, Marta Wiącek, Edward Wylęgała, Anna Machalińska, Małgorzata Mossakowska, Monika Puzianowska-Kuźnicka, Sławomir Teper and Anna Boguszewska-Chachulska
Genes 2024, 15(8), 1011; https://doi.org/10.3390/genes15081011 - 1 Aug 2024
Viewed by 1813
Abstract
We present the results of the first study of a large cohort of patients with inherited retinal dystrophies (IRD) performed for the Polish population using whole-exome sequencing (WES) in the years 2016–2019. Moreover, to facilitate such diagnostic analyses and enable future application of [...] Read more.
We present the results of the first study of a large cohort of patients with inherited retinal dystrophies (IRD) performed for the Polish population using whole-exome sequencing (WES) in the years 2016–2019. Moreover, to facilitate such diagnostic analyses and enable future application of gene therapy and genome editing for IRD patients, a Polish genomic reference database (POLGENOM) was created based on whole-genome sequences of healthy Polish Caucasian nonagenarians and centenarians. The newly constructed database served as a control, providing a comparison for variant frequencies in the Polish population. The diagnostic yield for the selected group of IRD patients reached 64.9%. The study uncovered the most common pathogenic variants in ABCA4 and USH2A in the European population, along with several novel causative variants. A significant frequency of the ABCA4 complex haplotype p.(Leu541Pro; Ala1038Val) was observed, as well as that of the p.Gly1961Glu variant. The first VCAN causative variant NM_004385.5:c.4004-2A>G in Poland was found and described. Moreover, one of the first patients with the RPE65 causative variants was identified, and, in consequence, could receive the dedicated gene therapy. The availability of the reference POLGENOM database enabled comprehensive variant characterisation during the NGS data analysis, confirming the utility of a population-specific genomic database for enhancing diagnostic accuracy. Study findings suggest the significance of genetic testing in elder patients with unclear aetiology of eye diseases. The combined approach of NGS and the reference genomic database can improve the diagnosis, management, and future treatment of IRDs. Full article
(This article belongs to the Special Issue Genetics of Eye Development and Diseases)
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