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Insights into Heritability of Glaucoma and Other Optic Neuropathies
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Insights into Heritability of Glaucoma and Other Optic Neuropathies

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 (5 July 2022) | Viewed by 35646

Special Issue Editor

Prof. Dr. Joan M. O'Brien

E-Mail Website1 Website2
Guest Editor
Scheie Eye Institute, University of Pennsylvania, Pennsylvania, PA 19104, USA
Interests: ophthalmology; opthalmic genetics; ophthalmic oncology; glaucoma; retinoblastoma; ocular melanoma; ocular lymphoma; health disparities; African Americans

Special Issue Information

Dear Colleagues,

Glaucoma is an insidious group of diseases causing degeneration of the optic nerve and progressive loss of vision. More than 80 million individuals have glaucoma as of 2020, making it the leading cause of irreversible blindness worldwide. However, despite its high prevalence, the pathophysiology of this familial disease remains poorly understood. There is only one treatable component of this disease (elevated intraocular pressure), and approximately 30% of patients continue to worsen despite treatment. This suggests that glaucoma—which has a strong genetic component—has additional disease mechanisms that could provide further therapeutic targets once elucidated. Such discoveries could also aid in the development of risk models and improved screening efforts, as more than half of glaucoma patients are unaware of their diagnosis.

Many other optic neuropathies also lead to irreversible loss of vision. In some optic neuropathies, optic nerve dysfunction is heritable, based on familial expression or genetic analysis. These optic neuropathies can be caused by mutations in nuclear or mitochondrial genes, and may reflect many different inheritance patterns. Better understanding of the genetic architecture of these optic neuropathies can inform presymptomatic testing and risk assessment, development of more targeted therapies, and genetic counselling of patients.

The purpose of this Special Issue is to publish original research papers describing the heritability of glaucoma and other optic neuropathies, including the genetic, molecular, and functional pathways associated with these diseases. We are interested in papers that elucidate the mechanisms associated with disease biology, ranging from basic scientific discoveries to large-scale genetic analyses. Other topics of interest include the evaluation of disease risk factors, biomarker analyses, and gene risk score models. Papers that investigate sub-phenotypes of glaucoma and optic neuropathies associated with genetic variation, as well as correlations with disease progression and severity, are also encouraged.

Prof. Joan M. O'Brien
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

  • Ophthalmology
  • Glaucoma
  • Optic neuropathies
  • Genetics
  • Genotype–phenotype correlation
  • Polygenic risk score
  • Meta-analysis
  • Epigenetic regulation
  • Biomarkers
  • Single-cell sequencing

Published Papers (13 papers)

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Research

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22 pages, 5379 KiB  
Article
Whole Exome Sequencing Reveals Novel Candidate Genes in Familial Forms of Glaucomatous Neurodegeneration
by Kiran Narta, Manoj Ramesh Teltumbade, Mansi Vishal, Samreen Sadaf, Mohd. Faruq, Hodan Jama, Naushin Waseem, Aparna Rao, Abhijit Sen, Kunal Ray and Arijit Mukhopadhyay
Genes 2023, 14(2), 495; https://0-doi-org.brum.beds.ac.uk/10.3390/genes14020495 - 15 Feb 2023
Viewed by 1912
Abstract
Glaucoma is the largest cause of irreversible blindness with a multifactorial genetic etiology. This study explores novel genes and gene networks in familial forms of primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG) to identify rare mutations with high penetrance. [...] Read more.
Glaucoma is the largest cause of irreversible blindness with a multifactorial genetic etiology. This study explores novel genes and gene networks in familial forms of primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG) to identify rare mutations with high penetrance. Thirty-one samples from nine MYOC-negative families (five POAG and four PACG) underwent whole-exome sequencing and analysis. A set of prioritized genes and variations were screened in an independent validation cohort of 1536 samples and the whole-exome data from 20 sporadic patients. The expression profiles of the candidate genes were analyzed in 17 publicly available expression datasets from ocular tissues and single cells. Rare, deleterious SNVs in AQP5, SRFBP1, CDH6 and FOXM1 from POAG families and in ACACB, RGL3 and LAMA2 from PACG families were found exclusively in glaucoma cases. AQP5, SRFBP1 and CDH6 also revealed significant altered expression in glaucoma in expression datasets. Single-cell expression analysis revealed enrichment of identified candidate genes in retinal ganglion cells and corneal epithelial cells in POAG; whereas for PACG families, retinal ganglion cells and Schwalbe’s Line showed enriched expression. Through an unbiased exome-wide search followed by validation, we identified novel candidate genes for familial cases of POAG and PACG. The SRFBP1 gene found in a POAG family is located within the GLC1M locus on Chr5q. Pathway analysis of candidate genes revealed enrichment of extracellular matrix organization in both POAG and PACG. Full article
(This article belongs to the Special Issue Insights into Heritability of Glaucoma and Other Optic Neuropathies)
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14 pages, 10329 KiB  
Article
Biallelic Optic Atrophy 1 (OPA1) Related Disorder—Case Report and Literature Review
by Bayan Al Othman, Jia Ern Ong and Alina V. Dumitrescu
Genes 2022, 13(6), 1005; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13061005 - 02 Jun 2022
Cited by 5 | Viewed by 2655
Abstract
Dominant optic atrophy (DOA), MIM # 605290, is the most common hereditary optic neuropathy inherited in an autosomal dominant pattern. Clinically, it presents a progressive decrease in vision, central visual field defects, and retinal ganglion cell loss. A biallelic mode of inheritance causes [...] Read more.
Dominant optic atrophy (DOA), MIM # 605290, is the most common hereditary optic neuropathy inherited in an autosomal dominant pattern. Clinically, it presents a progressive decrease in vision, central visual field defects, and retinal ganglion cell loss. A biallelic mode of inheritance causes syndromic DOA or Behr phenotype, MIM # 605290. This case report details a family with Biallelic Optic Atrophy 1 (OPA1). The proband is a child with a severe phenotype and two variants in the OPA1 gene. He presented with congenital nystagmus, progressive vision loss, and optic atrophy, as well as progressive ataxia, and was found to have two likely pathogenic variants in his OPA1 gene: c.2287del (p.Ser763Valfs*15) maternally inherited and c.1311A>G (p.lIle437Met) paternally inherited. The first variant is predicted to be pathogenic and likely to cause DOA. In contrast, the second is considered asymptomatic by itself but has been reported in patients with DOA phenotype and is presumed to act as a phenotypic modifier. On follow-up, he developed profound vision impairment, intractable seizures, and metabolic strokes. A literature review of reported biallelic OPA1-related Behr syndrome was performed. Twenty-one cases have been previously reported. All share an early-onset, severe ocular phenotype and systemic features, which seem to be the hallmark of the disease. Full article
(This article belongs to the Special Issue Insights into Heritability of Glaucoma and Other Optic Neuropathies)
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10 pages, 460 KiB  
Article
Evaluating TNF-α and Interleukin-2 (IL-2) Levels in African American Primary Open-Angle Glaucoma Patients
by Teja Alapati, Kyra M. Sagal, Harini V. Gudiseva, Maxwell Pistilli, Mark Pyfer, Venkata Ramana Murthy Chavali and Joan M. O’Brien
Genes 2022, 13(1), 54; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13010054 - 25 Dec 2021
Cited by 6 | Viewed by 2992
Abstract
Purpose: To establish if SNPs in TNF-α and IL-2 genes are associated with Primary Open-Angle Glaucoma (POAG) in African Americans (AA). We also determined whether plasma TNF-α and IL-2 levels could serve as biomarkers for POAG in African Americans using sandwich enzyme-linked immunosorbent [...] Read more.
Purpose: To establish if SNPs in TNF-α and IL-2 genes are associated with Primary Open-Angle Glaucoma (POAG) in African Americans (AA). We also determined whether plasma TNF-α and IL-2 levels could serve as biomarkers for POAG in African Americans using sandwich enzyme-linked immunosorbent assay. Methods: A single SNP association analysis was performed to investigate the association between potential gene variants in TNF-α and IL-2 genes and POAG in the AA population. Plasma samples from 190 African Americans (72 from normal subjects and 118 POAG cases) were obtained for TNF- α studies and 367 samples (135 from normal subjects and 232 from POAG cases) were obtained for IL-2 studies. TNF-α levels and IL-2 levels were measured by sandwich enzyme-linked immunosorbent assays (ELISA) and analyzed to see if they reached significance in cases with POAG and endophenotypes when compared to normal subjects. Results: The SNP, rs1800630, in TNF-α gene was found to be marginally associated with POAG. SNPs in IL-2 gene were not associated with POAG in the case-control analysis. No significant difference was found between TNF-α levels and IL-2 levels in normal and POAG case subjects in our study. IL-2 levels were inversely correlated with high IOP in POAG cases. Conclusions: Although we found a marginal SNP association of TNF-α, assessing the expression levels of TNF-α and IL-2 may serve as promising biomarkers for African American POAG. Further investigation is needed to determine if POAG can be subdivided into more specified cohorts of the disease, which may affect plasma cytokine levels differently. Full article
(This article belongs to the Special Issue Insights into Heritability of Glaucoma and Other Optic Neuropathies)
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14 pages, 4573 KiB  
Article
Single Cell Sequencing of Induced Pluripotent Stem Cell Derived Retinal Ganglion Cells (iPSC-RGC) Reveals Distinct Molecular Signatures and RGC Subtypes
by Harini V. Gudiseva, Vrathasha Vrathasha, Jie He, Devesh Bungatavula, Joan M. O’Brien and Venkata R. M. Chavali
Genes 2021, 12(12), 2015; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12122015 - 18 Dec 2021
Cited by 6 | Viewed by 4658
Abstract
We intend to identify marker genes with differential gene expression (DEG) and RGC subtypes in cultures of human-induced pluripotent stem cell (iPSC)-derived retinal ganglion cells. Single-cell sequencing was performed on mature and functional iPSC-RGCs at day 40 using Chromium Single Cell 3’ V3 [...] Read more.
We intend to identify marker genes with differential gene expression (DEG) and RGC subtypes in cultures of human-induced pluripotent stem cell (iPSC)-derived retinal ganglion cells. Single-cell sequencing was performed on mature and functional iPSC-RGCs at day 40 using Chromium Single Cell 3’ V3 protocols (10X Genomics). Sequencing libraries were run on Illumina Novaseq to generate 150 PE reads. Demultiplexed FASTQ files were mapped to the hg38 reference genome using the STAR package, and cluster analyses were performed using a cell ranger and BBrowser2 software. QC analysis was performed by removing the reads corresponding to ribosomal and mitochondrial genes, as well as cells that had less than 1X mean absolute deviation (MAD), resulting in 4705 cells that were used for further analyses. Cells were separated into clusters based on the gene expression normalization via PCA and TSNE analyses using the Seurat tool and/or Louvain clustering when using BBrowser2 software. DEG analysis identified subsets of RGCs with markers like MAP2, RBPMS, TUJ1, BRN3A, SOX4, TUBB3, SNCG, PAX6 and NRN1 in iPSC-RGCs. Differential expression analysis between separate clusters identified significant DEG transcripts associated with cell cycle, neuron regulatory networks, protein kinases, calcium signaling, growth factor hormones, and homeobox transcription factors. Further cluster refinement identified RGC diversity and subtype specification within iPSC-RGCs. DEGs can be used as biomarkers for RGC subtype classification, which will allow screening model systems that represent a spectrum of diseases with RGC pathology. Full article
(This article belongs to the Special Issue Insights into Heritability of Glaucoma and Other Optic Neuropathies)
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12 pages, 2917 KiB  
Article
A Precise Method to Evaluate 360 Degree Measures of Optic Cup and Disc Morphology in an African American Cohort and Its Genetic Applications
by Victoria Addis, Min Chen, Richard Zorger, Rebecca Salowe, Ebenezer Daniel, Roy Lee, Maxwell Pistilli, Jinpeng Gao, Maureen G. Maguire, Lilian Chan, Harini V. Gudiseva, Selam Zenebe-Gete, Sayaka Merriam, Eli J. Smith, Revell Martin, Candace Parker Ostroff, James C. Gee, Qi N. Cui, Eydie Miller-Ellis, Joan M. O’Brien and Prithvi S. Sankaradd Show full author list remove Hide full author list
Genes 2021, 12(12), 1961; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12121961 - 09 Dec 2021
Viewed by 2108
Abstract
(1) Background: Vertical cup-to-disc ratio (CDR) is an important measure for evaluating damage to the optic nerve head (ONH) in glaucoma patients. However, this measure often does not fully capture the irregular cupping observed in glaucomatous nerves. We developed and evaluated a method [...] Read more.
(1) Background: Vertical cup-to-disc ratio (CDR) is an important measure for evaluating damage to the optic nerve head (ONH) in glaucoma patients. However, this measure often does not fully capture the irregular cupping observed in glaucomatous nerves. We developed and evaluated a method to measure cup-to-disc ratio (CDR) at all 360 degrees of the ONH. (2) Methods: Non-physician graders from the Scheie Reading Center outlined the cup and disc on digital stereo color disc images from African American patients enrolled in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. After converting the resultant coordinates into polar representation, the CDR at each 360-degree location of the ONH was obtained. We compared grader VCDR values with clinical VCDR values, using Spearman correlation analysis, and validated significant genetic associations with clinical VCDR, using grader VCDR values. (3) Results: Graders delineated outlines of the cup contour and disc boundaries twice in each of 1815 stereo disc images. For both cases and controls, the mean CDR was highest at the horizontal bisector, particularly in the temporal region, as compared to other degree locations. There was a good correlation between grader CDR at the vertical bisector and clinical VCDR (Spearman Correlation OD: r = 0.78 [95% CI: 0.76–0.79]). An SNP in the MPDZ gene, associated with clinical VCDR in a prior genome-wide association study, showed a significant association with grader VCDR (p = 0.01) and grader CDR area ratio (p = 0.02). (4) Conclusions: The CDR of both glaucomatous and non-glaucomatous eyes varies by degree location, with the highest measurements in the temporal region of the eye. This method can be useful for capturing innate eccentric ONH morphology, tracking disease progression, and identifying genetic associations. Full article
(This article belongs to the Special Issue Insights into Heritability of Glaucoma and Other Optic Neuropathies)
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10 pages, 251 KiB  
Article
Association of the SNP rs112369934 near TRIM66 Gene with POAG Endophenotypes in African Americans
by Claire D. Kim, Harini V. Gudiseva, Brendan McGeehan, Ebenezer Daniel, Gui Shuang Ying, Venkata R. M. Chavali and Joan M. O’Brien
Genes 2021, 12(9), 1420; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091420 - 15 Sep 2021
Cited by 4 | Viewed by 1637
Abstract
We investigated the association of the single nucleotide polymorphism (SNP) rs112369934 near the TRIM66 gene with qualitative and quantitative phenotypes of primary open-angle glaucoma (POAG) in African Americans (AA). AA subjects over 35 years old were recruited for the Primary Open-Angle African American [...] Read more.
We investigated the association of the single nucleotide polymorphism (SNP) rs112369934 near the TRIM66 gene with qualitative and quantitative phenotypes of primary open-angle glaucoma (POAG) in African Americans (AA). AA subjects over 35 years old were recruited for the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study in Philadelphia, PA. Glaucoma cases were evaluated for phenotypes associated with POAG pathogenesis, and the associations between rs112369934 and phenotypes were investigated by logistic regression analysis and in gender-stratified case cohorts: The SNP rs112369934 was found to have a suggestive association with retinal nerve fiber layer (RNFL) thickness and cup-to-disc ratio (CDR) in 1087 male AA POAG cases, individuals with the TC genotype having thinner RNFL (95% CI 0.85 to 6.61, p = 0.01) and larger CDR (95% CI −0.07 to −0.01, p = 0.02) than those with wildtype TT. No other significant associations were found. In conclusion SNP rs112369934 may play a role in POAG pathogenesis in male AA individuals. However, this SNP has been implicated in higher POAG risk in both male and female AA POAG cases. Full article
(This article belongs to the Special Issue Insights into Heritability of Glaucoma and Other Optic Neuropathies)
9 pages, 233 KiB  
Article
Association of Single Nucleotide Polymorphisms Located in LOXL1 with Exfoliation Glaucoma in Southwestern Sweden
by Marcelo Ayala, Madeleine Zetterberg, Ingmar Skoog and Anna Zettergren
Genes 2021, 12(9), 1384; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091384 - 03 Sep 2021
Viewed by 1615
Abstract
Introduction: Glaucoma is an optic neuropathy that leads to visual field defects. Genetic mechanisms seem to be involved in glaucoma development. Lysyl Oxidase Like 1 (LOXL1) has been described in previous studies as a predictor factor for exfoliation glaucoma. The present [...] Read more.
Introduction: Glaucoma is an optic neuropathy that leads to visual field defects. Genetic mechanisms seem to be involved in glaucoma development. Lysyl Oxidase Like 1 (LOXL1) has been described in previous studies as a predictor factor for exfoliation glaucoma. The present article studied the association between three single nucleotide polymorphisms (SNPs) in the LOXL1 gene and the presence of exfoliation glaucoma in Southwestern Sweden. Methods: Case-control study for genetic association. In total, 136 patients and 1011 controls were included in the study. Patients with exfoliation glaucoma were recruited at the Eye Department of Sahlgrenska University Hospital and Skaraborgs Hospital, Sweden. Controls were recruited from the Gothenburg H70 Birth Cohort Study. Three different SNPs were genotyped: LOXL1_rs3825942, LOXL1_rs2165241 and LOXL1_rs1048661. Results: The distribution of allele frequencies was significantly different between controls and glaucoma patients; for rs3825942 (p = 2 × 10−12), for rs2165241 (p = 3 × 10−16) and for rs1048661 (p = 2 × 10−6). Logistic regression analyses using an additive genetic model, adjusted for sex and age, also showed associations between the studied SNPs and glaucoma (p = 9 × 10−6; p = 2 × 10−14; p = 1 × 10−4). Conclusion: A strong association was found between allele frequencies of three different SNPs (LOXL1_rs3825942, LOXL1_rs2165241, and LOXL1_rs1048661) and the presence of exfoliation glaucoma in a Southwestern Swedish population. Full article
(This article belongs to the Special Issue Insights into Heritability of Glaucoma and Other Optic Neuropathies)
9 pages, 232 KiB  
Article
LMX1B Locus Associated with Low-Risk Baseline Glaucomatous Features in the POAAGG Study
by Elana Meer, Vivian L. Qin, Harini V. Gudiseva, Brendan McGeehan, Rebecca Salowe, Maxwell Pistilli, Jie He, Ebenezer Daniel, Gui Shang Ying, Venkata R. M. Chavali and Joan M. O’Brien
Genes 2021, 12(8), 1252; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081252 - 16 Aug 2021
Cited by 3 | Viewed by 1691
Abstract
Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide and has been associated with multiple genetic risk factors. The LMX1B gene is a genetic susceptibility factor for POAG, and several single-nucleotide polymorphisms (SNPs) were shown to be associated with POAG [...] Read more.
Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide and has been associated with multiple genetic risk factors. The LMX1B gene is a genetic susceptibility factor for POAG, and several single-nucleotide polymorphisms (SNPs) were shown to be associated with POAG in our own prior Primary Open-Angle African American Glaucoma Genetics (POAAGG) study genome-wide association study (GWAS). This study evaluated the association of the LMX1B locus with baseline optic disc and clinical phenotypic characteristics of glaucoma patients from our African American cohort. Compared to the GG genotype in SNP rs187699205, the GC genotype in this SNP was found to be significantly associated with a smaller cup-to-disc ratio (CDR) and increased (better) visual field mean deviation (MD) in glaucoma cases. None of the glaucoma cases with the GC genotype had disc hemorrhages, disc notching, or beanpot disc appearance. In conclusion, glaucoma phenotypes differed significantly by LMX1B variant in African American patients with POAG, and a SNP variant was associated with certain disease features considered lower risk. Full article
(This article belongs to the Special Issue Insights into Heritability of Glaucoma and Other Optic Neuropathies)

Review

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9 pages, 404 KiB  
Review
Diversity in Polygenic Risk of Primary Open-Angle Glaucoma
by Jessica N. Cooke Bailey, Kaitlyn L. Funk, Lauren A. Cruz, Andrea R. Waksmunski, Tyler G. Kinzy, Janey L. Wiggs and Michael A. Hauser
Genes 2023, 14(1), 111; https://0-doi-org.brum.beds.ac.uk/10.3390/genes14010111 - 30 Dec 2022
Cited by 5 | Viewed by 1554
Abstract
Glaucoma is the leading cause of irreversible blindness worldwide. Primary open-angle glaucoma (POAG), the most common glaucoma subtype, is more prevalent and severe in individuals of African ancestry. Unfortunately, this ancestral group has been historically under-represented among genetic studies of POAG. Moreover, both [...] Read more.
Glaucoma is the leading cause of irreversible blindness worldwide. Primary open-angle glaucoma (POAG), the most common glaucoma subtype, is more prevalent and severe in individuals of African ancestry. Unfortunately, this ancestral group has been historically under-represented among genetic studies of POAG. Moreover, both genetic and polygenic risk scores (GRS, PRS) that are typically based on genetic data from European-descent populations are not transferable to individuals without a majority of European ancestry. Given the aspirations of leveraging genetic information for precision medicine, GRS and PRS demonstrate clinical potential but fall short, in part due to the lack of diversity in these studies. Prioritizing diversity in the discovery of risk variants will improve the performance and utility of GRS and PRS-derived risk estimation for disease stratification, which could bring about earlier POAG intervention and treatment for a disease that often goes undetected until significant damage has occurred. Full article
(This article belongs to the Special Issue Insights into Heritability of Glaucoma and Other Optic Neuropathies)
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21 pages, 392 KiB  
Review
Glaucoma Syndromes: Insights into Glaucoma Genetics and Pathogenesis from Monogenic Syndromic Disorders
by Daniel A. Balikov, Adam Jacobson and Lev Prasov
Genes 2021, 12(9), 1403; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091403 - 11 Sep 2021
Cited by 8 | Viewed by 3949
Abstract
Monogenic syndromic disorders frequently feature ocular manifestations, one of which is glaucoma. In many cases, glaucoma in children may go undetected, especially in those that have other severe systemic conditions that affect other parts of the eye and the body. Similarly, glaucoma may [...] Read more.
Monogenic syndromic disorders frequently feature ocular manifestations, one of which is glaucoma. In many cases, glaucoma in children may go undetected, especially in those that have other severe systemic conditions that affect other parts of the eye and the body. Similarly, glaucoma may be the first presenting sign of a systemic syndrome. Awareness of syndromes associated with glaucoma is thus critical both for medical geneticists and ophthalmologists. In this review, we highlight six categories of disorders that feature glaucoma and other ocular or systemic manifestations: anterior segment dysgenesis syndromes, aniridia, metabolic disorders, collagen/vascular disorders, immunogenetic disorders, and nanophthalmos. The genetics, ocular and systemic features, and current and future treatment strategies are discussed. Findings from rare diseases also uncover important genes and pathways that may be involved in more common forms of glaucoma, and potential novel therapeutic strategies to target these pathways. Full article
(This article belongs to the Special Issue Insights into Heritability of Glaucoma and Other Optic Neuropathies)
13 pages, 769 KiB  
Review
Glaucoma Heritability: Molecular Mechanisms of Disease
by Ryan Zukerman, Alon Harris, Francesco Oddone, Brent Siesky, Alice Verticchio Vercellin and Thomas A. Ciulla
Genes 2021, 12(8), 1135; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081135 - 27 Jul 2021
Cited by 17 | Viewed by 4273
Abstract
Glaucoma is one of the world’s leading causes of irreversible blindness. A complex, multifactorial disease, the underlying pathogenesis and reasons for disease progression are not fully understood. The most common form of glaucoma, primary open-angle glaucoma (POAG), was traditionally understood to be the [...] Read more.
Glaucoma is one of the world’s leading causes of irreversible blindness. A complex, multifactorial disease, the underlying pathogenesis and reasons for disease progression are not fully understood. The most common form of glaucoma, primary open-angle glaucoma (POAG), was traditionally understood to be the result of elevated intraocular pressure (IOP), leading to optic nerve damage and functional vision loss. Recently, researchers have suggested that POAG may have an underlying genetic component. In fact, studies of genetic association and heritability have yielded encouraging results showing that glaucoma may be influenced by genetic factors, and estimates for the heritability of POAG and disease-related endophenotypes show encouraging results. However, the vast majority of the underlying genetic variants and their molecular mechanisms have not been elucidated. Several genes have been suggested to have molecular mechanisms contributing to alterations in key endophenotypes such as IOP (LMX1B, MADD, NR1H3, and SEPT9), and VCDR (ABCA1, ELN, ASAP1, and ATOH7). Still, genetic studies about glaucoma and its molecular mechanisms are limited by the multifactorial nature of the disease and the large number of genes that have been identified to have an association with glaucoma. Therefore, further study into the molecular mechanisms of the disease itself are required for the future development of therapies targeted at genes leading to POAG endophenotypes and, therefore, increased risk of disease. Full article
(This article belongs to the Special Issue Insights into Heritability of Glaucoma and Other Optic Neuropathies)
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Other

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11 pages, 890 KiB  
Systematic Review
Age at Glaucoma Diagnosis in Germline Myocilin Mutation Patients: Associations with Polymorphisms in Protein Stabilities
by Tarin Tanji, Emily Cohen, Darrick Shen, Chi Zhang, Fei Yu, Anne L. Coleman and Jie J. Zheng
Genes 2021, 12(11), 1802; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12111802 - 16 Nov 2021
Cited by 6 | Viewed by 2913
Abstract
Glaucoma is the leading cause of irreversible blindness worldwide, with elevated intraocular pressure (IOP) as the only known modifiable risk factor. Trabecular meshwork (TM)-inducible myocilin (the MYOC gene) was the first to be identified and linked to juvenile and primary open-angle glaucoma. It [...] Read more.
Glaucoma is the leading cause of irreversible blindness worldwide, with elevated intraocular pressure (IOP) as the only known modifiable risk factor. Trabecular meshwork (TM)-inducible myocilin (the MYOC gene) was the first to be identified and linked to juvenile and primary open-angle glaucoma. It has been suggested that mutations in the MYOC gene and the aggregation of mutant myocilin in the endoplasmic reticulum (ER) of TM may cause ER stress, resulting in a reduced outflow of aqueous humor and an increase in IOP. We selected 20 MYOC mutations with experimentally determined melting temperatures of mutated myocilin proteins. We included 40 published studies with at least one glaucoma patient with one of these 20 MYOC mutations and information on age at glaucoma diagnosis. Based on data from 458 patients, we found that a statistically significant but weak correlation was present between age and melting temperature based on various assumptions for age. We therefore conclude that genetic analysis of MYOC mutations alone cannot be used to accurately predict age at glaucoma diagnosis. However, it might be an important prognostic factor combined with other clinical factors for critical and early detection of glaucoma. Full article
(This article belongs to the Special Issue Insights into Heritability of Glaucoma and Other Optic Neuropathies)
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10 pages, 2146 KiB  
Case Report
WDR36-Associated Neurodegeneration: A Case Report Highlights Possible Mechanisms of Normal Tension Glaucoma
by Elana Meer, Tomas S. Aleman and Ahmara G. Ross
Genes 2021, 12(10), 1624; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101624 - 15 Oct 2021
Cited by 2 | Viewed by 1798
Abstract
WDR36 is one of a number of genes implicated in the pathogenesis of adult-onset primary open angle glaucoma (POAG). Here we describe in detail the phenotype of a patient with pathogenic variation in WDR36 who presented with a protracted history of central vision [...] Read more.
WDR36 is one of a number of genes implicated in the pathogenesis of adult-onset primary open angle glaucoma (POAG). Here we describe in detail the phenotype of a patient with pathogenic variation in WDR36 who presented with a protracted history of central vision loss. On exam visual acuities were at 20/100 level, had a tritan color defect and showed central arcuate visual field defects on visual field testing. Enlarged cup-to-disk ratios with normal intraocular pressures were associated with severe thinning of the ganglion cell layer (GCL) and retinal nerve fiber layer consistent with a clinical diagnosis of normal tension glaucoma. Full-field electroretinograms revealed a severe inner retinal dysfunction with reduced amplitudes and remarkably delayed timings of the b-wave, but preserved photoreceptor (a-wave) function. The pattern described herein recapitulates some of the findings of an animal model of WDR36-associated POAG and suggests a mechanism of disease that involves a retina-wide inner retinal dysfunction and neurodegeneration beyond the GCL. Further detailed structural and functional characterizations of patients with a pathogenic variant in the WDR36 gene are required to confirm these findings. Full article
(This article belongs to the Special Issue Insights into Heritability of Glaucoma and Other Optic Neuropathies)
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