Special Issue "Genetics in Inherited Retinal Diseases"

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

Deadline for manuscript submissions: 20 October 2021.

Special Issue Editors

Prof. Dr. M. Dominik Fischer
E-Mail Website
Guest Editor
1. Oxford Eye Hospital, Oxford University Hospital NHS Foundation Trust, Oxford, UK
2. Nuffield Laboratory of Ophthalmology, NDCN, University of Oxford, Oxford, UK
Interests: gene therapy; vitreoretinal surgery; genetics; retina
Prof. Dr. Susan Downes
E-Mail Website
Co-Guest Editor
1. Oxford Eye Hospital, Oxford University Hospital NHS Foundation Trust, Oxford, UK
2. Nuffield Laboratory of Ophthalmology, NDCN, University of Oxford, Oxford, UK
Interests: genetics; medical retina; AMD; retina

Special Issue Information

Dear Colleagues,

With the first approved gene therapy for an inherited retinal disease (IRD), the genetics underlying these blinding conditions have received considerable attention. Together with technological advances, this new focus helps to gain momentum towards improved access to molecular genetic diagnostics and further academic work on existing knowledge gaps.

This Special Issue aims to provide a snapshot of some of the current IRDs in focus of translational efforts. Contributions might shed light on the genetic heterogeneity of mutations found in a specific disease gene, explore genotype-phenotype correlations, characterise model systems reflecting the genetic pathology, diagnostic biomarkers, pathophysiological mechanisms, and novel therapeutic approaches. To progress in the knowledge of such intricate issues, contributions by experts in the field in the form of research papers and critical reviews are called for.

Prof. Dr. M. Dominik Fischer
Prof. Dr. Susan Downes
Guest Editors

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 papers will be 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 2000 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

  • inherited retinal diseases
  • retina
  • genetics
  • genetic therapies

Published Papers (4 papers)

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Research

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Article
High-Throughput Sequencing to Identify Mutations Associated with Retinal Dystrophies
Genes 2021, 12(8), 1269; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081269 - 20 Aug 2021
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Abstract
Retinal dystrophies (RD) are clinically and genetically heterogenous disorders showing mutations in over 270 disease-associated genes. Several millions of people worldwide are affected with different types of RD. Studying the relevance of disease-associated sequence alterations will assist in understanding disorders and may lead [...] Read more.
Retinal dystrophies (RD) are clinically and genetically heterogenous disorders showing mutations in over 270 disease-associated genes. Several millions of people worldwide are affected with different types of RD. Studying the relevance of disease-associated sequence alterations will assist in understanding disorders and may lead to the development of therapeutic approaches. Here, we established a whole exome sequencing (WES) pipeline to rapidly identify disease-associated mutations in patients. Sanger sequencing was applied to identify deep-intronic variants and to verify the co-segregation of WES results within families. We analyzed 26 unrelated patients with different syndromic and non-syndromic clinical manifestations of RD. All patients underwent ophthalmic examinations. We identified nine novel disease-associated sequence variants among 37 variants identified in total. The sequence variants located to 17 different genes. Interestingly, two cases presenting with Stargardt disease carried deep-intronic variants in ABCA4. We have classified 21 variants as pathogenic variants, 4 as benign/likely benign variants, and 12 as variants of uncertain significance. This study highlights the importance of WES-based mutation analyses in RD patients supporting clinical decisions, broadly based genetic diagnosis and support genetic counselling. It is essential for any genetic therapy to expand the mutation spectrum, understand the genes’ function, and correlate phenotypes with genotypes. Full article
(This article belongs to the Special Issue Genetics in Inherited Retinal Diseases)
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Article
Molecular Characterization of Choroideremia-Associated Deletions Reveals an Unexpected Regulation of CHM Gene Transcription
Genes 2021, 12(8), 1111; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081111 - 22 Jul 2021
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Abstract
Choroideremia (CHM) is a X-linked recessive chorioretinal dystrophy due to deficiency of the CHM gene product, i.e., Rab escort protein isoform 1 (REP1). To date, gene therapy for CHM has shown variable effectiveness, likely because the underlying pathogenic mechanisms as well as genotype-phenotype [...] Read more.
Choroideremia (CHM) is a X-linked recessive chorioretinal dystrophy due to deficiency of the CHM gene product, i.e., Rab escort protein isoform 1 (REP1). To date, gene therapy for CHM has shown variable effectiveness, likely because the underlying pathogenic mechanisms as well as genotype-phenotype correlation are not yet fully known. Small nucleotide variants leading to premature termination codons (PTCs) are a major cause of CHM, but about 20% of patients has CHM gene deletions. To improve understanding of the disease mechanisms, we analyzed molecular features of seven deletions involving the CHM gene sequence. We mapped the deletion breakpoints by using polymerase chain reaction, sequencing and array comparative genomic hybridization; to identify rearrangement-promoting DNA sequences, we analyzed genomic architecture surrounding the breakpoint regions. Moreover, in some CHM patients with different mutation types, we measured transcript level of CHM and of CHML, encoding the REP2 isoform. Scattered along the whole CHM gene and in close proximity to the deletion breakpoints we found numerous repeat elements that generate a locus-specific rearrangement hot spot. Unexpectedly, patients with non-PTC variants had increased expression of the aberrant CHM mRNA; CHML expression was higher than normal in a patient lacking CHM and its putative regulatory sequences. This latest evidence suggests that mechanisms regulating CHM and CHML gene expression are worthy of further study, because their full knowledge could be also useful for developing effective therapies for this hitherto untreatable inherited retinal degeneration. Full article
(This article belongs to the Special Issue Genetics in Inherited Retinal Diseases)
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Article
Whole-Gene Deletions of FZD4 Cause Familial Exudative Vitreoretinopathy
Genes 2021, 12(7), 980; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12070980 - 27 Jun 2021
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Abstract
Familial exudative vitreoretinopathy (FEVR) is an inherited disorder characterized by abnormalities in the retinal vasculature. The FZD4 gene is associated with FEVR, but the prevalence and impact of FZD4 copy number variation (CNV) on FEVR patients are unknown. The aim of this study [...] Read more.
Familial exudative vitreoretinopathy (FEVR) is an inherited disorder characterized by abnormalities in the retinal vasculature. The FZD4 gene is associated with FEVR, but the prevalence and impact of FZD4 copy number variation (CNV) on FEVR patients are unknown. The aim of this study was to better understand the genetic features and clinical manifestations of patients with FZD4 CNVs. A total of 651 FEVR families were recruited. Families negative for mutations in FEVR-associated genes were selected for CNV analysis using SeqCNV. Semiquantitative multiplex polymerase chain reaction and multiplex ligation-dependent probe amplification were conducted to verify the CNVs. Four probands were found to carry whole-gene deletions of FZD4, accounting for 5% (4/80) of probands with FZD4 mutations and 0.6% (4/651) of all FEVR probands. The four probands exhibited similar phenotypes of unilateral retinal folds. FEVR in probands with CNVs was not more severe than in probands with FZD4 missense mutations (p = 1.000). Although this is the first report of FZD4 CNVs and the associated phenotypes, the interpretation of FZD4 CNVs should be emphasized when analyzing the next-generation sequencing data of FEVR patients because of their high prevalence. Full article
(This article belongs to the Special Issue Genetics in Inherited Retinal Diseases)
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Review

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Review
An Overview of the Genetics of ABCA4 Retinopathies, an Evolving Story
Genes 2021, 12(8), 1241; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081241 - 13 Aug 2021
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Abstract
Stargardt disease (STGD1) and ABCA4 retinopathies (ABCA4R) are caused by pathogenic variants in the ABCA4 gene inherited in an autosomal recessive manner. The gene encodes an importer flippase protein that prevents the build-up of vitamin A derivatives that are toxic to the RPE. [...] Read more.
Stargardt disease (STGD1) and ABCA4 retinopathies (ABCA4R) are caused by pathogenic variants in the ABCA4 gene inherited in an autosomal recessive manner. The gene encodes an importer flippase protein that prevents the build-up of vitamin A derivatives that are toxic to the RPE. Diagnosing ABCA4R is complex due to its phenotypic variability and the presence of other inherited retinal dystrophy phenocopies. ABCA4 is a large gene, comprising 50 exons; to date > 2000 variants have been described. These include missense, nonsense, splicing, structural, and deep intronic variants. Missense variants account for the majority of variants in ABCA4. However, in a significant proportion of patients with an ABCA4R phenotype, a second variant in ABCA4 is not identified. This could be due to the presence of yet unknown variants, or hypomorphic alleles being incorrectly classified as benign, or the possibility that the disease is caused by a variant in another gene. This underlines the importance of accurate genetic testing. The pathogenicity of novel variants can be predicted using in silico programs, but these rely on databases that are not ethnically diverse, thus highlighting the need for studies in differing populations. Functional studies in vitro are useful towards assessing protein function but do not directly measure the flippase activity. Obtaining an accurate molecular diagnosis is becoming increasingly more important as targeted therapeutic options become available; these include pharmacological, gene-based, and cell replacement-based therapies. The aim of this review is to provide an update on the current status of genotyping in ABCA4 and the status of the therapeutic approaches being investigated. Full article
(This article belongs to the Special Issue Genetics in Inherited Retinal Diseases)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

1.title: Clinical and genetic study of X-linked juvenile retinoschisis in the  Czech population

abstract: Purpose: To identify RS1 pathogenic variants in Czech patients with X-linked retinoschisis (XLRS) and to describe the associated phenotypes including natural history in some cases.
Methods: 21 affected males from 17 families were included in the study. The coding region of the RS1 gene was directly sequenced and segregation of the identified mutations was performed in available family members. All patients underwent ophthalmic evaluation, including spectral domain optical coherence tomography (SD-OCT). One patient had optical coherence tomography angiography (OCTA ).
Results: In total, 12 disease-causing variants  within RS1 were identified, of these c.20del, c.275G>A, c.[375_379del;386A>T], c.539C>A, c.575_576insT were novel, all predicted to be null alleles. The c.539C>A mutation occurred de novo. Three patients (aged 8, 11 and 19 years) were misdiagnosed as having intermediate uveitis and treated with systemic steroids. Repeated SD-OCT examinations documented in four eyes transition from cystoid macular lesions to macular atrophy in their fourth decade of life. Three individuals were treated with topical dorzolamide and in two of them complete diminishing of cystic macular lesions bilaterally was achieved after 3 months of administration, while one patient was noncompliant. Rebound phenomenon after discontinuation of dorzolamide for 7 days was documented in one patient. OCTA confirmed vascular abnormalities in the deep capillary plexus and widening of foveal avascular zone.
Conclusions: The first study reporting on XLRS in the Czech population further expands the spectrum of RS1 pathogenic variants. Misdiagnosis of XLRS for uveitis is not uncommon therefore identification of disease-causing mutations is of great benefit to the affected individuals.

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