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Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations and Inheritance...
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Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations and Inheritance Models

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 (1 October 2017) | Viewed by 95328

Special Issue Editors

Prof. Dr. Frans P.M. Cremers

E-Mail Website
Guest Editor
Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
Interests: genetics of inherited retinal dystrophies; Stargardt disease; genomics; stem cell technology; transcriptomics; non-coding variants
Prof. Dr. Camiel J.F. Boon

E-Mail Website
Co-Guest Editor
Department of Ophthalmology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands; Department of Ophthalmology, Academic Medical Center, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands
Interests: clinical and genetic characteristics of inherited retinal diseases; gene therapy; central serous chorioretinopathy; age-related macular degeneration; vitreoretinal surgery
Dr. Kinga Bujakowska

E-Mail Website
Co-Guest Editor
Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA
Interests: genetics of inherited retinal degenerations, modeling of the inherited retinal degenerations in cell, zebrafish and mouse models
Dr. Christina Zeitz

E-Mail Website
Co-Guest Editor
INSERM, CNRS, Institut de la Vision, Sorbonne Université, F-75012 Paris, France
Interests: gene identification; next generation sequencing; phenotype–genotype correlations in patients with different retinal diseases; congenital stationary night blindness; using genetics to dissect retinal signaling; decipher signaling from photoreceptors to bipolar cells; molecular biology; human genetics; functional in vitro and in vivo characterization of retinal proteins; gene therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Knowledge on the genetic defects and molecular mechanisms underlying inherited retinal diseases (IRDs) has steadily grown in the last three decades. Based on comprehensive genotyping studies (e.g., using whole-exome sequencing, WES) we can deduce that the majority of genetic defects can be found in the currently identified ~150 genes implicated in non-syndromic IRDs. The downside of this huge genetic heterogeneity is that we are now facing new challenges to identify the remaining genetic causes. An increasing number of candidate IRD genes is being identified which are mutated in a single patient or family. Due to the large genetic heterogeneity in IRDs, a significant proportion of healthy individuals and IRD cases carry heterozygous variants in one or a few IRD-associated genes. This could be coincidental findings, but also may mean that we are missing ‘second alleles’ because of their location outside the coding segments that are not analyzed using WES. We are beginning to understand the complex interplay between variants in different IRD genes and still need to investigate the nature of modifiers in IRD-associated genes and in other genes, and how they influence the clinical characteristics in patients. Importantly, knowing the genetic defects and molecular mechanisms of disease is not only important for accurate genetic counseling and disease prognosis, but also is necessary to select patients for gradually emerging therapies, many of which are based on knowledge of the mutated gene or genetic variant(s).This issue is not meant to include papers on multifactorial eye diseases, such as age-related macular degeneration, glaucoma or myopia, unless they deal with familial forms of these macular degeneration or glaucoma. We also do not invite paper submissions on therapeutics of IRDs.

Prof. Dr. Frans P.M. Cremers
Guest Editor

Prof. Dr. Camiel J.F. Boon
Dr. Kinga Bujakowska
Dr. Christina Zeitz
Co-Guest Editors

Manuscript Submission Information

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Keywords

  • Retina
  • Genetics
  • Ophthalmology
  • Retinitis pigmentosa
  • Modifiers
  • Genomics
  • Digenic inheritance

Published Papers (17 papers)

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Editorial

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10 pages, 498 KiB  
Editorial
Special Issue Introduction: Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations, and Inheritance Models
by Frans P. M. Cremers, Camiel J. F. Boon, Kinga Bujakowska and Christina Zeitz
Genes 2018, 9(4), 215; https://0-doi-org.brum.beds.ac.uk/10.3390/genes9040215 - 16 Apr 2018
Cited by 57 | Viewed by 7734
Abstract
Inherited retinal diseases (IRDs) are genetically and clinically heterogeneous disorders.[...] Full article
(This article belongs to the Special Issue Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations and Inheritance Models)
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Research

Jump to: Editorial, Other

10 pages, 3809 KiB  
Article
Autosomal Recessive NRL Mutations in Patients with Enhanced S-Cone Syndrome
by Karin W. Littink, Patricia T. Y. Stappers, Frans C. C. Riemslag, Herman E. Talsma, Maria M. Van Genderen, Frans P. M. Cremers, Rob W. J. Collin and L. Ingeborgh Van den Born
Genes 2018, 9(2), 68; https://0-doi-org.brum.beds.ac.uk/10.3390/genes9020068 - 30 Jan 2018
Cited by 31 | Viewed by 4719 | Correction
Abstract
Enhanced S-cone syndrome (ESCS) is mainly associated with mutations in the NR2E3 gene. However, rare mutations in the NRL gene have been reported in patients with ESCS. We report on an ESCS phenotype in additional patients with autosomal recessive NRL (arNRL) [...] Read more.
Enhanced S-cone syndrome (ESCS) is mainly associated with mutations in the NR2E3 gene. However, rare mutations in the NRL gene have been reported in patients with ESCS. We report on an ESCS phenotype in additional patients with autosomal recessive NRL (arNRL) mutations. Three Moroccan patients of two different families with arNRL mutations were enrolled in this study. The mutation in the DNA of one patient, from a consanguineous marriage, was detected by homozygosity mapping. The mutation in the DNA of two siblings from a second family was detected in a targeted next-generation sequencing project. Full ophthalmic examination was performed, including best-corrected visual acuity, slit-lamp biomicroscopy, funduscopy, Goldmann kinetic perimetry, optical coherence tomography, fundus autofluorescence, and extended electroretinography including an amber stimulus on a blue background and a blue stimulus on an amber background. One patient carried a homozygous missense mutation (c.508C>A; p.Arg170Ser) in the NRL gene, whereas the same mutation was identified heterozygously in the two siblings of a second family, in combination with a one base-pair deletion (c.654del; p.Cys219Valfs*4) on the other allele. All patients had reduced visual acuity and showed a typical clumped pigmentary retinal degeneration (CPRD). Foveal schisis-like changes were observed in the oldest patient. An electroretinogram (ERG) under dark-adapted conditions showed absent responses for low stimulus strengths and reduced responses for high stimulus strengths, with constant b-wave latencies despite increasing stimulus strength. A relatively high amplitude was detected with a blue stimulus on an amber background, while an amber stimulus on a blue background showed reduced responses. The arNRL mutations cause a phenotype with typical CPRD. This phenotype has previously been described in patients with ESCS caused by NR2E3 mutations, and rarely by NRL mutations. Based on our findings in ERG testing, we conclude that S-cone function is enhanced in our patients in a similar manner as in patients with NR2E3-associated ESCS, confirming previous reports of NRL as a second gene to cause ESCS. Full article
(This article belongs to the Special Issue Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations and Inheritance Models)
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16 pages, 3059 KiB  
Article
Identification of Inherited Retinal Disease-Associated Genetic Variants in 11 Candidate Genes
by Galuh D. N. Astuti, L. Ingeborgh Van den Born, M. Imran Khan, Christian P. Hamel, Béatrice Bocquet, Gaël Manes, Mathieu Quinodoz, Manir Ali, Carmel Toomes, Martin McKibbin, Mohammed E. El-Asrag, Lonneke Haer-Wigman, Chris F. Inglehearn, Graeme C. M. Black, Carel B. Hoyng, Frans P. M. Cremers and Susanne Roosing
Genes 2018, 9(1), 21; https://0-doi-org.brum.beds.ac.uk/10.3390/genes9010021 - 10 Jan 2018
Cited by 19 | Viewed by 6358
Abstract
Inherited retinal diseases (IRDs) display an enormous genetic heterogeneity. Whole exome sequencing (WES) recently identified genes that were mutated in a small proportion of IRD cases. Consequently, finding a second case or family carrying pathogenic variants in the same candidate gene often is [...] Read more.
Inherited retinal diseases (IRDs) display an enormous genetic heterogeneity. Whole exome sequencing (WES) recently identified genes that were mutated in a small proportion of IRD cases. Consequently, finding a second case or family carrying pathogenic variants in the same candidate gene often is challenging. In this study, we searched for novel candidate IRD gene-associated variants in isolated IRD families, assessed their causality, and searched for novel genotype-phenotype correlations. Whole exome sequencing was performed in 11 probands affected with IRDs. Homozygosity mapping data was available for five cases. Variants with minor allele frequencies ≤ 0.5% in public databases were selected as candidate disease-causing variants. These variants were ranked based on their: (a) presence in a gene that was previously implicated in IRD; (b) minor allele frequency in the Exome Aggregation Consortium database (ExAC); (c) in silico pathogenicity assessment using the combined annotation dependent depletion (CADD) score; and (d) interaction of the corresponding protein with known IRD-associated proteins. Twelve unique variants were found in 11 different genes in 11 IRD probands. Novel autosomal recessive and dominant inheritance patterns were found for variants in Small Nuclear Ribonucleoprotein U5 Subunit 200 (SNRNP200) and Zinc Finger Protein 513 (ZNF513), respectively. Using our pathogenicity assessment, a variant in DEAH-Box Helicase 32 (DHX32) was the top ranked novel candidate gene to be associated with IRDs, followed by eight medium and lower ranked candidate genes. The identification of candidate disease-associated sequence variants in 11 single families underscores the notion that the previously identified IRD-associated genes collectively carry > 90% of the defects implicated in IRDs. To identify multiple patients or families with variants in the same gene and thereby provide extra proof for pathogenicity, worldwide data sharing is needed. Full article
(This article belongs to the Special Issue Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations and Inheritance Models)
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5698 KiB  
Article
Molecular Screening of 43 Brazilian Families Diagnosed with Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy
by Fernanda B. O. Porto, Evan M. Jones, Justin Branch, Zachry T. Soens, Igor Mendes Maia, Isadora F. G. Sena, Shirley A. M. Sampaio, Renata T. Simões and Rui Chen
Genes 2017, 8(12), 355; https://0-doi-org.brum.beds.ac.uk/10.3390/genes8120355 - 29 Nov 2017
Cited by 19 | Viewed by 6697
Abstract
Leber congenital amaurosis (LCA) is a severe disease that leads to complete blindness in children, typically before the first year of life. Due to the clinical and genetic heterogeneity among LCA and other retinal diseases, providing patients with a molecular diagnosis is essential [...] Read more.
Leber congenital amaurosis (LCA) is a severe disease that leads to complete blindness in children, typically before the first year of life. Due to the clinical and genetic heterogeneity among LCA and other retinal diseases, providing patients with a molecular diagnosis is essential to assigning an accurate clinical diagnosis. Using our gene panel that targets 300 genes that are known to cause retinal disease, including 24 genes reported to cause LCA, we sequenced 43 unrelated probands with Brazilian ancestry. We identified 42 unique variants and were able to assign a molecular diagnosis to 30/43 (70%) Brazilian patients. Among these, 30 patients were initially diagnosed with LCA or a form of early-onset retinal dystrophy, 17 patients harbored mutations in LCA-associated genes, while 13 patients had mutations in genes that were reported to cause other diseases involving the retina. Full article
(This article belongs to the Special Issue Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations and Inheritance Models)
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3192 KiB  
Article
Target 5000: Target Capture Sequencing for Inherited Retinal Degenerations
by Adrian Dockery, Kirk Stephenson, David Keegan, Niamh Wynne, Giuliana Silvestri, Peter Humphries, Paul F. Kenna, Matthew Carrigan and G. Jane Farrar
Genes 2017, 8(11), 304; https://0-doi-org.brum.beds.ac.uk/10.3390/genes8110304 - 03 Nov 2017
Cited by 41 | Viewed by 6546
Abstract
There are an estimated 5000 people in Ireland who currently have an inherited retinal degeneration (IRD). It is the goal of this study, through genetic diagnosis, to better enable these 5000 individuals to obtain a clearer understanding of their condition and improved access [...] Read more.
There are an estimated 5000 people in Ireland who currently have an inherited retinal degeneration (IRD). It is the goal of this study, through genetic diagnosis, to better enable these 5000 individuals to obtain a clearer understanding of their condition and improved access to potentially applicable therapies. Here we show the current findings of a target capture next-generation sequencing study of over 750 patients from over 520 pedigrees currently situated in Ireland. We also demonstrate how processes can be implemented to retrospectively analyse patient datasets for the detection of structural variants in previously obtained sequencing reads. Pathogenic or likely pathogenic mutations were detected in 68% of pedigrees tested. We report nearly 30 novel mutations including three large structural variants. The population statistics related to our findings are presented by condition and credited to their respective candidate gene mutations. Rediagnosis rates of clinical phenotypes after genotyping are discussed. Possible causes of failure to detect a candidate mutation are evaluated. Future elements of this project, with a specific emphasis on structural variants and non-coding pathogenic variants, are expected to increase detection rates further and thereby produce an even more comprehensive representation of the genetic landscape of IRDs in Ireland. Full article
(This article belongs to the Special Issue Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations and Inheritance Models)
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2100 KiB  
Communication
Allelic Expression Imbalance in the Human Retinal Transcriptome and Potential Impact on Inherited Retinal Diseases
by Pablo Llavona, Michele Pinelli, Margherita Mutarelli, Veer Singh Marwah, Simone Schimpf-Linzenbold, Sebastian Thaler, Efdal Yoeruek, Jan Vetter, Susanne Kohl and Bernd Wissinger
Genes 2017, 8(10), 283; https://0-doi-org.brum.beds.ac.uk/10.3390/genes8100283 - 20 Oct 2017
Cited by 16 | Viewed by 5271
Abstract
Inherited retinal diseases (IRDs) are often associated with variable clinical expressivity (VE) and incomplete penetrance (IP). Underlying mechanisms may include environmental, epigenetic, and genetic factors. Cis-acting expression quantitative trait loci (cis-eQTLs) can be implicated in the regulation of genes by [...] Read more.
Inherited retinal diseases (IRDs) are often associated with variable clinical expressivity (VE) and incomplete penetrance (IP). Underlying mechanisms may include environmental, epigenetic, and genetic factors. Cis-acting expression quantitative trait loci (cis-eQTLs) can be implicated in the regulation of genes by favoring or hampering the expression of one allele over the other. Thus, the presence of such loci elicits allelic expression imbalance (AEI) that can be traced by massive parallel sequencing techniques. In this study, we performed an AEI analysis on RNA-sequencing (RNA-seq) data, from 52 healthy retina donors, that identified 194 imbalanced single nucleotide polymorphisms(SNPs) in 67 IRD genes. Focusing on SNPs displaying AEI at a frequency higher than 10%, we found evidence of AEI in several IRD genes regularly associated with IP and VE (BEST1, RP1, PROM1, and PRPH2). Based on these SNPs commonly undergoing AEI, we performed pyrosequencing in an independent sample set of 17 healthy retina donors in order to confirm our findings. Indeed, we were able to validate CDHR1, BEST1, and PROM1 to be subjected to cis-acting regulation. With this work, we aim to shed light on differentially expressed alleles in the human retina transcriptome that, in the context of autosomal dominant IRD cases, could help to explain IP or VE. Full article
(This article belongs to the Special Issue Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations and Inheritance Models)
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3265 KiB  
Article
Clinical and Genetic Evaluation of a Cohort of Pediatric Patients with Severe Inherited Retinal Dystrophies
by Valentina Di Iorio, Marianthi Karali, Raffaella Brunetti-Pierri, Mariaelena Filippelli, Giuseppina Di Fruscio, Mariateresa Pizzo, Margherita Mutarelli, Vincenzo Nigro, Francesco Testa, Sandro Banfi and Francesca Simonelli
Genes 2017, 8(10), 280; https://0-doi-org.brum.beds.ac.uk/10.3390/genes8100280 - 20 Oct 2017
Cited by 22 | Viewed by 5137
Abstract
We performed a clinical and genetic characterization of a pediatric cohort of patients with inherited retinal dystrophy (IRD) to identify the most suitable cases for gene therapy. The cohort comprised 43 patients, aged between 2 and 18 years, with severe isolated IRD at [...] Read more.
We performed a clinical and genetic characterization of a pediatric cohort of patients with inherited retinal dystrophy (IRD) to identify the most suitable cases for gene therapy. The cohort comprised 43 patients, aged between 2 and 18 years, with severe isolated IRD at the time of presentation. The ophthalmological characterization also included assessment of the photoreceptor layer integrity in the macular region (ellipsoid zone (EZ) band). In parallel, we carried out a targeted, next-generation sequencing (NGS)-based analysis using a panel that covers over 150 genes with either an established or a candidate role in IRD pathogenesis. Based on the ophthalmological assessment, the cohort was composed of 24 Leber congenital amaurosis, 14 early onset retinitis pigmentosa, and 5 achromatopsia patients. We identified causative mutations in 58.1% of the cases. We also found novel genotype-phenotype correlations in patients harboring mutations in the CEP290 and CNGB3 genes. The EZ band was detectable in 40% of the analyzed cases, also in patients with genotypes usually associated with severe clinical manifestations. This study provides the first detailed clinical-genetic assessment of severe IRDs with infantile onset and lays the foundation of a standardized protocol for the selection of patients that are more likely to benefit from gene replacement therapeutic approaches. Full article
(This article belongs to the Special Issue Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations and Inheritance Models)
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7677 KiB  
Article
Further Insights into the Ciliary Gene and Protein KIZ and Its Murine Ortholog PLK1S1 Mutated in Rod-Cone Dystrophy
by Said El Shamieh, Cécile Méjécase, Matteo Bertelli, Angélique Terray, Christelle Michiels, Christel Condroyer, Stéphane Fouquet, Maxime Sadoun, Emmanuelle Clérin, Binqian Liu, Thierry Léveillard, Olivier Goureau, José-Alain Sahel, Isabelle Audo and Christina Zeitz
Genes 2017, 8(10), 277; https://0-doi-org.brum.beds.ac.uk/10.3390/genes8100277 - 18 Oct 2017
Cited by 7 | Viewed by 4706
Abstract
We identified herein additional patients with rod-cone dystrophy (RCD) displaying mutations in KIZ, encoding the ciliary centrosomal protein kizuna and performed functional characterization of the respective protein in human fibroblasts and of its mouse ortholog PLK1S1 in the retina. Mutation screening was [...] Read more.
We identified herein additional patients with rod-cone dystrophy (RCD) displaying mutations in KIZ, encoding the ciliary centrosomal protein kizuna and performed functional characterization of the respective protein in human fibroblasts and of its mouse ortholog PLK1S1 in the retina. Mutation screening was done by targeted next generation sequencing and subsequent Sanger sequencing validation. KIZ mRNA levels were assessed on blood and serum-deprived human fibroblasts from a control individual and a patient, compound heterozygous for the c.52G>T (p.Glu18*) and c.119_122del (p.Lys40Ilefs*14) mutations in KIZ. KIZ localization, documentation of cilium length and immunoblotting were performed in these two fibroblast cell lines. In addition, PLK1S1 immunolocalization was conducted in mouse retinal cryosections and isolated rod photoreceptors. Analyses of additional RCD patients enabled the identification of two homozygous mutations in KIZ, the known c.226C>T (p.Arg76*) mutation and a novel variant, the c.3G>A (p.Met1?) mutation. Albeit the expression levels of KIZ were three-times lower in the patient than controls in whole blood cells, further analyses in control- and mutant KIZ patient-derived fibroblasts unexpectedly revealed no significant difference between the two genotypes. Furthermore, the averaged monocilia length in the two fibroblast cell lines was similar, consistent with the preserved immunolocalization of KIZ at the basal body of the primary cilia. Analyses in mouse retina and isolated rod photoreceptors showed PLK1S1 localization at the base of the photoreceptor connecting cilium. In conclusion, two additional patients with mutations in KIZ were identified, further supporting that defects in KIZ/PLK1S1, detected at the basal body of the primary cilia in fibroblasts, and the photoreceptor connecting cilium in mouse, respectively, are involved in RCD. However, albeit the mutations were predicted to lead to nonsense mediated mRNA decay, we could not detect changes upon expression levels, protein localization or cilia length in KIZ-mutated fibroblast cells. Together, our findings unveil the limitations of fibroblasts as a cellular model for RCD and call for other models such as induced pluripotent stem cells to shed light on retinal pathogenic mechanisms of KIZ mutations. Full article
(This article belongs to the Special Issue Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations and Inheritance Models)
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5119 KiB  
Article
The Genetic Basis of Pericentral Retinitis Pigmentosa—A Form of Mild Retinitis Pigmentosa
by Jason Comander, Carol Weigel-DiFranco, Matthew Maher, Emily Place, Aliete Wan, Shyana Harper, Michael A. Sandberg, Daniel Navarro-Gomez and Eric A. Pierce
Genes 2017, 8(10), 256; https://0-doi-org.brum.beds.ac.uk/10.3390/genes8100256 - 05 Oct 2017
Cited by 31 | Viewed by 7588
Abstract
Pericentral retinitis pigmentosa (RP) is an atypical form of RP that affects the near-peripheral retina first and tends to spare the far periphery. This study was performed to further define the genetic basis of this phenotype. We identified a cohort of 43 probands [...] Read more.
Pericentral retinitis pigmentosa (RP) is an atypical form of RP that affects the near-peripheral retina first and tends to spare the far periphery. This study was performed to further define the genetic basis of this phenotype. We identified a cohort of 43 probands with pericentral RP based on a comprehensive analysis of their retinal phenotype. Genetic analyses of DNA samples from these patients were performed using panel-based next-generation sequencing, copy number variations, and whole exome sequencing (WES). Mutations provisionally responsible for disease were found in 19 of the 43 families (44%) analyzed. These include mutations in RHO (five patients), USH2A (four patients), and PDE6B (two patients). Of 28 putatively pathogenic alleles, 15 (54%) have been previously identified in patients with more common forms of typical RP, while the remaining 13 mutations (46%) were novel. Burden testing of WES data successfully identified HGSNAT as a cause of pericentral RP in at least two patients, suggesting it is also a relatively common cause of pericentral RP. While additional sequencing might uncover new genes specifically associated with pericentral RP, the current results suggest that genetically pericentral RP is not a separate clinical entity, but rather is part of the spectrum of mild RP phenotypes. Full article
(This article belongs to the Special Issue Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations and Inheritance Models)
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4189 KiB  
Article
Whole Genome Sequencing Revealed Mutations in Two Independent Genes as the Underlying Cause of Retinal Degeneration in an Ashkenazi Jewish Pedigree
by Kevin Gustafson, Jacque L. Duncan, Pooja Biswas, Angel Soto-Hermida, Hiroko Matsui, David Jakubosky, John Suk, Amalio Telenti, Kelly A. Frazer and Radha Ayyagari
Genes 2017, 8(9), 210; https://0-doi-org.brum.beds.ac.uk/10.3390/genes8090210 - 24 Aug 2017
Cited by 13 | Viewed by 4909 | Correction
Abstract
Retinitis pigmentosa (RP) causes progressive photoreceptor loss resulting from mutations in over 80 genes. This study identified the genetic cause of RP in three members of a non-consanguineous pedigree. Detailed ophthalmic evaluation was performed in the three affected family members. Whole exome sequencing [...] Read more.
Retinitis pigmentosa (RP) causes progressive photoreceptor loss resulting from mutations in over 80 genes. This study identified the genetic cause of RP in three members of a non-consanguineous pedigree. Detailed ophthalmic evaluation was performed in the three affected family members. Whole exome sequencing (WES) and whole genome sequencing (WGS) were performed in the three affected and the two unaffected family members and variants were filtered to detect rare, potentially deleterious variants segregating with disease. WES and WGS did not identify potentially pathogenic variants shared by all three affected members. However, WES identified a previously reported homozygous nonsense mutation in KIZ (c.226C>T, p.Arg76*) in two affected sisters, but not in their affected second cousin. WGS revealed a novel 1.135 kb homozygous deletion in a retina transcript of C21orf2 and a novel 30.651 kb heterozygous deletion in CACNA2D4 in the affected second cousin. The sisters with the KIZ mutation carried no copies of the C21orf2 or CACNA2D4 deletions, while the second cousin with the C21orf2 and CACNA2D4 deletions carried no copies of the KIZ mutation. This study identified two independent, homozygous mutations in genes previously reported in autosomal recessive RP in a non-consanguineous family, and demonstrated the value of WGS when WES fails to identify likely disease-causing mutations. Full article
(This article belongs to the Special Issue Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations and Inheritance Models)
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2700 KiB  
Article
A Rare Form of Retinal Dystrophy Caused by Hypomorphic Nonsense Mutations in CEP290
by Susanne Roosing, Frans P. M. Cremers, Frans C. C. Riemslag, Marijke N. Zonneveld-Vrieling, Herman E. Talsma, Francoise J. M. Klessens-Godfroy, Anneke I. Den Hollander and L. Ingeborgh Van den Born
Genes 2017, 8(8), 208; https://0-doi-org.brum.beds.ac.uk/10.3390/genes8080208 - 22 Aug 2017
Cited by 22 | Viewed by 4752
Abstract
Purpose: To identify the gene defect and to study the clinical characteristics and natural course of disease in a family originally diagnosed with oligocone trichromacy (OT), a rare congenital cone dysfunction syndrome. Methods: Extensive clinical and ophthalmologic assessment was performed on two siblings [...] Read more.
Purpose: To identify the gene defect and to study the clinical characteristics and natural course of disease in a family originally diagnosed with oligocone trichromacy (OT), a rare congenital cone dysfunction syndrome. Methods: Extensive clinical and ophthalmologic assessment was performed on two siblings with OT and long-term follow up data were analyzed. Subsequently, whole exome sequencing (WES) and Sanger sequence analysis of CEP290 was performed in the two siblings. Additionally, the identified CEP290 mutations were analyzed in persons with achromatopsia (ACHM) (n = 23) and autosomal recessive or isolated cone dystrophy (CD; n = 145). Results: In the first decade of life, the siblings were diagnosed with OT based on low visual acuity, photophobia, nystagmus, and absent cone response on electroretinography , but with normal color discrimination. Over time, the phenotype of OT evolved to a progressive degenerative disease without any CEP290-associated non-ocular features. In both siblings, two nonsense mutations (c.451C>T; p.(Arg151*) and c.4723A>T; p.(Lys1575*)) in CEP290 were found. Previously, p.(Arg151*) was demonstrated to induce nonsense-mediated alternative splicing events leading to intact open reading frames of the resulting mRNA products (p.(Leu148_Glu165del) and p.(Leu148_Lys172del)). mRNA analysis for p.(Lys1575*) confirmed a suspected hypomorphic character, as exon 36 skipping was observed in a small fraction of CEP290 mRNA, resulting in a 36 aa in-frame deletion (p.(Glu1569_Trp1604del)). No additional cases carrying these variants were identified in the ACHM and CD cohorts. Conclusions: Compound heterozygous hypomorphic mutations in CEP290 may lead to a rare form of cone-dominated retinal dystrophy, a novel phenotype belonging to the CEP290-associated spectrum of ciliopathies. These findings provide insight into the effect of CEP290 mutations on the clinical phenotype. Full article
(This article belongs to the Special Issue Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations and Inheritance Models)
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7148 KiB  
Article
EYS Mutations Causing Autosomal Recessive Retinitis Pigmentosa: Changes of Retinal Structure and Function with Disease Progression
by David B. McGuigan, Elise Heon, Artur V. Cideciyan, Rinki Ratnapriya, Monica Lu, Alexander Sumaroka, Alejandro J. Roman, Vaishnavi Batmanabane, Alexandra V. Garafalo, Edwin M. Stone, Anand Swaroop and Samuel G. Jacobson
Genes 2017, 8(7), 178; https://0-doi-org.brum.beds.ac.uk/10.3390/genes8070178 - 12 Jul 2017
Cited by 33 | Viewed by 7273
Abstract
Mutations in the EYS (eyes shut homolog) gene are a common cause of autosomal recessive (ar) retinitis pigmentosa (RP). Without a mammalian model of human EYS disease, there is limited understanding of details of disease expression and rates of progression of the retinal [...] Read more.
Mutations in the EYS (eyes shut homolog) gene are a common cause of autosomal recessive (ar) retinitis pigmentosa (RP). Without a mammalian model of human EYS disease, there is limited understanding of details of disease expression and rates of progression of the retinal degeneration. We studied clinically and with chromatic static perimetry, spectral-domain optical coherence tomography (OCT), and en face autofluoresence imaging, a cohort of 15 patients (ages 12–51 at first visit), some of whom had longitudinal data of function and structure. Rod sensitivity was able to be measured by chromatic perimetry in most patients at their earliest visits and some patients retained patchy rod function into the fifth decade of life. As expected from RP, cone sensitivity persisted after rod function was no longer measurable. The photoreceptor nuclear layer of the central retina was abnormal except at the fovea in most patients at first visit. Perifoveal disease measured over a period of years indicated that photoreceptor structural loss was followed by dysmorphology of the inner retina and loss of retinal pigment epithelial integrity. Although there could be variability in severity, preliminary analyses of the rates of vision loss suggested that EYS is a more rapidly progressive disease than other ciliopathies causing arRP, such as USH2A and MAK. Full article
(This article belongs to the Special Issue Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations and Inheritance Models)
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Article
Mutations in the Genes for Interphotoreceptor Matrix Proteoglycans, IMPG1 and IMPG2, in Patients with Vitelliform Macular Lesions
by Caroline Brandl, Heidi L. Schulz, Peter Charbel Issa, Johannes Birtel, Richard Bergholz, Clemens Lange, Claudia Dahlke, Ditta Zobor, Bernhard H. F. Weber and Heidi Stöhr
Genes 2017, 8(7), 170; https://0-doi-org.brum.beds.ac.uk/10.3390/genes8070170 - 23 Jun 2017
Cited by 22 | Viewed by 6395
Abstract
A significant portion of patients diagnosed with vitelliform macular dystrophy (VMD) do not carry causative mutations in the classic VMD genes BEST1 or PRPH2. We therefore performed a mutational screen in a cohort of 106 BEST1/PRPH2-negative VMD patients in two genes [...] Read more.
A significant portion of patients diagnosed with vitelliform macular dystrophy (VMD) do not carry causative mutations in the classic VMD genes BEST1 or PRPH2. We therefore performed a mutational screen in a cohort of 106 BEST1/PRPH2-negative VMD patients in two genes encoding secreted interphotoreceptor matrix proteoglycans-1 and -2 (IMPG1 and IMPG2). We identified two novel mutations in IMPG1 in two simplex VMD cases with disease onset in their early childhood, a heterozygous p.(Leu238Pro) missense mutation and a homozygous c.807 + 5G > A splice site mutation. The latter induced partial skipping of exon 7 of IMPG1 in an in vitro splicing assay. Furthermore, we found heterozygous mutations including three stop [p.(Glu226*), p.(Ser522*), p.(Gln856*)] and five missense mutations [p.(Ala243Pro), p.(Gly1008Asp), p.(Phe1016Ser), p.(Tyr1042Cys), p.(Cys1077Phe)] in the IMPG2 gene, one of them, p.(Cys1077Phe), previously associated with VMD. Asymptomatic carriers of the p.(Ala243Pro) and p.(Cys1077Phe) mutations show subtle foveal irregularities that could characterize a subclinical stage of disease. Taken together, our results provide further evidence for an involvement of dominant and recessive mutations in IMPG1 and IMPG2 in VMD pathology. There is a remarkable similarity in the clinical appearance of mutation carriers, presenting with bilateral, central, dome-shaped foveal accumulation of yellowish material with preserved integrity of the retinal pigment epithelium (RPE). Clinical symptoms tend to be more severe for IMPG1 mutations. Full article
(This article belongs to the Special Issue Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations and Inheritance Models)
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2 pages, 2053 KiB  
Correction
Correction: Littink, K. W.; et al. Autosomal Recessive NRL Mutations in Patients with Enhanced S-Cone Syndrome. Genes 2018, 9, 68
by Karin W. Littink, Patricia T.Y. Stappers, Frans C.C. Riemslag, Herman E. Talsma, Maria M. Van Genderen, Frans P.M. Cremers, Rob W.J. Collin and L. Ingeborgh Van den Born
Genes 2018, 9(3), 145; https://0-doi-org.brum.beds.ac.uk/10.3390/genes9030145 - 07 Mar 2018
Cited by 9 | Viewed by 2891
Abstract
The authors wish to make the following correction to this paper [1]. [...] Full article
(This article belongs to the Special Issue Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations and Inheritance Models)
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1335 KiB  
Case Report
An Expanded Multi-Organ Disease Phenotype Associated with Mutations in YARS
by Anna Tracewska-Siemiątkowska, Lonneke Haer-Wigman, Danielle G. M. Bosch, Deborah Nickerson, Michael J. Bamshad, University of Washington Center for Mendelian Genomics, Maartje Van de Vorst, Nanna Dahl Rendtorff, Claes Möller, Ulrika Kjellström, Sten Andréasson, Frans P. M. Cremers and Lisbeth Tranebjærg
Genes 2017, 8(12), 381; https://0-doi-org.brum.beds.ac.uk/10.3390/genes8120381 - 11 Dec 2017
Cited by 20 | Viewed by 5405
Abstract
Whole exome sequence analysis was performed in a Swedish mother–father-affected proband trio with a phenotype characterized by progressive retinal degeneration with congenital nystagmus, profound congenital hearing impairment, primary amenorrhea, agenesis of the corpus callosum, and liver disease. A homozygous variant c.806T > C, [...] Read more.
Whole exome sequence analysis was performed in a Swedish mother–father-affected proband trio with a phenotype characterized by progressive retinal degeneration with congenital nystagmus, profound congenital hearing impairment, primary amenorrhea, agenesis of the corpus callosum, and liver disease. A homozygous variant c.806T > C, p.(F269S) in the tyrosyl-tRNA synthetase gene (YARS) was the only identified candidate variant consistent with autosomal recessive inheritance. Mutations in YARS have previously been associated with both autosomal dominant Charcot-Marie-Tooth syndrome and a recently reported autosomal recessive multiorgan disease. Herein, we propose that mutations in YARS underlie another clinical phenotype adding a second variant of the disease, including retinitis pigmentosa and deafness, to the spectrum of YARS-associated disorders. Full article
(This article belongs to the Special Issue Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations and Inheritance Models)
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Graphical abstract

333 KiB  
Correction
Correction: Gustafson et al., Whole Genome Sequencing Revealed Mutations in Two Independent Genes as the Underlying Cause of Retinal Degeneration in an Ashkenazi Jewish Pedigree. Genes 2017, 8, 210
by Kevin Gustafson, Jacque L. Duncan, Pooja Biswas, Angel Soto-Hermida, Hiroko Matsui, David Jakubosky, John Suk, Amalio Telenti, Kelly A. Frazer and Radha Ayyagari
Genes 2017, 8(10), 286; https://0-doi-org.brum.beds.ac.uk/10.3390/genes8100286 - 23 Oct 2017
Cited by 3 | Viewed by 3539
Abstract
Following publication of our article [1], we identified discrepancies between the pedigree shown in Figure 1 and the rest of the text.[...] Full article
(This article belongs to the Special Issue Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations and Inheritance Models)
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1438 KiB  
Case Report
Outcome of Full-Thickness Macular Hole Surgery in Choroideremia
by Mays Talib, Leonoor S. Koetsier, Robert E. MacLaren and Camiel J.F. Boon
Genes 2017, 8(7), 187; https://0-doi-org.brum.beds.ac.uk/10.3390/genes8070187 - 21 Jul 2017
Cited by 7 | Viewed by 3883
Abstract
The development of a macular hole is relatively common in retinal dystrophies eligible for gene therapy such as choroideremia. However, the subretinal delivery of gene therapy requires an uninterrupted retina to allow dispersion of the viral vector. A macular hole may thus hinder [...] Read more.
The development of a macular hole is relatively common in retinal dystrophies eligible for gene therapy such as choroideremia. However, the subretinal delivery of gene therapy requires an uninterrupted retina to allow dispersion of the viral vector. A macular hole may thus hinder effective gene therapy. Little is known about the outcome of macular hole surgery and its possible beneficial and/or adverse effects on retinal function in patients with choroideremia. We describe a case of a unilateral full-thickness macular hole (FTMH) in a 45year-old choroideremia patient (c.1349_1349+2dup mutation in CHM gene) and its management. Pars plana vitrectomy with internal limiting membrane (ILM) peeling and 20% SF6 gas tamponade was performed, and subsequent FTMH closure was confirmed at 4 weeks, 3 months and 5 months postoperatively. No postoperative adverse events occurred, and fixation stability improved on microperimetry from respectively 11% and 44% of fixation points located within a 1° and 2° radius, preoperatively, to 94% and 100% postoperatively. This case underlines that pars plana vitrectomy with ILM peeling and gas tamponade can successfully close a FTMH in choroideremia patients, with subsequent structural and functional improvement. Macular hole closure may be important for patients to be eligible for future submacular gene therapy. Full article
(This article belongs to the Special Issue Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations and Inheritance Models)
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