Special Issue "Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations and Inheritance Models"

A special issue of Genes (ISSN 2073-4425).

Deadline for manuscript submissions: closed (1 October 2017)

Special Issue Editors

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

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
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Interests: genetics of inherited retinal dystrophies; Stargardt disease; genomics; stem cell technology; transcriptomics; non-coding variants
Co-Guest Editor
Prof. Dr. Camiel J.F. Boon

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
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Interests: clinical and genetic characteristics of inherited retinal diseases; gene therapy; central serous chorioretinopathy; age-related macular degeneration; vitreoretinal surgery
Co-Guest Editor
Dr. Kinga Bujakowska

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

INSERM, UMR_S968, CNRS, UMR_7210, Université Pierre et Marie Curie Paris 6 Institut de la Vision, Department of Genetics, 17, rue Moreau, 75012 Paris, France
Website | E-Mail
Interests: Gene defect identification underlying progressive and non progressive retinal disorders, prevalence studies, prepare patients for therapeutic trials, in vitro and in vivo functional analysis of novel gene defects, gene therapies, decipher retinal signaling

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

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Keywords

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

Published Papers (10 papers)

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Open AccessArticle Clinical and Genetic Evaluation of a Cohort of Pediatric Patients with Severe Inherited Retinal Dystrophies
Genes 2017, 8(10), 280; doi:10.3390/genes8100280
Received: 29 June 2017 / Revised: 2 October 2017 / Accepted: 13 October 2017 / Published: 20 October 2017
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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
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Open AccessCommunication Allelic Expression Imbalance in the Human Retinal Transcriptome and Potential Impact on Inherited Retinal Diseases
Genes 2017, 8(10), 283; doi:10.3390/genes8100283
Received: 30 June 2017 / Revised: 11 October 2017 / Accepted: 16 October 2017 / Published: 20 October 2017
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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
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Open AccessArticle Further Insights into the Ciliary Gene and Protein KIZ and Its Murine Ortholog PLK1S1 Mutated in Rod-Cone Dystrophy
Genes 2017, 8(10), 277; doi:10.3390/genes8100277
Received: 28 July 2017 / Revised: 4 October 2017 / Accepted: 6 October 2017 / Published: 18 October 2017
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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
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Open AccessArticle The Genetic Basis of Pericentral Retinitis Pigmentosa—A Form of Mild Retinitis Pigmentosa
Genes 2017, 8(10), 256; doi:10.3390/genes8100256
Received: 11 July 2017 / Revised: 6 September 2017 / Accepted: 19 September 2017 / Published: 5 October 2017
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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
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Open AccessArticle Whole Genome Sequencing Revealed Mutations in Two Independent Genes as the Underlying Cause of Retinal Degeneration in an Ashkenazi Jewish Pedigree
Genes 2017, 8(9), 210; doi:10.3390/genes8090210
Received: 30 June 2017 / Revised: 5 August 2017 / Accepted: 18 August 2017 / Published: 24 August 2017
Cited by 1 | PDF Full-text (11353 KB) | HTML Full-text | XML Full-text | Correction | Supplementary Files
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
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Open AccessArticle A Rare Form of Retinal Dystrophy Caused by Hypomorphic Nonsense Mutations in CEP290
Genes 2017, 8(8), 208; doi:10.3390/genes8080208
Received: 30 June 2017 / Revised: 11 August 2017 / Accepted: 13 August 2017 / Published: 22 August 2017
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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
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Open AccessArticle EYS Mutations Causing Autosomal Recessive Retinitis Pigmentosa: Changes of Retinal Structure and Function with Disease Progression
Genes 2017, 8(7), 178; doi:10.3390/genes8070178
Received: 6 May 2017 / Revised: 6 July 2017 / Accepted: 6 July 2017 / Published: 12 July 2017
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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
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Open AccessArticle Mutations in the Genes for Interphotoreceptor Matrix Proteoglycans, IMPG1 and IMPG2, in Patients with Vitelliform Macular Lesions
Genes 2017, 8(7), 170; doi:10.3390/genes8070170
Received: 19 May 2017 / Revised: 20 June 2017 / Accepted: 20 June 2017 / Published: 23 June 2017
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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
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Open AccessCorrection 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
Genes 2017, 8(10), 286; doi:10.3390/genes8100286 (registering DOI)
Received: 16 October 2017 / Revised: 16 October 2017 / Accepted: 16 October 2017 / Published: 23 October 2017
PDF Full-text (242 KB)
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
Open AccessCase Report Outcome of Full-Thickness Macular Hole Surgery in Choroideremia
Genes 2017, 8(7), 187; doi:10.3390/genes8070187
Received: 29 June 2017 / Revised: 14 July 2017 / Accepted: 19 July 2017 / Published: 21 July 2017
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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
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