Ophthalmic Genetics

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

Deadline for manuscript submissions: closed (15 June 2022) | Viewed by 26538

Special Issue Editors


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Guest Editor
1. Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
2. UCL Institute of Ophthalmology, University College London, London, UK
3. Moorfields Eye Hospital, London, UK
4. Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
Interests: ophthalmic genetics; inherited retinal diseases; retinal imaging; clinical electrophysiology; genomic analyses; population genetics; application of artificial intelligence; genotype–phenotype correlation; clinical trials; gene therapy

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Guest Editor
1. UCL Institute of Ophthalmology, University College London, London, UK
2. Moorfields Eye Hospital, London, UK
Interests: achromatopsia; cone-rod dystrophies; rod-cone dystrophies; leber congenital amaurosis; retinal imaging

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Guest Editor
Centre for Ophthalmology and Visual Science, The University of Western Australia, Lions Eye Institute, Perth, Western Australia, Australia
Interests: inherited retinal diseases; vitreoretinal surgery; stem cells; retinal imaging; clinical trials

Special Issue Information

Dear Colleagues,

Inherited retinal disease (IRD) is the leading cause of blindness in the working age population. Advances in molecular genetic techniques, through targeted gene panel analysis with application of next generation sequencing methods, have expedited molecular diagnosis. Similarly, advances in ophthalmic imaging and visual function testing have improved our knowledge of the natural history, which is key to monitoring the treatment effects in clinical trials of novel IRD therapies. Many of these proposed therapies that slow progression or improve retinal function remain under development. Ongoing and upcoming clinical trials emphasise the increasing need for further detailed investigation of the ocular structures and functions in order to better understand the underlying molecular biology of these diseases. The reliability and repeatability of the different assessment modalities is also needed, as well as clearly defined inclusion criteria, prognostic indicators, and trial endpoints. The scope of this Special Issue is the field of ophthalmic genetics, encompassing genomics, molecular biology, therapeutic interventions, and recommended clinical assessments.

Prof. Kaoru Fujinami
Dr. Michalis Georgiou
Dr. Fred K. Chen
Guest Editors

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Keywords

  • Ophthalmic genetics
  • Inherited retinal disease
  • Genomics
  • Molecular biology
  • Retinal imaging
  • Clinical electrophysiology
  • Genotype-phenotype correlation
  • Clinical trials
  • Gene therapy
  • Stem cells

Published Papers (10 papers)

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10 pages, 407 KiB  
Article
Association of APOE Serum Levels and APOE ε2, ε3, and ε4 Alleles with Optic Neuritis
by Liucija Momkute, Alvita Vilkeviciute, Greta Gedvilaite, Gabriele Dubinskaite, Loresa Kriauciuniene and Rasa Liutkeviciene
Genes 2022, 13(7), 1188; https://doi.org/10.3390/genes13071188 - 1 Jul 2022
Cited by 4 | Viewed by 1723
Abstract
Optical neuritis (ON), otherwise known as optical nerve damage, is a term used to describe various environmental and body conditions that lead to optic nerve dysfunction. Neurologists are well aware of conditions that cause optic neuropathy, such as trauma, infections, malnutrition, and various [...] Read more.
Optical neuritis (ON), otherwise known as optical nerve damage, is a term used to describe various environmental and body conditions that lead to optic nerve dysfunction. Neurologists are well aware of conditions that cause optic neuropathy, such as trauma, infections, malnutrition, and various toxins. As optic neuritis is a multifactorial demyelinating or infectious process, genetic predisposition may also influence the progression of optic neuritis. This study aimed to evaluate the association of ON (with and without multiple sclerosis) with APOE alleles and APOE serum levels. We found that the APOE ε3/ε3 genotype was statistically less common in the ON group of males than in the control group (p = 0.045). Moreover, the APOE ε3/ε3 genotype had a 3.7-fold increase in the odds of ON development in males (OR = 3.698; CI: 1.503–9.095; p = 0.004). In contrast, the APOE ε3/ε4 genotype had a 4.1-fold decrease in the odds of ON development in males (OR = 0.242; CI: 0.083–0.704; p = 0.009). APOE serum levels were statistically significantly higher in the ON group than in the control group (p = 0.042). The APOE ε3/ε3 genotype may increase males’ risk of developing ON, while the ε3/ε4 genotype may reduce males’ risk of developing ON. Full article
(This article belongs to the Special Issue Ophthalmic Genetics)
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10 pages, 1047 KiB  
Article
MicroRNA Expression in Pseudoexfoliation Syndrome with the Use of Next-Generation Sequencing
by Martyna Tomczyk-Socha, Julia Kręcicka, Marta Misiuk-Hojło and Anna Turno-Kręcicka
Genes 2022, 13(4), 582; https://doi.org/10.3390/genes13040582 - 25 Mar 2022
Cited by 8 | Viewed by 2059
Abstract
Pseudoexfoliation syndrome (PEX) is a clinically important and biologically intriguing systemic disorder of the extracellular matrix. PEX etiopathogenesis was proved to be connected to multiple genes and other factors. However, the exact etiopathogenesis remains unknown. The aim of this study was to analyze [...] Read more.
Pseudoexfoliation syndrome (PEX) is a clinically important and biologically intriguing systemic disorder of the extracellular matrix. PEX etiopathogenesis was proved to be connected to multiple genes and other factors. However, the exact etiopathogenesis remains unknown. The aim of this study was to analyze miR expression in PEX using next-generation sequencing. An attempt was made to find the most commonly occurring miR in PEX, to evaluate miR that may have an essential role in the etiology of PEX syndrome. In addition, the correlation between the selected miRs’ expressions and age was investigated. Anterior lens capsules were obtained during cataract surgery. Next-generation sequencing was conducted on Illumina MiSeq. The average age was 68.2 years (with standard deviation +/− 6.92 years). Ten miRs with the highest level of expression represent approx. 95% of all readings. Four miRs with statistically significant differences in expression between groups have been distinguished: miR-671-3p, miR374a-5p, miR-1307-5p and miR-708-5p. The relationship between the most frequent miRs’ expressions and age has been evaluated and no correlation has been detected. In view of the above, it seems reasonable to examine the influence of miR on the biogenesis of PEX. Further studies on miR-671-3p, miR-374a-5p, miR-1307-5p and miR-708-5p expression in PEX are needed. Full article
(This article belongs to the Special Issue Ophthalmic Genetics)
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13 pages, 7395 KiB  
Article
Beyond Sector Retinitis Pigmentosa: Expanding the Phenotype and Natural History of the Rhodopsin Gene Codon 106 Mutation (Gly-to-Arg) in Autosomal Dominant Retinitis Pigmentosa
by Brian G. Ballios, Emily M. Place, Luis Martinez-Velazquez, Eric A. Pierce, Jason I. Comander and Rachel M. Huckfeldt
Genes 2021, 12(12), 1853; https://doi.org/10.3390/genes12121853 - 23 Nov 2021
Cited by 5 | Viewed by 2518
Abstract
Sector and pericentral are two rare, regional forms of retinitis pigmentosa (RP). While usually defined as stable or only very slowly progressing, the available literature to support this claim is limited. Additionally, few studies have analyzed the spectrum of disease within a particular [...] Read more.
Sector and pericentral are two rare, regional forms of retinitis pigmentosa (RP). While usually defined as stable or only very slowly progressing, the available literature to support this claim is limited. Additionally, few studies have analyzed the spectrum of disease within a particular genotype. We identified all cases (9 patients) with an autosomal dominant Rhodopsin variant previously associated with sector RP (RHO c.316G > A, p.Gly106Arg) at our institution. Clinical histories were reviewed, and testing included visual fields, multimodal imaging, and electroretinography. Patients demonstrated a broad phenotypic spectrum that spanned regional phenotypes from sector-like to pericentral RP, as well as generalized disease. We also present evidence of significant intrafamilial variability in regional phenotypes. Finally, we present the longest-reported follow-up for a patient with RHO-associated sector-like RP, showing progression from sectoral to pericentral disease over three decades. In the absence of comorbid macular disease, the long-term prognosis for central visual acuity is good. However, we found that significant progression of RHO p.Gly106Arg disease can occur over protracted periods, with impact on peripheral vision. Longitudinal widefield imaging and periodic ERG reassessment are likely to aid in monitoring disease progression. Full article
(This article belongs to the Special Issue Ophthalmic Genetics)
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16 pages, 37818 KiB  
Article
Genetic and Phenotypic Landscape of PRPH2-Associated Retinal Dystrophy in Japan
by Akio Oishi, Kaoru Fujinami, Go Mawatari, Nobuhisa Naoi, Yasuhiro Ikeda, Shinji Ueno, Kazuki Kuniyoshi, Takaaki Hayashi, Hiroyuki Kondo, Atsushi Mizota, Kei Shinoda, Sentaro Kusuhara, Makoto Nakamura, Takeshi Iwata, Akitaka Tsujikawa and Kazushige Tsunoda
Genes 2021, 12(11), 1817; https://doi.org/10.3390/genes12111817 - 18 Nov 2021
Cited by 10 | Viewed by 3441
Abstract
Peripherin-2 (PRPH2) is one of the causative genes of inherited retinal dystrophy. While the gene is relatively common in Caucasians, reports from Asian ethnicities are limited. In the present study, we report 40 Japanese patients from 30 families with PRPH2-associated [...] Read more.
Peripherin-2 (PRPH2) is one of the causative genes of inherited retinal dystrophy. While the gene is relatively common in Caucasians, reports from Asian ethnicities are limited. In the present study, we report 40 Japanese patients from 30 families with PRPH2-associated retinal dystrophy. We identified 17 distinct pathogenic or likely pathogenic variants using next-generation sequencing. Variants p.R142W and p.V200E were relatively common in the cohort. The age of onset was generally in the 40’s; however, some patients had earlier onset (age: 5 years). Visual acuity of the patients ranged from hand motion to 1.5 (Snellen equivalent 20/13). The patients showed variable phenotypes such as retinitis pigmentosa, cone-rod dystrophy, and macular dystrophy. Additionally, intrafamilial phenotypic variability was observed. Choroidal neovascularization was observed in three eyes of two patients with retinitis pigmentosa. The results demonstrate the genotypic and phenotypic variations of the disease in the Asian cohort. Full article
(This article belongs to the Special Issue Ophthalmic Genetics)
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17 pages, 2769 KiB  
Article
Determinants of Disease Penetrance in PRPF31-Associated Retinopathy
by Samuel McLenachan, Dan Zhang, Janya Grainok, Xiao Zhang, Zhiqin Huang, Shang-Chih Chen, Khine Zaw, Alanis Lima, Luke Jennings, Danial Roshandel, Sang Yoon Moon, Rachael C. Heath Jeffery, Mary S. Attia, Jennifer A. Thompson, Tina M. Lamey, Terri L. McLaren, John De Roach, Sue Fletcher and Fred K. Chen
Genes 2021, 12(10), 1542; https://doi.org/10.3390/genes12101542 - 28 Sep 2021
Cited by 10 | Viewed by 2651
Abstract
Retinitis pigmentosa 11 (RP11) is caused by dominant mutations in PRPF31, however a significant proportion of mutation carriers do not develop retinopathy. Here, we investigated the relationship between CNOT3 polymorphism, MSR1 repeat copy number and disease penetrance in RP11 patients and non-penetrant [...] Read more.
Retinitis pigmentosa 11 (RP11) is caused by dominant mutations in PRPF31, however a significant proportion of mutation carriers do not develop retinopathy. Here, we investigated the relationship between CNOT3 polymorphism, MSR1 repeat copy number and disease penetrance in RP11 patients and non-penetrant carriers (NPCs). We further characterized PRPF31 and CNOT3 expression in fibroblasts from eight RP11 patients and one NPC from a family carrying the c.1205C>T variant. Retinal organoids (ROs) and retinal pigment epithelium (RPE) were differentiated from induced pluripotent stem cells derived from RP11 patients, an NPC and a control subject. All RP11 patients were homozygous for the 3-copy MSR1 repeat in the PRPF31 promoter, while 3/5 NPCs carried a 4-copy MSR1 repeat. The CNOT3 rs4806718 genotype did not correlate with disease penetrance. PRFP31 expression declined with age in adult cadaveric retina. PRPF31 and CNOT3 expression was reduced in RP11 fibroblasts, RO and RPE compared with controls. Both RP11 and NPC RPE displayed shortened primary cilia compared with controls, however a subpopulation of cells with normal cilia lengths was present in NPC RPE monolayers. Our results indicate that RP11 non-penetrance is associated with the inheritance of a 4-copy MSR1 repeat, but not with CNOT3 polymorphisms. Full article
(This article belongs to the Special Issue Ophthalmic Genetics)
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15 pages, 1332 KiB  
Article
The Phenotypic Spectrum of Patients with PHARC Syndrome Due to Variants in ABHD12: An Ophthalmic Perspective
by Xuan-Thanh-An Nguyen, Hind Almushattat, Ine Strubbe, Michalis Georgiou, Catherina H. Z. Li, Mary J. van Schooneveld, Inge Joniau, Elfride De Baere, Ralph J. Florijn, Arthur A. Bergen, Carel B. Hoyng, Michel Michaelides, Bart P. Leroy and Camiel J. F. Boon
Genes 2021, 12(9), 1404; https://doi.org/10.3390/genes12091404 - 11 Sep 2021
Cited by 8 | Viewed by 2913
Abstract
This study investigated the phenotypic spectrum of PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and early-onset cataract) syndrome caused by biallelic variants in the ABHD12 gene. A total of 15 patients from 12 different families were included, with a mean age of 36.7 [...] Read more.
This study investigated the phenotypic spectrum of PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and early-onset cataract) syndrome caused by biallelic variants in the ABHD12 gene. A total of 15 patients from 12 different families were included, with a mean age of 36.7 years (standard deviation [SD] ± 11.0; range from 17.5 to 53.9) at the most recent examination. The presence and onset of neurological, audiological and ophthalmic symptoms were variable, with no evident order of symptom appearance. The mean best-corrected visual acuity was 1.1 logMAR (SD ± 0.9; range from 0.1 to 2.8; equivalent to 20/250 Snellen) and showed a trend of progressive decline. Different types of cataract were observed in 13 out of 15 patients (87%), which also included congenital forms of cataract. Fundus examination revealed macular involvement in all patients, ranging from alterations of the retinal pigment epithelium to macular atrophy. Intraretinal spicular hyperpigmentation was observed in 7 out of 15 patients (47%). From an ophthalmic perspective, clinical manifestations in patients with PHARC demonstrate variability with regard to their onset and severity. Given the variable nature of PHARC, an early multidisciplinary assessment is recommended to assess disease severity. Full article
(This article belongs to the Special Issue Ophthalmic Genetics)
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18 pages, 9894 KiB  
Article
Clinical Evidence for the Importance of the Wild-Type PRPF31 Allele in the Phenotypic Expression of RP11
by Danial Roshandel, Jennifer A. Thompson, Rachael C. Heath Jeffery, Dan Zhang, Tina M. Lamey, Terri L. McLaren, John N. De Roach, Samuel McLenachan, David A. Mackey and Fred K. Chen
Genes 2021, 12(6), 915; https://doi.org/10.3390/genes12060915 - 14 Jun 2021
Cited by 8 | Viewed by 2712
Abstract
PRPF31-associated retinopathy (RP11) is a common form of autosomal dominant retinitis pigmentosa (adRP) that exhibits wide variation in phenotype ranging from non-penetrance to early-onset RP. Herein, we report inter-familial and intra-familial variation in the natural history of RP11 using multimodal imaging and [...] Read more.
PRPF31-associated retinopathy (RP11) is a common form of autosomal dominant retinitis pigmentosa (adRP) that exhibits wide variation in phenotype ranging from non-penetrance to early-onset RP. Herein, we report inter-familial and intra-familial variation in the natural history of RP11 using multimodal imaging and microperimetry. Patients were recruited prospectively. The age of symptom onset, best-corrected visual acuity, microperimetry mean sensitivity (MS), residual ellipsoid zone span and hyperautofluorescent ring area were recorded. Genotyping was performed using targeted next-generation and Sanger sequencing and copy number variant analysis. PRPF31 mutations were found in 14 individuals from seven unrelated families. Four disease patterns were observed: (A) childhood onset with rapid progression (N = 4), (B) adult-onset with rapid progression (N = 4), (C) adult-onset with slow progression (N = 4) and (D) non-penetrance (N = 2). Four different patterns were observed in a family harbouring c.267del; patterns B, C and D were observed in a family with c.772_773delins16 and patterns A, B and C were observed in 3 unrelated individuals with large deletions. Our findings suggest that the RP11 phenotype may be related to the wild-type PRPF31 allele rather than the type of mutation. Further studies that correlate in vitro wild-type PRPF31 allele expression level with the disease patterns are required to investigate this association. Full article
(This article belongs to the Special Issue Ophthalmic Genetics)
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11 pages, 3777 KiB  
Brief Report
Delineating the Molecular and Phenotypic Spectrum of the CNGA3-Related Cone Photoreceptor Disorder in Pakistani Families
by Sairah Yousaf, Nabeela Tariq, Zureesha Sajid, Shakeel A. Sheikh, Tasleem Kausar, Yar M. Waryah, Rehan S. Shaikh, Ali M. Waryah, Saumil Sethna, Saima Riazuddin and Zubair M. Ahmed
Genes 2022, 13(4), 617; https://doi.org/10.3390/genes13040617 - 29 Mar 2022
Cited by 1 | Viewed by 2055
Abstract
Cone photoreceptor dysfunction represents a clinically heterogenous group of disorders characterized by nystagmus, photophobia, reduced central or color vision, and macular dystrophy. Here, we described the molecular findings and clinical manifestations of achromatopsia, a partial or total absence of color vision, co-segregating with [...] Read more.
Cone photoreceptor dysfunction represents a clinically heterogenous group of disorders characterized by nystagmus, photophobia, reduced central or color vision, and macular dystrophy. Here, we described the molecular findings and clinical manifestations of achromatopsia, a partial or total absence of color vision, co-segregating with three known missense variants of CNGA3 in three large consanguineous Pakistani families. Fundus examination and optical coherence tomography (OCT) imaging revealed myopia, thin retina, retinal pigment epithelial cells loss at fovea/perifovea, and macular atrophy. Combination of Sanger and whole exome sequencing revealed three known homozygous missense variants (c.827A>G, p.(Asn276Ser); c.847C>T, p.(Arg283Trp); c.1279C>T, p.(Arg427Cys)) in CNGA3, the α-subunit of the cyclic nucleotide-gated cation channel in cone photoreceptor cells. All three variants are predicted to replace evolutionary conserved amino acids, and to be pathogenic by specific in silico programs, consistent with the observed altered membrane targeting of CNGA3 in heterologous cells. Insights from our study will facilitate counseling regarding the molecular and phenotypic landscape of CNGA3-related cone dystrophies. Full article
(This article belongs to the Special Issue Ophthalmic Genetics)
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12 pages, 26175 KiB  
Brief Report
Variable Anterior Segment Dysgenesis and Cardiac Anomalies Caused by a Novel Truncating Variant of FOXC1
by Mariya R. Ahmed, Saumil Sethna, Laura A. Krueger, Michael B. Yang and Robert B. Hufnagel
Genes 2022, 13(3), 411; https://doi.org/10.3390/genes13030411 - 24 Feb 2022
Cited by 2 | Viewed by 1995
Abstract
Anterior segment dysgenesis (ASD) encompasses a wide spectrum of developmental abnormalities of the anterior ocular segment, including congenital cataract, iris hypoplasia, aniridia, iridocorneal synechiae, as well as Peters, Axenfeld, and Rieger anomalies. Here, we report a large five-generation Caucasian family exhibiting atypical syndromic [...] Read more.
Anterior segment dysgenesis (ASD) encompasses a wide spectrum of developmental abnormalities of the anterior ocular segment, including congenital cataract, iris hypoplasia, aniridia, iridocorneal synechiae, as well as Peters, Axenfeld, and Rieger anomalies. Here, we report a large five-generation Caucasian family exhibiting atypical syndromic ASD segregating with a novel truncating variant of FOXC1. The family history is consistent with highly variable autosomal dominant symptoms including isolated glaucoma, iris hypoplasia, aniridia, cataract, hypothyroidism, and congenital heart anomalies. Whole-exome sequencing revealed a novel variant [c.313_314insA; p.(Tyr105*)] in FOXC1 that disrupts the α-helical region of the DNA-binding forkhead box domain. In vitro studies using a heterologous cell system revealed aberrant cytoplasmic localization of FOXC1 harboring the Tyr105* variant, likely precluding downstream transcription function. Meta-analysis of the literature highlighted the intrafamilial variability related to FOXC1 truncating alleles. This study highlights the clinical variability in ASD and signifies the importance of combining both clinical and molecular analysis approaches to establish a complete diagnosis. Full article
(This article belongs to the Special Issue Ophthalmic Genetics)
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6 pages, 700 KiB  
Brief Report
Genotype-Specific Lesion Growth Rates in Stargardt Disease
by Rachael C. Heath Jeffery, Jennifer A. Thompson, Johnny Lo, Tina M. Lamey, Terri L. McLaren, Ian L. McAllister, Ian J. Constable, John N. De Roach and Fred K. Chen
Genes 2021, 12(12), 1981; https://doi.org/10.3390/genes12121981 - 14 Dec 2021
Cited by 6 | Viewed by 2083
Abstract
Reported growth rates (GR) of atrophic lesions in Stargardt disease (STGD1) vary widely. In the present study, we report the longitudinal natural history of patients with confirmed biallelic ABCA4 mutations from five genotype groups: c.6079C>T, c.[2588G>C;5603A>T], c.3113C>T, c.5882G>A and c.5603A>T. Fundus autofluorescence (AF) [...] Read more.
Reported growth rates (GR) of atrophic lesions in Stargardt disease (STGD1) vary widely. In the present study, we report the longitudinal natural history of patients with confirmed biallelic ABCA4 mutations from five genotype groups: c.6079C>T, c.[2588G>C;5603A>T], c.3113C>T, c.5882G>A and c.5603A>T. Fundus autofluorescence (AF) 30° × 30° images were manually segmented for boundaries of definitely decreased autofluorescence (DDAF). The primary outcome was the effective radius GR across five genotype groups. The age of DDAF formation in each eye was calculated using the x-intercept of the DDAF effective radius against age. Discordance between age at DDAF formation and symptom onset was compared. A total of 75 eyes from 39 STGD1 patients (17 male [44%]; mean ± SD age 45 ± 19 years; range 21–86) were recruited. Patients with c.3113C>T or c.6079C>T had a significantly faster effective radius GR at 0.17 mm/year (95% CI 0.12 to 0.22; p < 0.001 and 0.14 to 0.21; p < 0.001) respectively, as compared to those patients harbouring c.5882G>A at 0.06 mm/year (95% CI 0.03–0.09), respectively. Future clinical trial design should consider the effect of genotype on the effective radius GR and the timing of DDAF formation relative to symptom onset. Full article
(This article belongs to the Special Issue Ophthalmic Genetics)
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