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Genetics and Pathogenesis of Inherited Eye Diseases

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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 (10 May 2023) | Viewed by 19722

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Special Issue Editors

Prof. Dr. Mariya Moosajee

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Guest Editor

Institute of Ophthalmology, University College London, London EC1V 9EL, UK
Interests: genomics; genetics; eye; retina; inherited retinal disease; ocular maldevelopment; transcriptomics; ophthalmology; childhood cataracts; anterior segment dysgenesis; developmental glaucoma; inherited optic neuropathy
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Dr. Robert B Hufnagel

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Guest Editor

National Eye Institute, Bethesda, MD 20892-2510, USA
Interests: genomics; genetics; eye; retina; inherited retinal disease; ocular syndromes; transcriptomics; ophthalmology; foveal hypoplasia; inherited maculopathies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Background: The field of genetic eye diseases is advancing, with numerous clinical trials underway and the first retinal gene therapy available for patients as an approved treatment, made possible due to an improved molecular diagnosis and greater understanding in disease mechanisms. A plethora of genes and variants have been discovered to cause inherited eye diseases. Whole-genome sequencing has advanced our ability to solve genetic cases, diagnose the yield for patients and broaden our understanding of these conditions, having helped to identify new variants, including deep intronic and noncoding regulatory changes. With the expansion of these genotypes, we can now begin to establish clearer genotype–phenotype correlations to guide the prognosis and accurate management of patients through a multidisciplinary team approach. Disease models are used to validate novel variants and dissect disease mechanisms, going on to reveal therapeutic targets for pre-clinical testing.

Aim and scope: In this Special Issue, we plan to highlight the genetics of inherited eye diseases to build on our knowledge of genotype–phenotype correlations and establish the optimal management pathways for patients. We also plan to showcase the pathogenesis of these conditions that could lead to therapeutic targets and the development of new treatment strategies.

Cutting-edge research: Multiomics approaches in patients and disease models (animals and cellular) are helping to identify new variants, including deep intronic and noncoding regulatory changes, epigenetic and transcriptomic changes that lead to genetic eye diseases, with ophthalmology at the vanguard of this field.

What kind of papers we are soliciting: Original research articles, reviews and cohort studies

Prof. Dr. Mariya Moosajee
Dr. Robert B Hufnagel
Guest Editors

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Keywords

genetic eye disease
inherited retinal disease
ocular malformations
genomics
genetics
transcriptomics

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Published Papers (8 papers)

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Research

Jump to: Review

13 pages, 3900 KiB

Open AccessArticle

Phenotype-Based Genetic Analysis Reveals Missing Heritability of KIF11-Related Retinopathy: Clinical and Genetic Findings

by Haoyu Chang, Xin Zhang, Ke Xu, Nien Li, Yue Xie, Weiyu Yan and Yang Li

Genes 2023, 14(1), 212; https://doi.org/10.3390/genes14010212 - 13 Jan 2023

Cited by 3 | Viewed by 2036

Abstract

The purpose of this study was to detect the missing heritability of patients with KIF11-related retinopathy and to describe their clinical and genetic characteristics. We enrolled 10 individuals from 7 unrelated families harboring a pathogenic monoallelic variant in KIF11. All subjects underwent ophthalmic assessment and extraocular phenotype evaluations, as well as comprehensive molecular genetic analyses using next-generation sequencing. Minigene assays were performed to observe the effects of one novel deep intron variant (DIV) and one novel synonymous variant on pre-mRNA splicing. We detected 6 novel different disease-causing variants of KIF11 in the seven pedigrees. Co-segregation analysis and ultra-deep sequencing results indicated that 5 variants arose de novo in 5 families (71%). Functional validation revealed that the synonymous variant leads to an exon skip, while the DIV causes a pseudoexon (PE) inclusion. The patients presented with high variations in their phenotype, and two families exhibited incomplete penetrance. Ocular manifestations and characteristic facial features were observed in all patients, as well as microcephaly in seven patients, intellectual disability in five patients, and lymphedema in one patient. The key retinal features for KIF11-related retinopathy were retinal folds, tractional retinal detachment, and chorioretinal dysplasia. All seven probands had more severe visual detects than other affected family members. Our findings widen the genetic spectrum of KIF11 variants. DIV explained rare unresolved cases with KIF11-related retinopathy. The patients displayed a variable phenotype expressivity and incomplete penetrance, indicating the importance of genetic analysis for patients with KIF11-related retinopathy. Full article

(This article belongs to the Special Issue Genetics and Pathogenesis of Inherited Eye Diseases)

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14 pages, 438 KiB

Open AccessArticle

Effective smMIPs-Based Sequencing of Maculopathy-Associated Genes in Stargardt Disease Cases and Allied Maculopathies from the UK

by Benjamin Mc Clinton, Zelia Corradi, Martin McKibbin, Daan M. Panneman, Susanne Roosing, Erica G. M. Boonen, Manir Ali, Christopher M. Watson, David H. Steel, Frans P. M. Cremers, Chris F. Inglehearn, Rebekkah J. Hitti-Malin and Carmel Toomes

Genes 2023, 14(1), 191; https://doi.org/10.3390/genes14010191 - 11 Jan 2023

Cited by 1 | Viewed by 2301

Abstract

Macular dystrophies are a group of individually rare but collectively common inherited retinal dystrophies characterised by central vision loss and loss of visual acuity. Single molecule Molecular Inversion Probes (smMIPs) have proved effective in identifying genetic variants causing macular dystrophy. Here, a previously established smMIPs panel tailored for genes associated with macular diseases has been used to examine 57 UK macular dystrophy cases, achieving a high solve rate of 63.2% (36/57). Among 27 bi-allelic STGD1 cases, only three novel ABCA4 variants were identified, illustrating that the majority of ABCA4 variants in Caucasian STGD1 cases are currently known. We examined cases with ABCA4-associated disease in detail, comparing our results with a previously reported variant grading system, and found this model to be accurate and clinically useful. In this study, we showed that ABCA4-associated disease could be distinguished from other forms of macular dystrophy based on clinical evaluation in the majority of cases (34/36) Full article

(This article belongs to the Special Issue Genetics and Pathogenesis of Inherited Eye Diseases)

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9 pages, 935 KiB

Open AccessArticle

Twins’ Macular Pigment Optical Density Assessment and Relation with SCARB1 Gene Polymorphism

by Edita Kunceviciene, Ruta Mockute, Aiste Petrauskaite, Brigita Budiene, Alina Smalinskiene, Ieva Zvykaite and Rasa Liutkeviciene

Genes 2023, 14(1), 125; https://doi.org/10.3390/genes14010125 - 2 Jan 2023

Cited by 1 | Viewed by 2000

Abstract

The aim of the study: to assess the influence of genetic and environmental factors using twin studies and evaluate the associations of SCARB1 gene variants (rs11057841) with AMD and MPOD. Material and methods: a total of 108 healthy twins (56 MZ and 52 DZ twins) were tested in this study. The MPOD was measured using the one-wavelength reflectometry method. Fundus reflectance (Visucam 500, reflectance of a single 460 nm wavelength) was used to measure the MPOD levels, MPOD parameters including max and mean optical density (OD), and area and volume. Real-time polymerase chain reaction was used to detect single nucleotide polymorphisms. Results: we detected a positive correlation of MPOD in the right and left eyes in MZ twin pairs (r = 0.830 and r = 0.860, respectively) (p < 0.0001) and a negative correlation of MPOD in the right and left eyes in DZ twin pairs (r = 0.314 and r = 0.408, respectively) (p < 0.05). The study was able to identify statistically significant differences in mean MPOD values in the right and left eyes between subjects with a wild-type CC genotype and a CT genotype with a risk allele. A decrease in the mean MPOD value was observed in group II with a CT genotype (0.110 d.u.) compared with the CC genotype (0.117 d.u.) in the right eye (p = 0.037) and in the left eye with a CT genotype (0.109 d.u.) compared with a CC genotype in the subjects (0.114 d.u.) (p = 0.038). In the right eye, in group II (0.101–0.128 d.u.), those with a CT genotype (n = 6) with one risk allele had a statistically significantly lower (0.110 d.u.) mean average MPOD value compared with those with a wild-type CC genotype (n = 25) (0.117 d.u.) (p = 0.037). Conclusion: this twin study showed a strong heritability of the retina pigment, which was 86% prevalent in Lithuania. Individuals with a CT genotype of the SCARB1 rs11057841 with a risk allele had statistically significantly lower mean MPOD values in both eyes compared to subjects with a wild-type CC genotype. Full article

(This article belongs to the Special Issue Genetics and Pathogenesis of Inherited Eye Diseases)

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13 pages, 1808 KiB

Open AccessArticle

Robust Genetic Analysis of the X-Linked Anophthalmic (Ie) Mouse

by Brianda A. Hernandez-Moran, Andrew S. Papanastasiou, David Parry, Alison Meynert, Philippe Gautier, Graeme Grimes, Ian R. Adams, Violeta Trejo-Reveles, Hemant Bengani, Margaret Keighren, Ian J. Jackson, David J. Adams, David R. FitzPatrick and Joe Rainger

Genes 2022, 13(10), 1797; https://doi.org/10.3390/genes13101797 - 5 Oct 2022

Viewed by 2597

Abstract

Anophthalmia (missing eye) describes a failure of early embryonic ocular development. Mutations in a relatively small set of genes account for 75% of bilateral anophthalmia cases, yet 25% of families currently are left without a molecular diagnosis. Here, we report our experimental work that aimed to uncover the developmental and genetic basis of the anophthalmia characterising the X-linked Ie (eye-ear reduction) X-ray-induced allele in mouse that was first identified in 1947. Histological analysis of the embryonic phenotype showed failure of normal eye development after the optic vesicle stage with particularly severe malformation of the ventral retina. Linkage analysis mapped this mutation to a ~6 Mb region on the X chromosome. Short- and long-read whole-genome sequencing (WGS) of affected and unaffected male littermates confirmed the Ie linkage but identified no plausible causative variants or structural rearrangements. These analyses did reduce the critical candidate interval and revealed evidence of multiple variants within the ancestral DNA, although none were found that altered coding sequences or that were unique to Ie. To investigate early embryonic events at a genetic level, we then generated mouse ES cells derived from male Ie embryos and wild type littermates. RNA-seq and accessible chromatin sequencing (ATAC-seq) data generated from cultured optic vesicle organoids did not reveal any large differences in gene expression or accessibility of putative cis-regulatory elements between Ie and wild type. However, an unbiased TF-footprinting analysis of accessible chromatin regions did provide evidence of a genome-wide reduction in binding of transcription factors associated with ventral eye development in Ie, and evidence of an increase in binding of the Zic-family of transcription factors, including Zic3, which is located within the Ie-refined critical interval. We conclude that the refined Ie critical region at chrX: 56,145,000–58,385,000 contains multiple genetic variants that may be linked to altered cis regulation but does not contain a convincing causative mutation. Changes in the binding of key transcription factors to chromatin causing altered gene expression during development, possibly through a subtle mis-regulation of Zic3, presents a plausible cause for the anophthalmia phenotype observed in Ie, but further work is required to determine the precise causative allele and its genetic mechanism. Full article

(This article belongs to the Special Issue Genetics and Pathogenesis of Inherited Eye Diseases)

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6 pages, 777 KiB

Open AccessArticle

Clinical Features and Novel Genetic Variants Associated with Hermansky-Pudlak Syndrome

by Chonglin Chen, Ruixin Wang, Yongguang Yuan, Jun Li and Xinping Yu

Genes 2022, 13(7), 1283; https://doi.org/10.3390/genes13071283 - 20 Jul 2022

Cited by 4 | Viewed by 2005

Abstract

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive syndromic form of albinism, characterized by oculocutaneous albinism (OCA) and other systemic complications. The purpose of this study was to investigate patients with HPS-associated gene mutations and describe associated ocular and extraocular phenotypes. Fifty-four probands clinically diagnosed as albinism were enrolled. Ophthalmic examinations and genetic testing were performed in all subjects. The phenotypic and genetic features were evaluated. HPS-associated gene mutation was identified in four of the patients with albinism phenotype. Clinically, photophobia, and nystagmus was detected in all (4/4) patients, and strabismus was found in one (1/4) patient. Fundus examination revealed fundus hypopigmentation and foveal hypoplasia in all (8/8) eyes. Eight novel causative mutations were detected in these four HPS probands. Five (62.5%, 5/8) of the mutations were nonsense, two of the mutations were missense (25%, 2/8), and one of the mutations was frameshift (12.5%, 1/8). All patients in our study carried compound heterozygous variants, and all these pathogenic variants were identified to be novel, with most (62.5%, 5/8) of the mutations being nonsense. Our results improved the understanding of clinical ocular features, and expanded the spectrum of known variants and the genetic background of HPS. Full article

(This article belongs to the Special Issue Genetics and Pathogenesis of Inherited Eye Diseases)

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14 pages, 3056 KiB

Open AccessArticle

Ocular Manifestations in a Chinese Pedigree of Familial Amyloidotic Polyneuropathy Carrying the Transthyretin Mutation c.401A>G (p.Tyr134Cys)

by Xiaonan Zhuang, Zhongcui Sun, Fengjuan Gao, Min Wang, Wenyi Tang, Wei Liu, Keyan Wang, Jihong Wu, Rui Jiang and Gezhi Xu

Genes 2022, 13(5), 886; https://doi.org/10.3390/genes13050886 - 16 May 2022

Viewed by 2152

Abstract

Familial amyloid polyneuropathy (FAP) caused by a genetic mutation in transthyretin (TTR) is an autosomal dominant hereditary disease. The retrospective, observational case series study presents the ocular clinicopathological findings of five cases carrying the TTR mutation c.401A>G (p.Tyr134Cys). Multimodal retinal imaging and electrophysiological examination, Congo red staining and immunohistochemical analysis of specimens, and genetic analyses were performed. Cases 1 and 2 were symptomatic with vitreous and retinal amyloid deposition and poor visual recovery. Case 3 had a symptomatic vitreous haze in the left eye with good postoperative visual recovery. The right eye of case 3 and the eyes of cases 4 and 5 were asymptomatic. Thicker retinal nerve fiber layer, retinal venous tortuosity with prolonged arteriovenous passage time on fluorescein angiography and retinal dysfunction detected by multifocal electroretinogram occurred even in asymptomatic eyes. Moreover, the internal limiting membrane from patients with FAP was stained positive for Congo red and transforming growth factor-β1. The results highlight the amyloid deposition of mutant TTR in the optic disc and retina, even in the asymptomatic stage. The deposited amyloid leads to increased resistance to venous return and retinal functional abnormalities. Therefore, careful follow-up of structural and functional changes in the retina is needed, even in asymptomatic patients with FAP. Full article

(This article belongs to the Special Issue Genetics and Pathogenesis of Inherited Eye Diseases)

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13 pages, 1755 KiB

Open AccessArticle

Predominant Founder Effect among Recurrent Pathogenic Variants for an X-Linked Disorder

by Chelsea Bender, Elizabeth Geena Woo, Bin Guan, Ehsan Ullah, Eric Feng, Amy Turriff, Santa J. Tumminia, Paul A. Sieving, Catherine A. Cukras and Robert B. Hufnagel

Genes 2022, 13(4), 675; https://doi.org/10.3390/genes13040675 - 12 Apr 2022

Cited by 3 | Viewed by 2517

Abstract

For disorders with X-linked inheritance, variants may be transmitted through multiple generations of carrier females before an affected male is ascertained. Pathogenic RS1 variants exclusively cause X-linked retinoschisis (XLRS). While RS1 is constrained to variation, recurrent variants are frequently observed in unrelated probands. Here, we investigate recurrent pathogenic variants to determine the relative burden of mutational hotspot and founder allele events to this phenomenon. A cohort RS1 variant analysis and standardized classification, including variant enrichment in the XLRS cohort and in RS1 functional domains, were performed on 332 unrelated XLRS probands. A total of 108 unique RS1 variants were identified. A subset of 19 recurrently observed RS1 variants were evaluated in 190 probands by a haplotype analysis, using microsatellite and single nucleotide polymorphisms. Fourteen variants had at least two probands with common variant-specific haplotypes over ~1.95 centimorgans (cM) flanking RS1. Overall, 99/190 of reportedly unrelated probands had 25 distinct shared haplotypes. Examination of this XLRS cohort for common RS1 haplotypes indicates that the founder effect plays a significant role in this disorder, including variants in mutational hotspots. This improves the accuracy of clinical variant classification and may be generalizable to other X-linked disorders. Full article

(This article belongs to the Special Issue Genetics and Pathogenesis of Inherited Eye Diseases)

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Review

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17 pages, 4556 KiB

Open AccessEditor’s ChoiceReview

Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3): Role in Retinal Development and Disease

by Maria Toms, Natasha Ward and Mariya Moosajee

Genes 2023, 14(7), 1325; https://doi.org/10.3390/genes14071325 - 23 Jun 2023

Cited by 9 | Viewed by 2892

Abstract

NR2E3 is a nuclear hormone receptor gene required for the correct development of the retinal rod photoreceptors. Expression of NR2E3 protein in rod cell precursors suppresses cone-specific gene expression and, in concert with other transcription factors including NRL, activates the expression of rod-specific genes. Pathogenic variants involving NR2E3 cause a spectrum of retinopathies, including enhanced S-cone syndrome, Goldmann–Favre syndrome, retinitis pigmentosa, and clumped pigmentary retinal degeneration, with limited evidence of genotype–phenotype correlations. A common feature of NR2E3-related disease is an abnormally high number of cone photoreceptors that are sensitive to short wavelength light, the S-cones. This characteristic has been supported by mouse studies, which have also revealed that loss of Nr2e3 function causes photoreceptors to develop as cells that are intermediate between rods and cones. While there is currently no available cure for NR2E3-related retinopathies, there are a number of emerging therapeutic strategies under investigation, including the use of viral gene therapy and gene editing, that have shown promise for the future treatment of patients with NR2E3 variants and other inherited retinal diseases. This review provides a detailed overview of the current understanding of the role of NR2E3 in normal development and disease, and the associated clinical phenotypes, animal models, and therapeutic studies. Full article

(This article belongs to the Special Issue Genetics and Pathogenesis of Inherited Eye Diseases)

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