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Genomics and Therapeutics of Hereditary Eye Disease

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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 (31 December 2020) | Viewed by 43854

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Special Issue Editor

Prof. Dr. Mariya Moosajee

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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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Special Issue Information

Dear Colleagues,

We are in an era of advanced molecular diagnostics and therapeutics for patients with genetic eye diseases. Whole genome sequencing has increased the diagnostic yield and unearthed new deep intronic and non-coding regulatory variants that require further evidence of pathogenicity. Multiple phenotypes are emerging with a single gene cause, which require extensive genotype-phenotype investigations to establish correlation. To further understand hereditary eye disease, cell and animal models are used to dissect disease mechanisms, identify treatment targets, and for therapeutic pre-clinical testing. The field of therapeutics has led to the first retinal gene approval with voretigene neparovec. There are many gene therapy trials in the pipeline and novel approaches to treating these disorders including targeting common disease pathways and creating mutation-specific gene- and cell replacement strategies. In this Special Issue, we will sample the genomics, management and therapeutics that must be considered for hereditary eye diseases.

Dr. Mariya Moosajee
Guest Editor

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Keywords

Genetic eye disease
Developmental eye disorders
Inherited retinal disease
iPSC and animal models
Gene therapy
Small molecule drugs
Mutation-based therapy

Published Papers (11 papers)

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Research

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10 pages, 1063 KiB

Open AccessArticle

Accurate Quantification of AAV Vector Genomes by Quantitative PCR

by Cristina Martinez-Fernandez de la Camara, Michelle E. McClements and Robert E. MacLaren

Genes 2021, 12(4), 601; https://doi.org/10.3390/genes12040601 - 19 Apr 2021

Cited by 10 | Viewed by 6188

Abstract

The ability to accurately determine the dose of an adeno-associated viral (AAV) therapeutic vector is critical to the gene therapy process. Quantitative PCR (qPCR) is one of the common methods to quantify the AAV vector titre, but different variables can lead to inconsistent results. The aim of this study was to analyze the influence of the conformation of the DNA used as the standard control, and the enzymatic digestion was performed to release the viral genome from the protein capsid on the physical genome titration of a clinically relevant AAV8.RPGR vector, made to good laboratory practice standards in an academic setting. The results of this study showed that the conformation of the DNA used as standard has a significant impact on the accuracy of absolute quantification by qPCR. The use of supercoiled undigested plasmid DNA template generated a higher apparent titer, as compared to the use of linearized plasmid as the standard. In contrast to previous studies, the pre-treatment of the samples with Proteinase K, in addition to the high temperature step used after DNase I digestion, resulted in a reduction on AAV titers. Ideally, all AAV documentation should state which form of reference plasmid and which pre-treatment of the samples have been used to calculate titers, so that appropriate comparisons relating to dose toxicity and transduction efficacy can be made in the clinical scenario. Full article

(This article belongs to the Special Issue Genomics and Therapeutics of Hereditary Eye Disease)

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17 pages, 7815 KiB

Open AccessArticle

Optic Atrophy and Inner Retinal Thinning in CACNA1F-Related Congenital Stationary Night Blindness

by Kate E Leahy, Tom Wright, Monika K Grudzinska Pechhacker, Isabelle Audo, Anupreet Tumber, Erika Tavares, Heather MacDonald, Jeff Locke, Cynthia VandenHoven, Christina Zeitz, Elise Heon, J Raymond Buncic and Ajoy Vincent

Genes 2021, 12(3), 330; https://doi.org/10.3390/genes12030330 - 25 Feb 2021

Cited by 7 | Viewed by 2501

Abstract

Hemizygous pathogenic variants in CACNA1F lead to defective signal transmission from retinal photoreceptors to bipolar cells and cause incomplete congenital stationary night blindness in humans. Although the primary defect is at the terminal end of first-order neurons (photoreceptors), there is limited knowledge of higher-order neuronal changes (inner retinal) in this disorder. This study aimed to investigate inner retinal changes in CACNA1F-retinopathy by analyzing macular ganglion cell layer-inner plexiform layer (GCL-IPL) thickness and optic disc pallor in 22 subjects with molecularly confirmed CACNA1F-retinopathy. Detailed ocular phenotypic data including distance and color vision, refraction and electroretinogram (ERG) were collected. Distance vision was universally reduced (mean: 0.42 LogMAR), six had abnormal color vision and myopia was common (n = 15; mean: −6.32 diopters). Mean GCL-IPL thickness was significantly lower in patients (55.00 µm) compared to age-matched controls (n = 87; 84.57 µm; p << 0.001). The GCL-IPL thickness correlated with scotopic standard (p = 0.04) and bright-flash (p = 0.014) ERG b/a ratios and photopic b-wave amplitudes (p = 0.05). Twenty-one patients had some degree of disc pallor (bilateral in 19). Fifteen putative disease-causing, including five novel variants were identified. This study establishes macular inner retinal thinning and optic atrophy as characteristic features of CACNA1F-retinopathy, which are independent of myopia and could impact potential future treatment strategies. Full article

(This article belongs to the Special Issue Genomics and Therapeutics of Hereditary Eye Disease)

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9 pages, 865 KiB

Open AccessArticle

Acceptability of Telegenetics for Families with Genetic Eye Diseases

by Suzannah Bell, Urvi Karamchandani, Kirsten Malcolmson and Mariya Moosajee

Genes 2021, 12(2), 276; https://doi.org/10.3390/genes12020276 - 15 Feb 2021

Cited by 5 | Viewed by 2243

Abstract

Healthcare providers around the world have implemented remote routine consultations to minimise disruption during the COVID-19 pandemic. Virtual clinics are particularly suitable for patients with genetic eye diseases as they rely on detailed histories with genetic counselling. During April–June 2019, the opinion of carers of children with inherited eye disorders attending the ocular genetics service at Moorfields Eye Hospital NHS Foundation Trust (MEH) were canvassed. Sixty-five percent of families (n = 35/54) preferred to have investigations carried out locally rather than travel to MEH, with 64% opting for a virtual consultation to interpret the results. The most popular mode of remote contact was via telephone (14/31), with video call being least preferred (8/31). Hence, 54 families who had received a telephone consultation mid-pandemic (November 2020–January 2021) were contacted to re-evaluate the acceptability of telegenetics using the Clinical Genetics Satisfaction Indicator and Telemedicine Satisfaction Questionnaire. Overall, 50 carers participated (response rate 93%); 58% of participants found teleconsultations acceptable and 54% agreed they increased their access to care, but 67.5% preferred to be seen in person. Patient satisfaction was high with 90% strongly agreeing/agreeing they shared and received all necessary information. Ocular genetics is well-suited for remote service delivery, ideally alternated with face-to-face consultations. Full article

(This article belongs to the Special Issue Genomics and Therapeutics of Hereditary Eye Disease)

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14 pages, 795 KiB

Open AccessArticle

Ocular Phenotype Associated with DYRK1A Variants

by Cécile Méjécase, Christopher M. Way, Nicholas Owen and Mariya Moosajee

Genes 2021, 12(2), 234; https://doi.org/10.3390/genes12020234 - 5 Feb 2021

Cited by 8 | Viewed by 3764

Abstract

Dual-specificity tyrosine phosphorylation-regulated kinase 1A or DYRK1A, contributes to central nervous system development in a dose-sensitive manner. Triallelic DYRK1A is implicated in the neuropathology of Down syndrome, whereas haploinsufficiency causes the rare DYRK1A-related intellectual disability syndrome (also known as mental retardation 7). It is characterised by intellectual disability, autism spectrum disorder and microcephaly with a typical facial gestalt. Preclinical studies elucidate a role for DYRK1A in eye development and case studies have reported associated ocular pathology. In this study families of the DYRK1A Syndrome International Association were asked to self-report any co-existing ocular abnormalities. Twenty-six patients responded but only 14 had molecular confirmation of a DYRK1A pathogenic variant. A further nineteen patients from the UK Genomics England 100,000 Genomes Project were identified and combined with 112 patients reported in the literature for further analysis. Ninety out of 145 patients (62.1%) with heterozygous DYRK1A variants revealed ocular features, these ranged from optic nerve hypoplasia (13%, 12/90), refractive error (35.6%, 32/90) and strabismus (21.1%, 19/90). Patients with DYRK1A variants should be referred to ophthalmology as part of their management care pathway to prevent amblyopia in children and reduce visual comorbidity, which may further impact on learning, behaviour, and quality of life. Full article

(This article belongs to the Special Issue Genomics and Therapeutics of Hereditary Eye Disease)

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11 pages, 1152 KiB

Open AccessArticle

Clinical Spectrum and Genetic Diagnosis of 54 Consecutive Patients Aged 0–25 with Bilateral Cataracts

by Suzannah Bell, Samantha Malka, Ian Christopher Lloyd and Mariya Moosajee

Genes 2021, 12(2), 131; https://doi.org/10.3390/genes12020131 - 21 Jan 2021

Cited by 8 | Viewed by 3121

Abstract

Childhood cataract affects 2.5–3.5 per 10,000 children in the UK, with a genetic mutation identified in 50–90% of bilateral cases. However, cataracts can also manifest in adolescence and early adulthood in isolation, as part of a complex ocular phenotype or with systemic features making accurate diagnosis more challenging. We investigate our real-world experience through a retrospective review of consecutive bilateral cataract patients (0–25 years) presenting to the ocular genetics service at Moorfields Eye Hospital between 2017 and 2020. Fifty-four patients from 44 unrelated families were identified, with a median age of 13.5 years (range 1 to 68 years) and a median age at diagnosis of 43.9 months IQR (1.7–140.3 months); 40.7% were female and 46.3% were Caucasian. Overall, 37 patients from 27 families (61.4%) were genetically solved (50%) or likely solved (additional 11.4%), with 26 disease-causing variants (8 were novel) in 21 genes; the most common were crystallin genes, in 8 (29.6%) families, with half occurring in the CRYBB2 gene. There was no significant difference in the molecular diagnostic rates between sporadic and familial inheritance (P = 0.287). Associated clinical diagnoses were retinal dystrophies in five (18.5%) and aniridia in three (11.1%) families. Bilateral cataracts were the presenting feature in 27.3% (6/22) of either complex or syndromic cases, and isolated cataract patients were 11.5 years younger (rank-sum Z = 3.668, P = 0.0002). Prompt genetic investigation with comprehensive panel testing can aid with diagnosis and optimise management of cataract patients. Full article

(This article belongs to the Special Issue Genomics and Therapeutics of Hereditary Eye Disease)

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15 pages, 844 KiB

Open AccessArticle

Genetic and Clinical Findings in an Ethnically Diverse Cohort with Retinitis Pigmentosa Associated with Pathogenic Variants in CERKL

by Susan M. Downes, Tham Nguyen, Vicky Tai, Suzanne Broadgate, Mital Shah, Saoud Al-Khuzaei, Robert E. MacLaren, Morag Shanks, Penny Clouston and Stephanie Halford

Genes 2020, 11(12), 1497; https://doi.org/10.3390/genes11121497 - 12 Dec 2020

Cited by 3 | Viewed by 2651

Abstract

Autosomal recessive retinitis pigmentosa is caused by mutations in over 40 genes, one of which is the ceramide kinase-like gene (CERKL). We present a case series of six patients from six unrelated families diagnosed with inherited retinal dystrophies (IRD) and with two variants in CERKL recruited from a multi-ethnic British population. A retrospective review of clinical data in these patients was performed and included colour fundus photography, fundus autofluorescence (AF) imaging, spectral domain–optical coherence tomography (SD–OCT), visual fields and electroretinogram (ERG) assessment where available. Three female and three male patients were included. Age at onset ranged from 7 years old to 45 years, with three presenting in their 20s and two presenting in their 40s. All but one had central visual loss as one of their main presenting symptoms. Four patients had features of retinitis pigmentosa with significant variation in severity and extent of disease, and two patients had no pigment deposition with only macular involvement clinically. Seven variants in CERKL were identified, of which three are novel. The inherited retinopathies associated with the CERKL gene vary in age at presentation and in degree of severity, but generally are characterised by a central visual impairment early on. Full article

(This article belongs to the Special Issue Genomics and Therapeutics of Hereditary Eye Disease)

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17 pages, 2916 KiB

Open AccessArticle

Novel Pathogenic Sequence Variants in NR2E3 and Clinical Findings in Three Patients

by Saoud Al-khuzaei, Suzanne Broadgate, Stephanie Halford, Jasleen K. Jolly, Morag Shanks, Penny Clouston and Susan M. Downes

Genes 2020, 11(11), 1288; https://doi.org/10.3390/genes11111288 - 29 Oct 2020

Cited by 8 | Viewed by 2966

Abstract

A retrospective review of the clinical records of patients seen at the Oxford Eye Hospital identified as having NR2E3 mutations was performed. The data included symptoms, best-corrected visual acuity, multimodal retinal imaging, visual fields and electrophysiology testing. Three participants were identified with biallelic NR2E3 pathogenic sequence variants detected using a targeted NGS gene panel, two of which were novel. Participant I was a Nepalese male aged 68 years, and participants II and III were white Caucasian females aged 69 and 10 years old, respectively. All three had childhood onset nyctalopia, a progressive decrease in central vision, and visual field loss. Patients I and III had photopsia, patient II had photosensitivity and patient III also had photophobia. Visual acuities in patients I and II were preserved even into the seventh decade, with the worst visual acuity measured at 6/36. Visual field constriction was severe in participant I, less so in II, and fields were full to bright targets targets in participant III. Electrophysiology testing in all three demonstrated loss of rod function. The three patients share some of the typical distinctive features of NR2E3 retinopathies, as well as a novel clinical observation of foveal ellipsoid thickening. Full article

(This article belongs to the Special Issue Genomics and Therapeutics of Hereditary Eye Disease)

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20 pages, 4100 KiB

Open AccessArticle

Characterization of the Frmd7 Knock-Out Mice Generated by the EUCOMM/COMP Repository as a Model for Idiopathic Infantile Nystagmus (IIN)

by Ahmed Salman, Samuel B. Hutton, Tutte Newall, Jennifer A. Scott, Helen L. Griffiths, Helena Lee, Diego Gomez-Nicola, Andrew J. Lotery and Jay E. Self

Genes 2020, 11(10), 1157; https://doi.org/10.3390/genes11101157 - 30 Sep 2020

Cited by 4 | Viewed by 2581

Abstract

In this study, we seek to exclude other pathophysiological mechanisms by which Frmd7 knock-down may cause Idiopathic Infantile Nystagmus (IIN) using the Frmd7^.tm1a and Frmd7^.tm1b murine models. We used a combination of genetic, histological and visual function techniques to characterize the role of Frmd7 gene in IIN using a novel murine model for the disease. We demonstrate that the Frmd7^.tm1b allele represents a more robust model of Frmd7 knock-out at the mRNA level. The expression of Frmd7 was investigated using both antibody staining and X-gal staining confirming previous reports that Frmd7 expression in the retina is restricted to starburst amacrine cells and demonstrating that X-gal staining recapitulates the expression pattern in this model. Thus, it offers a useful tool for further expression studies. We also show that gross retinal morphology and electrophysiology are unchanged in these Frmd7 mutant models when compared with wild-type mice. High-speed eye-tracking recordings of Frmd7 mutant mice confirm a specific horizontal optokinetic reflex defect. In summary, our study confirms the likely role for Frmd7 in the optokinetic reflex in mice mediated by starburst amacrine cells. We show that the Frmd7^.tm1b model provides a more robust knock-out than the Frmd7^.tm1a model at the mRNA level, although the functional consequence is unchanged. Finally, we establish a robust eye-tracking technique in mice that can be used in a variety of future studies using this model and others. Although our data highlight a deficit in the optiokinetic reflex as a result of the starburst amacrine cells in the retina, this does not rule out the involvement of other cells, in the brain or the retina where Frmd7 is expressed, in the pathophysiology of IIN. Full article

(This article belongs to the Special Issue Genomics and Therapeutics of Hereditary Eye Disease)

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15 pages, 937 KiB

Open AccessReview

From Transcriptomics to Treatment in Inherited Optic Neuropathies

by Michael James Gilhooley, Nicholas Owen, Mariya Moosajee and Patrick Yu Wai Man

Genes 2021, 12(2), 147; https://doi.org/10.3390/genes12020147 - 22 Jan 2021

Cited by 7 | Viewed by 3711

Abstract

Inherited optic neuropathies, including Leber Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA), are monogenetic diseases with a final common pathway of mitochondrial dysfunction leading to retinal ganglion cell (RGC) death and ultimately loss of vision. They are, therefore, excellent models with which to investigate this ubiquitous disease process—implicated in both common polygenetic ocular diseases (e.g., Glaucoma) and late-onset central nervous system neurodegenerative diseases (e.g., Parkinson disease). In recent years, cellular and animal models of LHON and DOA have matured in parallel with techniques (such as RNA-seq) to determine and analyze the transcriptomes of affected cells. This confluence leaves us at a particularly exciting time with the potential for the identification of novel pathogenic players and therapeutic targets. Here, we present a discussion of the importance of inherited optic neuropathies and how transcriptomic techniques can be exploited in the development of novel mutation-independent, neuroprotective therapies. Full article

(This article belongs to the Special Issue Genomics and Therapeutics of Hereditary Eye Disease)

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29 pages, 2184 KiB

Open AccessEditor’s ChoiceReview

Mechanisms of Photoreceptor Death in Retinitis Pigmentosa

by Fay Newton and Roly Megaw

Genes 2020, 11(10), 1120; https://doi.org/10.3390/genes11101120 - 24 Sep 2020

Cited by 103 | Viewed by 10952

Abstract

Retinitis pigmentosa (RP) is the most common cause of inherited blindness and is characterised by the progressive loss of retinal photoreceptors. However, RP is a highly heterogeneous disease and, while much progress has been made in developing gene replacement and gene editing treatments for RP, it is also necessary to develop treatments that are applicable to all causative mutations. Further understanding of the mechanisms leading to photoreceptor death is essential for the development of these treatments. Recent work has therefore focused on the role of apoptotic and non-apoptotic cell death pathways in RP and the various mechanisms that trigger these pathways in degenerating photoreceptors. In particular, several recent studies have begun to elucidate the role of microglia and innate immune response in the progression of RP. Here, we discuss some of the recent progress in understanding mechanisms of rod and cone photoreceptor death in RP and summarise recent clinical trials targeting these pathways. Full article

(This article belongs to the Special Issue Genomics and Therapeutics of Hereditary Eye Disease)

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8 pages, 3375 KiB

Open AccessCase Report

A Novel Splice-Site Variant in CACNA1F Causes a Phenotype Synonymous with Åland Island Eye Disease and Incomplete Congenital Stationary Night Blindness

by Usman Mahmood, Cécile Méjécase, Syed M. A. Ali, Mariya Moosajee and Igor Kozak

Genes 2021, 12(2), 171; https://doi.org/10.3390/genes12020171 - 27 Jan 2021

Cited by 10 | Viewed by 2227

Abstract

Background: CACNA1F-related disorders encompass progressive and non-progressive disorders, including Åland island eye disease and incomplete congenital stationary night blindness. These two X-linked disorders are characterized by nystagmus, color vision defect, myopia, and electroretinography (ERG) abnormalities. Ocular hypopigmentation and iris transillumination are reported only in patients with Åland island eye disease. Around 260 variants were reported to be associated with these two non-progressive disorders, with 19 specific to Åland island eye disease and 14 associated with both Åland island eye disease and incomplete congenital stationary night blindness. CACNA1F variants spread on the gene and further analysis are needed to reveal phenotype-genotype correlation. Case Report: A complete ocular exam and genetic testing were performed on a 13-year-old boy. A novel splice-site variant, c.4294-11C>G in intron 36 in CACNA1F, was identified at hemizygous state in the patient and at heterozygous state in his asymptomatic mother and explained the phenotype synonymous with Åland island eye disease and incomplete congenital stationary night blindness observed in the patient. Conclusion: We present a novel variant in the CACNA1F gene causing phenotypic and electrophysiologic findings indistinguishable from those of AIED/CSNB2A disease. This finding further expands the mutational spectrum and our knowledge of CACNA1F-related disease. Full article

(This article belongs to the Special Issue Genomics and Therapeutics of Hereditary Eye Disease)

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