Publications by authors named "Gavin Arno"

111 Publications

Comparison of in silico strategies to prioritize rare genomic variants impacting RNA splicing for the diagnosis of genomic disorders.

Sci Rep 2021 Oct 18;11(1):20607. Epub 2021 Oct 18.

North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, St Mary's Hospital, Manchester, UK.

The development of computational methods to assess pathogenicity of pre-messenger RNA splicing variants is critical for diagnosis of human disease. We assessed the capability of eight algorithms, and a consensus approach, to prioritize 249 variants of uncertain significance (VUSs) that underwent splicing functional analyses. The capability of algorithms to differentiate VUSs away from the immediate splice site as being 'pathogenic' or 'benign' is likely to have substantial impact on diagnostic testing. We show that SpliceAI is the best single strategy in this regard, but that combined usage of tools using a weighted approach can increase accuracy further. We incorporated prioritization strategies alongside diagnostic testing for rare disorders. We show that 15% of 2783 referred individuals carry rare variants expected to impact splicing that were not initially identified as 'pathogenic' or 'likely pathogenic'; one in five of these cases could lead to new or refined diagnoses.
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http://dx.doi.org/10.1038/s41598-021-99747-2DOI Listing
October 2021

Pathogenic variants cause a developmental ocular phenotype recapitulated in a mutant mouse model.

Brain Commun 2021 20;3(3):fcab162. Epub 2021 Jul 20.

Department of Ophthalmology, University Hospital of Nimes, Nimes, France.

Pathogenic variants cause a rare autosomal dominant neurodevelopmental disorder referred to as the Bosch-Boonstra-Schaaf Optic Atrophy Syndrome. Although visual loss is a prominent feature seen in affected individuals, the molecular and cellular mechanisms contributing to visual impairment are still poorly characterized. We conducted a deep phenotyping study on a cohort of 22 individuals carrying pathogenic variants to document the neurodevelopmental and ophthalmological manifestations, in particular the structural and functional changes within the retina and the optic nerve, which have not been detailed previously. The visual impairment became apparent in early childhood with small and/or tilted hypoplastic optic nerves observed in 10 cases. High-resolution optical coherence tomography imaging confirmed significant loss of retinal ganglion cells with thinning of the ganglion cell layer, consistent with electrophysiological evidence of retinal ganglion cells dysfunction. Interestingly, for those individuals with available longitudinal ophthalmological data, there was no significant deterioration in visual function during the period of follow-up. Diffusion tensor imaging tractography studies showed defective connections and disorganization of the extracortical visual pathways. To further investigate how pathogenic variants impact on retinal and optic nerve development, we took advantage of an mutant mouse disease model. Abnormal retinogenesis in early stages of development was observed in mutant mice with decreased retinal ganglion cell density and disruption of retinal ganglion cell axonal guidance from the neural retina into the optic stalk, accounting for the development of optic nerve hypoplasia. The mutant mice showed significantly reduced visual acuity based on electrophysiological parameters with marked conduction delay and decreased amplitude of the recordings in the superficial layers of the visual cortex. The clinical observations in our study cohort, supported by the mouse data, suggest an early neurodevelopmental origin for the retinal and optic nerve head defects caused by pathogenic variants, resulting in congenital vision loss that seems to be non-progressive. We propose as a major gene that orchestrates early retinal and optic nerve head development, playing a key role in the maturation of the visual system.
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http://dx.doi.org/10.1093/braincomms/fcab162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397830PMC
July 2021

A rare canonical splice-site variant in VPS13B causes attenuated Cohen syndrome.

Ophthalmic Genet 2021 Aug 23:1-6. Epub 2021 Aug 23.

UCL Institute of Ophthalmology, London, UK.

Background: To describe a patient with a history of obesity, retinal dystrophy, type II diabetes, and mild cognitive impairment; found to harbour biallelic splice-site variants in .

Materials & Methods: A complete ophthalmic evaluation was performed at Moorfields Eye Hospital (London, United Kingdom), consisting of measurement of best-corrected visual acuity (BCVA), slit lamp and dilated fundus evaluation, colour, autofluorescence and near-infrared retinal imaging, spectral domain-optical coherence tomography, and electroretinogram (ERG). Whole-genome sequencing was performed as part of the UK's 100,000 Genomes Project.

Results: A 26-year-old Pakistani man with normal appearance, stature, and head size presented with decreased BCVA and severely constricted visual fields to our Ophthalmic Genetics clinic. He had a history of obesity, type II diabetes, and mild cognitive impairment. His evaluation showed retina-wide, severe photoreceptor dysfunction in both eyes, with undetectable scotopic and photopic ERG waveforms. Genomic analysis identified a homozygous rare splice donor variant in the gene (c.5024+2T>C) that was demonstrated to lead to skipping of the in-frame exon 31 (p.Gln1607_Ser1675delinsHis).

Conclusions: Exon 31 skipping in may lead to a hypomorphic change, with partial gene function and an incomplete, mild Cohen syndrome-like phenotype.
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http://dx.doi.org/10.1080/13816810.2021.1970194DOI Listing
August 2021

Broadening INPP5E phenotypic spectrum: detection of rare variants in syndromic and non-syndromic IRD.

NPJ Genom Med 2021 Jun 29;6(1):53. Epub 2021 Jun 29.

Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.

Pathogenic variants in INPP5E cause Joubert syndrome (JBTS), a ciliopathy with retinal involvement. However, despite sporadic cases in large cohort sequencing studies, a clear association with non-syndromic inherited retinal degenerations (IRDs) has not been made. We validate this association by reporting 16 non-syndromic IRD patients from ten families with bi-allelic mutations in INPP5E. Additional two patients showed early onset IRD with limited JBTS features. Detailed phenotypic description for all probands is presented. We report 14 rare INPP5E variants, 12 of which have not been reported in previous studies. We present tertiary protein modeling and analyze all INPP5E variants for deleteriousness and phenotypic correlation. We observe that the combined impact of INPP5E variants in JBTS and non-syndromic IRD patients does not reveal a clear genotype-phenotype correlation, suggesting the involvement of genetic modifiers. Our study cements the wide phenotypic spectrum of INPP5E disease, adding proof that sequence defects in this gene can lead to early-onset non-syndromic IRD.
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http://dx.doi.org/10.1038/s41525-021-00214-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242099PMC
June 2021

Novel disease-causing variant in presenting with autosomal dominant retinitis pigmentosa.

Br J Ophthalmol 2021 May 24. Epub 2021 May 24.

Cell and Gene Therapy, University College London Institute of Ophthalmology, London, UK

Aim: To describe the clinical and molecular features of a novel, autosomal dominant -retinopathy.

Methods: Retrospective cross-sectional study. Twelve individuals from a four-generation British pedigree underwent ophthalmic examination, genotyping using next generation sequencing, including whole genome sequencing and multimodal retinal imaging including fundus photography, optical coherence tomography (OCT), autofluorescence imaging and adaptive optics (AO) scanning light ophthalmoscopy were performed. Visual electrophysiology was performed in a subset.

Results: Eight family members were confirmed as affected by genotyping heterozygous for c.763delG. Visual acuity ranged from -0.1 to 0.2 logMAR. Affected individuals had constricted visual fields. A parafoveal and peripapillary ring of hyper-autofluorescence was seen initially, and with progression the area of perifoveal hypo-autofluorescence increased to involve the parafoveal area. Mild retinal thinning was identified on OCT imaging with reduction in both foveal total retinal and outer nuclear layer thickness. Cone densities along the temporal meridian were reduced in affected individuals compared with normative values at all temporal eccentricities studied. One individual with incomplete penetrance, was identified as clinically affected primarily on the basis of AO imaging. Full-field electroretinography demonstrated a rod-cone pattern of dysfunction and large-field pattern electroretinography identified peripheral macular dysfunction.

Conclusions: This novel heterozygous variant c.763delG is associated with a rod-cone dystrophy with variable expression. Determination of the degree of penetrance may depend on the modality employed to phenotypically characterise an individual. This rare and specific heterozygous (dominant) variant is predicted to result in a gain of function, that causes disease in a gene typically associated with biallelic (recessive) variants.
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http://dx.doi.org/10.1136/bjophthalmol-2020-318034DOI Listing
May 2021

Long-Read Sequencing to Unravel Complex Structural Variants of Leading to Cone-Rod Dystrophy and Hearing Loss.

Front Cell Dev Biol 2021 21;9:664317. Epub 2021 Apr 21.

Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.

Inactivating variants as well as a missense variant in the centrosomal gene have been identified in autosomal recessive cone-rod dystrophy with hearing loss (CRDHL), a rare syndromic inherited retinal disease distinct from Usher syndrome. Apart from this, a complex structural variant (SV) implicating has been reported in CRDHL. Here we aimed to expand the genetic architecture of typical CRDHL by the identification of complex SVs of the region and characterization of their underlying mechanisms. Approaches used for the identification of the SVs are shallow whole-genome sequencing (sWGS) combined with quantitative polymerase chain reaction (PCR) and long-range PCR, or ExomeDepth analysis on whole-exome sequencing (WES) data. Targeted or whole-genome nanopore long-read sequencing (LRS) was used to delineate breakpoint junctions at the nucleotide level. For all SVs cases, the effect of the SVs on expression was assessed using quantitative PCR on patient-derived RNA. Apart from two novel canonical splice variants and a frameshifting single-nucleotide variant (SNV), two SVs affecting were identified in three unrelated individuals with CRDHL: a heterozygous total gene deletion of 235 kb and a partial gene deletion of 15 kb in a heterozygous and homozygous state, respectively. Assessment of the molecular consequences of the SVs on patient's materials displayed a loss-of-function effect. Delineation and characterization of the 15-kb deletion using targeted LRS revealed the previously described complex SV, suggestive of a recurrent genomic rearrangement. A founder haplotype was demonstrated for the latter SV in cases of Belgian and British origin, respectively. The novel 235-kb deletion was delineated using whole-genome LRS. Breakpoint analysis showed microhomology and pointed to a replication-based underlying mechanism. Moreover, data mining of bulk and single-cell human and mouse transcriptional datasets, together with CEP78 immunostaining on human retina, linked the CEP78 expression domain with its phenotypic manifestations. Overall, this study supports that the locus is prone to distinct SVs and that SV analysis should be considered in a genetic workup of CRDHL. Finally, it demonstrated the power of sWGS and both targeted and whole-genome LRS in identifying and characterizing complex SVs in patients with ocular diseases.
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http://dx.doi.org/10.3389/fcell.2021.664317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097100PMC
April 2021

Expanding the FDXR-Associated Disease Phenotype: Retinal Dystrophy Is a Recurrent Ocular Feature.

Invest Ophthalmol Vis Sci 2021 05;62(6)

Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom.

Purpose: The purpose of this study was to report retinal dystrophy as a novel clinical feature and expand the ocular phenotype in patients harboring biallelic candidate FDXR variants.

Methods: Patients carrying biallelic candidate FDXR variants were identified by whole genome sequencing (WGS) as part of the National Institute for Health Research BioResource rare-disease and the UK's 100,000 Genomes Project (100KGP) with an additional case identified by exome sequencing. Retrospective clinical data were collected from the medical records. Haplotype reconstruction was performed in families harboring the same missense variant.

Results: Ten individuals from 8 unrelated families with biallelic candidate variants in FDXR were identified. In addition to bilateral optic atrophy and variable extra-ocular findings, 7 of 10 individuals manifested retinal dystrophy comprising dysfunction and degeneration of both rod and cone photoreceptors. Five of 10 subjects had sensorineural hearing loss. The previously unreported missense variant (c.1115C > A, p.(Pro372His)) was found in 5 of 8 (62.5%) study families. Haplotype reconstruction using WGS data demonstrated a likely ancestral haplotype.

Conclusions: FDXR-associated disease is a phenotypically heterogeneous disorder with retinal dystrophy being a major clinical feature observed in this cohort. In addition, we hypothesize that a number of factors are likely to drive the pathogenesis of optic atrophy, retinal degeneration, and perhaps the associated systemic manifestations.
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http://dx.doi.org/10.1167/iovs.62.6.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107637PMC
May 2021

Panel-based genetic testing for inherited retinal disease screening 176 genes.

Mol Genet Genomic Med 2021 Mar 22:e1663. Epub 2021 Mar 22.

Moorfields Eye Hospital NHS Foundation Trust, London, UK.

Background: This case series reports the performance of a next-generation sequencing (NGS) panel of 176 retinal genes (NGS 176) in patients with inherited retinal disease (IRD).

Methods: Subjects are patients who underwent genetic testing between 1 August 2016 and 1 January 2018 at Moorfields Eye Hospital, London, UK. Panel-based genetic testing was performed unless a specific gene (e.g., RS1) or small group of genes (e.g., ABCA4, PRPH2) were suspected. If a novel variant was identified, a further comment on their predicted pathogenicity and evolutionary conservation was offered and segregation studies performed. The main outcome measure is the likelihood of obtaining a genetic diagnosis using NGS 176.

Results: 488 patients were included. A molecular diagnosis was obtained for 59.4% of patients. Younger patients were more likely to receive a molecular diagnosis; with 92% of children under the age of 6 years receiving a conclusive result. There was a change in their initially assigned inheritance pattern in 8.4% of patients following genetic testing. Selected IRD diagnoses (e.g., achromatopsia, congenital stationary night blindness) were associated with high diagnostic yields.

Conclusion: This study confirms that NGS 176 is a useful first-tier genetic test for most IRD patients. Age and initial clinical diagnosis were strongly associated with diagnostic yield.
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http://dx.doi.org/10.1002/mgg3.1663DOI Listing
March 2021

KCNV2-Associated Retinopathy: Detailed Retinal Phenotype and Structural Endpoints-KCNV2 Study Group Report 2.

Am J Ophthalmol 2021 Mar 15;230:1-11. Epub 2021 Mar 15.

Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, the Hebrew University of Jerusalem, Jerusalem, Israel.

Purpose: To describe the detailed retinal phenotype of KCNV2-associated retinopathy.

Study Design: Multicenter international retrospective case series.

Methods: Review of retinal imaging including fundus autofluorescence (FAF) and optical coherence tomography (OCT), including qualitative and quantitative analyses.

Results: Three distinct macular FAF features were identified: (1) centrally increased signal (n = 35, 41.7%), (2) decreased autofluorescence (n = 27, 31.1%), and (3) ring of increased signal (n = 37, 44.0%). Five distinct FAF groups were identified based on combinations of those features, with 23.5% of patients changing the FAF group over a mean (range) follow-up of 5.9 years (1.9-13.1 years). Qualitative assessment was performed by grading OCT into 5 grades: (1) continuous ellipsoid zone (EZ) (20.5%); (2) EZ disruption (26.1%); (3) EZ absence, without optical gap and with preserved retinal pigment epithelium complex (21.6%); (4) loss of EZ and a hyporeflective zone at the foveola (6.8%); and (5) outer retina and retinal pigment epithelium complex loss (25.0%). Eighty-six patients had scans available from both eyes, with 83 (96.5%) having the same grade in both eyes, and 36.1% changed OCT grade over a mean follow-up of 5.5 years. The annual rate of outer nuclear layer thickness change was similar for right and left eyes.

Conclusions: KCNV2-associated retinopathy is a slowly progressive disease with early retinal changes, which are predominantly symmetric between eyes. The identification of a single OCT or FAF measurement as an endpoint to determine progression that applies to all patients may be challenging, although outer nuclear layer thickness is a potential biomarker. Findings suggest a potential window for intervention until 40 years of age.
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http://dx.doi.org/10.1016/j.ajo.2021.03.004DOI Listing
March 2021

KCNV2-Associated Retinopathy: Genetics, Electrophysiology, and Clinical Course-KCNV2 Study Group Report 1.

Am J Ophthalmol 2021 05 11;225:95-107. Epub 2020 Dec 11.

Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.

Purpose: To investigate genetics, electrophysiology, and clinical course of KCNV2-associated retinopathy in a cohort of children and adults.

Study Design: This was a multicenter international clinical cohort study.

Methods: Review of clinical notes and molecular genetic testing. Full-field electroretinography (ERG) recordings, incorporating the international standards, were reviewed and quantified and compared with age and recordings from control subjects.

Results: In total, 230 disease-associated alleles were identified from 117 patients, corresponding to 75 different KCNV2 variants, with 28 being novel. The mean age of onset was 3.9 years old. All patients were symptomatic before 12 years of age (range, 0-11 years). Decreased visual acuity was present in all patients, and 4 other symptoms were common: reduced color vision (78.6%), photophobia (53.5%), nyctalopia (43.6%), and nystagmus (38.6%). After a mean follow-up of 8.4 years, the mean best-corrected visual acuity (BCVA ± SD) decreased from 0.81 ± 0.27 to 0.90 ± 0.31 logarithm of minimal angle of resolution. Full-field ERGs showed pathognomonic waveform features. Quantitative assessment revealed a wide range of ERG amplitudes and peak times, with a mean rate of age-associated reduction indistinguishable from the control group. Mean amplitude reductions for the dark-adapted 0.01 ERG, dark-adapted 10 ERG a-wave, and LA 3.0 30 Hz and LA3 ERG b-waves were 55%, 21%, 48%, and 74%, respectively compared with control values. Peak times showed stability across 6 decades.

Conclusion: In KCNV2-associated retinopathy, full-field ERGs are diagnostic and consistent with largely stable peripheral retinal dysfunction. Report 1 highlights the severity of the clinical phenotype and established a large cohort of patients, emphasizing the unmet need for trials of novel therapeutics.
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http://dx.doi.org/10.1016/j.ajo.2020.11.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186730PMC
May 2021

New variants and in silico analyses in GRK1 associated Oguchi disease.

Hum Mutat 2021 Feb 30;42(2):164-176. Epub 2020 Nov 30.

Division of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds, UK.

Biallelic mutations in G-Protein coupled receptor kinase 1 (GRK1) cause Oguchi disease, a rare subtype of congenital stationary night blindness (CSNB). The purpose of this study was to identify disease causing GRK1 variants and use in-depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity. Patients' genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Disease associated variants, published and novel, were compared to nondisease associated missense variants. The impact of GRK1 missense variants at the protein level were then predicted using a series of computational tools. We identified twelve previously unpublished cases with biallelic disease associated GRK1 variants, including eight novel variants, and reviewed all GRK1 disease associated variants. Further structure-based scoring revealed a hotspot for missense variants in the kinase domain. In addition, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate disease associated from nondisease associated variants. We identified GRK1 variants in Oguchi disease patients and investigated how disease-causing variants may impede protein function in-silico.
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http://dx.doi.org/10.1002/humu.24140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898643PMC
February 2021

Phenotype and Genotype Correlations in Inherited Retinal Diseases: Population-Guided Variant Interpretation, Variable Expressivity and Incomplete Penetrance.

Genes (Basel) 2020 10 29;11(11). Epub 2020 Oct 29.

University College London Institute of Ophthalmology, London EC1V 9EL, UK.

Inherited retinal diseases (IRDs) are a diverse and variable group of rare human disorders [...].
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http://dx.doi.org/10.3390/genes11111274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692259PMC
October 2020

Clinical and Genetic Findings in CTNNA1-Associated Macular Pattern Dystrophy.

Ophthalmology 2021 06 1;128(6):952-955. Epub 2020 Nov 1.

UCL Institute of Ophthalmology, University College London, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom; Section of Ophthalmology, King's College London, St. Thomas' Hospital, London, United Kingdom; Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.ophtha.2020.10.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162661PMC
June 2021

Ceramide synthase TLCD3B is a novel gene associated with human recessive retinal dystrophy.

Genet Med 2021 03 20;23(3):488-497. Epub 2020 Oct 20.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.

Purpose: Previous studies suggest that ceramide is a proapoptotic lipid as high levels of ceramides can lead to apoptosis of neuronal cells, including photoreceptors. However, no pathogenic variant in ceramide synthases has been identified in human patients and knockout of various ceramide synthases in mice has not led to photoreceptor degeneration.

Methods: Exome sequencing was used to identify candidate disease genes in patients with vision loss as confirmed by standard evaluation methods, including electroretinography (ERG) and optical coherence tomography. The vision loss phenotype in mice was evaluated by ERG and histological analyses.

Results: Here we have identified four patients with cone-rod dystrophy or maculopathy from three families carrying pathogenic variants in TLCD3B. Consistent with the phenotype observed in patients, the Tlcd3b mice exhibited a significant reduction of the cone photoreceptor light responses, thinning of the outer nuclear layer, and loss of cone photoreceptors across the retina.

Conclusion: Our results provide a link between loss-of-function variants in a ceramide synthase gene and human retinal dystrophy. Establishment of the Tlcd3b knockout murine model, an in vivo photoreceptor cell degeneration model due to loss of a ceramide synthase, will provide a unique opportunity in probing the role of ceramide in survival and function of photoreceptor cells.
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http://dx.doi.org/10.1038/s41436-020-01003-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936949PMC
March 2021

Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa.

Am J Hum Genet 2020 11 5;107(5):802-814. Epub 2020 Oct 5.

University of Cape Town/MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, 7935, South Africa.

The cause of autosomal-dominant retinitis pigmentosa (adRP), which leads to loss of vision and blindness, was investigated in families lacking a molecular diagnosis. A refined locus for adRP on Chr17q22 (RP17) was delineated through genotyping and genome sequencing, leading to the identification of structural variants (SVs) that segregate with disease. Eight different complex SVs were characterized in 22 adRP-affected families with >300 affected individuals. All RP17 SVs had breakpoints within a genomic region spanning YPEL2 to LINC01476. To investigate the mechanism of disease, we reprogrammed fibroblasts from affected individuals and controls into induced pluripotent stem cells (iPSCs) and differentiated them into photoreceptor precursor cells (PPCs) or retinal organoids (ROs). Hi-C was performed on ROs, and differential expression of regional genes and a retinal enhancer RNA at this locus was assessed by qPCR. The epigenetic landscape of the region, and Hi-C RO data, showed that YPEL2 sits within its own topologically associating domain (TAD), rich in enhancers with binding sites for retinal transcription factors. The Hi-C map of RP17 ROs revealed creation of a neo-TAD with ectopic contacts between GDPD1 and retinal enhancers, and modeling of all RP17 SVs was consistent with neo-TADs leading to ectopic retinal-specific enhancer-GDPD1 accessibility. qPCR confirmed increased expression of GDPD1 and increased expression of the retinal enhancer that enters the neo-TAD. Altered TAD structure resulting in increased retinal expression of GDPD1 is the likely convergent mechanism of disease, consistent with a dominant gain of function. Our study highlights the importance of SVs as a genomic mechanism in unsolved Mendelian diseases.
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http://dx.doi.org/10.1016/j.ajhg.2020.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675008PMC
November 2020

Practical guide to genetic screening for inherited eye diseases.

Ther Adv Ophthalmol 2020 Jan-Dec;12:2515841420954592. Epub 2020 Sep 22.

Professor, Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.

Genetic eye diseases affect around one in 1000 people worldwide for which the molecular aetiology remains unknown in the majority. The identification of disease-causing gene variant(s) allows a better understanding of the disorder and its inheritance. There is now an approved retinal gene therapy for autosomal recessive retinopathy, and numerous ocular gene/mutation-targeted clinical trials underway, highlighting the importance of establishing a genetic diagnosis so patients can fully access the latest research developments and treatment options. In this review, we will provide a practical guide to managing patients with these conditions including an overview of inheritance patterns, required pre- and post-test genetic counselling, different types of cytogenetic and genetic testing available, with a focus on next generation sequencing using targeted gene panels, whole exome and genome sequencing. We will expand on the pros and cons of each modality, variant interpretation and options for family planning for the patient and their family. With the advent of genomic medicine, genetic screening will soon become mainstream within all ophthalmology subspecialties for prevention of disease and provision of precision therapeutics.
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http://dx.doi.org/10.1177/2515841420954592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513416PMC
September 2020

Ocular genetics in the genomics age.

Am J Med Genet C Semin Med Genet 2020 09 8;184(3):860-868. Epub 2020 Sep 8.

University College London Institute of Ophthalmology, London, UK.

Current genetic screening methods for inherited eye diseases are concentrated on the coding exons of known disease genes (gene panels, clinical exome). These tests have a variable and often limited diagnostic rate depending on the clinical presentation, size of the gene panel and our understanding of the inheritance of the disorder (with examples described in this issue). There are numerous possible explanations for the missing heritability of these cases including undetected variants within the relevant gene (intronic, up/down-stream and structural variants), variants harbored in genes outside the targeted panel, intergenic variants, variants undetectable by the applied technology, complex/non-Mendelian inheritance, and nongenetic phenocopies. In this article we further explore and review methods to investigate these sources of missing heritability.
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http://dx.doi.org/10.1002/ajmg.c.31844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170588PMC
September 2020

RP2-associated retinal disorder in a Japanese cohort: Report of novel variants and a literature review, identifying a genotype-phenotype association.

Am J Med Genet C Semin Med Genet 2020 09 1;184(3):675-693. Epub 2020 Sep 1.

Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.

The retinitis pigmentosa 2 (RP2) gene is one of the causative genes for X-linked inherited retinal disorder. We characterized the clinical/genetic features of four patients with RP2-associated retinal disorder (RP2-RD) from four Japanese families in a nationwide cohort. A systematic review of RP2-RD in the Japanese population was also performed. All four patients were clinically diagnosed with retinitis pigmentosa (RP). The mean age at examination was 36.5 (10-47) years, and the mean visual acuity in the right/left eye was 1.40 (0.52-2.0)/1.10 (0.52-1.7) in the logarithm of the minimum angle of resolution unit, respectively. Three patients showed extensive retinal atrophy with macular involvement, and one had central retinal atrophy. Four RP2 variants were identified, including two novel missense (p.Ser6Phe, p.Leu189Pro) and two previously reported truncating variants (p.Arg120Ter, p.Glu269CysfsTer3). The phenotypes of two patients with truncating variants were more severe than the phenotypes of two patients with missense variants. A systematic review revealed additional 11 variants, including three missense and eight deleterious (null) variants, and a statistically significant association between phenotype severity and genotype severity was revealed. The clinical and genetic spectrum of RP2-RD was illustrated in the Japanese population, identifying the characteristic features of a severe form of RP with early macular involvement.
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http://dx.doi.org/10.1002/ajmg.c.31830DOI Listing
September 2020

Clinical and molecular findings in a cohort of 152 Brazilian severe early onset inherited retinal dystrophy patients.

Am J Med Genet C Semin Med Genet 2020 09 31;184(3):728-752. Epub 2020 Aug 31.

Department of Ophthalmology, Universidade Federal de São Paulo, Sao Paulo, Brazil.

Leber congenital amaurosis (LCA) and early-onset retinal dystrophy (EORD) are severe inherited retinal dystrophy that can cause deep blindness childhood. They represent 5% of all retinal dystrophies in the world population and about 10% in Brazil. Clinical findings and molecular basis of syndromic and nonsyndromic LCA/EORD in a Brazilian sample (152 patients/137 families) were studied. In this population, 15 genes were found to be related to the phenotype, 38 new variants were detected and four new complex alleles were discovered. Among 123 variants found, the most common were CEP290: c.2991+1655A>G, CRB1: p.Cys948Tyr, and RPGRIP1: exon10-18 deletion.
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http://dx.doi.org/10.1002/ajmg.c.31828DOI Listing
September 2020

Introduction to the special issue on Ophthalmic Genetics: Vision in 2020.

Am J Med Genet C Semin Med Genet 2020 09 31;184(3):535-537. Epub 2020 Aug 31.

University College London Institute of Ophthalmology, London, UK.

In this special issue of the American Journal of Medical Genetics, Part C, we explore the ever-expanding field of Ophthalmic Genetics. The eye is unique among organs for its accessibility to physical examination, permitting exploration of every tissue by slit lamp microscopy, ophthalmoscopy, and imaging including color and autofluorescent photography, ultrasound, optical coherence tomography (OCT), electrophysiology, and adaptive optics confocal and scanning laser ophthalmoscopy. This accessibility permits a variety of surgical and nonsurgical treatments, including the first FDA-approved gene therapy, voretigene neparvovec-rzyl for RPE65-associated Leber Congenital Amaurosis. In this issue, we sought to provide a survey highlighting how heritable ophthalmic disorders are recognizable and accessible to clinical geneticists as well as ophthalmologists.
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http://dx.doi.org/10.1002/ajmg.c.31841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117941PMC
September 2020

The X-linked retinopathies: Physiological insights, pathogenic mechanisms, phenotypic features and novel therapies.

Prog Retin Eye Res 2021 05 26;82:100898. Epub 2020 Aug 26.

UCL Institute of Ophthalmology, University College London, UK; Moorfields Eye Hospital NHS Foundation Trust, London, UK; Department of Ophthalmology, Guy's & St Thomas' NHS Foundation Trust, London, UK; Section of Ophthalmology, King's College London, UK; Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK. Electronic address:

X-linked retinopathies represent a significant proportion of monogenic retinal disease. They include progressive and stationary conditions, with and without syndromic features. Many are X-linked recessive, but several exhibit a phenotype in female carriers, which can help establish diagnosis and yield insights into disease mechanisms. The presence of affected carriers can misleadingly suggest autosomal dominant inheritance. Some disorders (such as RPGR-associated retinopathy) show diverse phenotypes from variants in the same gene and also highlight limitations of current genetic sequencing methods. X-linked disease frequently arises from loss of function, implying potential for benefit from gene replacement strategies. We review X-inactivation and X-linked inheritance, and explore burden of disease attributable to X-linked genes in our clinically and genetically characterised retinal disease cohort, finding correlation between gene transcript length and numbers of families. We list relevant genes and discuss key clinical features, disease mechanisms, carrier phenotypes and novel experimental therapies. We consider in detail the following: RPGR (associated with retinitis pigmentosa, cone and cone-rod dystrophy), RP2 (retinitis pigmentosa), CHM (choroideremia), RS1 (X-linked retinoschisis), NYX (complete congenital stationary night blindness (CSNB)), CACNA1F (incomplete CSNB), OPN1LW/OPN1MW (blue cone monochromacy, Bornholm eye disease, cone dystrophy), GPR143 (ocular albinism), COL4A5 (Alport syndrome), and NDP (Norrie disease and X-linked familial exudative vitreoretinopathy (FEVR)). We use a recently published transcriptome analysis to explore expression by cell-type and discuss insights from electrophysiology. In the final section, we present an algorithm for genes to consider in diagnosing males with non-syndromic X-linked retinopathy, summarise current experimental therapeutic approaches, and consider questions for future research.
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http://dx.doi.org/10.1016/j.preteyeres.2020.100898DOI Listing
May 2021

Clinical and Genetic Characteristics of 15 Affected Patients From 12 Japanese Families with -Associated Retinal Disorder.

Transl Vis Sci Technol 2020 05 11;9(6). Epub 2020 May 11.

Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Meguro-ku, Tokyo, Japan.

Purpose: To determine the clinical and genetic characteristics of patients with -associated retinal disorder (-RD).

Methods: Fifteen patients from 12 families with inherited retinal disorder (IRD) and harboring variants were ascertained from 730 Japanese families with IRD. Comprehensive ophthalmological examinations, including visual acuity (VA) measurement, retinal imaging, and electrophysiological assessment were performed to classify patients into three phenotype subgroups; macular dystrophy (MD), cone-rod dystrophy (CORD), and Leber congenital amaurosis (LCA). In silico analysis was performed for the detected variants, and the molecularly confirmed inheritance pattern was determined (autosomal dominant/recessive [AD/AR]).

Results: The median age of onset/examination was 22.0/38.0 years (ranges, 0-55 and 1-73) with a median VA of 0.80/0.70 LogMAR units (ranges, 0.00-1.52 and 0.10-1.52) in the right/left eye, respectively. Macular atrophy was identified in seven patients (46.7%), and two had diffuse fundus disturbance (13.3%), and six had an essentially normal fundus (40.0%). There were 11 patients with generalized cone-rod dysfunction (78.6%), two with entire functional loss (14.3%), and one with confined macular dysfunction (7.1%). There were nine families with ADCORD, one with ARCORD, one with ADMD, and one with ARLCA. Ten variants were identified, including four novel variants (p.Val56GlyfsTer262, p.Met246Ile, p.Arg761Trp, p.Glu874Lys).

Conclusions: This large cohort study delineates the disease spectrum of -RD. Diverse clinical presentations with various severities of ADCORD and the early-onset severe phenotype of ARLCA are illustrated. A relatively lower prevalence of -RD for ADCORD and ARLCA in the Japanese population was revealed.

Translational Relevance: The obtained data help to monitor and counsel patients, especially in East Asia, as well as to design future therapeutic approaches.
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http://dx.doi.org/10.1167/tvst.9.6.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408927PMC
May 2020

Clinical and genetic characteristics of 10 Japanese patients with PROM1-associated retinal disorder: A report of the phenotype spectrum and a literature review in the Japanese population.

Am J Med Genet C Semin Med Genet 2020 09 20;184(3):656-674. Epub 2020 Aug 20.

Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.

Variants in the PROM1 gene are associated with cone (-rod) dystrophy, macular dystrophy, and other phenotypes. We describe the clinical and genetic characteristics of 10 patients from eight Japanese families with PROM1-associated retinal disorder (PROM1-RD) in a nationwide cohort. A literature review of PROM1-RD in the Japanese population was also performed. The median age at onset/examination of 10 patients was 31.0 (range, 10-45)/44.5 (22-73) years. All 10 patients showed atrophic macular changes. Seven patients (70.0%) had spared fovea to various degrees, approximately half of whom had maintained visual acuity. Generalized cone (-rod) dysfunction was demonstrated in all nine subjects with available electrophysiological data. Three PROM1 variants were identified in this study: one recurrent disease-causing variant (p.Arg373Cys), one novel putative disease-causing variant (p.Cys112Arg), and one novel variant of uncertain significance (VUS; p.Gly53Asp). Characteristic features of macular atrophy with generalized cone-dominated retinal dysfunction were shared among all 10 subjects with PROM1-RD, and the presence of foveal sparing was crucial in maintaining visual acuity. Together with the three previously reported variants [p.R373C, c.1551+1G>A (pathogenic), p.Asn580His (likely benign)] in the literature of Japanese patients, one prevalent missense variant (p.Arg373Cys, 6/9 families, 66.7%) detected in multiple studies was determined in the Japanese population, which was also frequently detected in the European population.
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http://dx.doi.org/10.1002/ajmg.c.31826DOI Listing
September 2020

Macula-predominant retinopathy associated with biallelic variants in .

Ophthalmic Genet 2020 12 13;41(6):612-615. Epub 2020 Aug 13.

UCL Institute of Ophthalmology, University College London , London, UK.

Purpose: To describe the clinical, electrophysiological, and molecular features of an unusual macula-predominant retinopathy in two unrelated probands with biallelic variants in .

Methods: Retrospective case series.

Results: A 29-year-old female presented with visual loss since the age of 14 years. Retinal examination revealed symmetric outer retinal atrophy in the posterior pole with peripapillary sparing. Fundus autofluorescence (AF) showed patchy loss of AF in the posterior pole, with hyper-autofluorescent borders. Optical coherence tomography (OCT) showed loss of the macular outer retinal layers. Pattern electroretinography (PERG) showed macular dysfunction and full-field ERG indicated mild loss of photoreceptor function. Next-generation sequencing (NGS) identified two variants in : p.(Arg234His) and c.448 + 1 G > A in . The second patient was a 10-year-old male with bilateral macular changes and visual loss. Retinal examination showed bilateral macular cloverleaf-like outer retinal changes, with relative foveal sparing. Fundus AF showed bilateral macular hypo-autofluorescent patches with a border of increased signal and preserved foveal AF. OCT showed attenuation of the perifoveal outer retinal layers in the regions of reduced AF signal. PERG showed macular dysfunction, but the full-field ERG was normal. NGS and whole-genome sequencing identified two variants in : p.(Arg234His) and p.(Cys245_Leu247deI) in .

Conclusions: Disease-causing variants in are typically associated with early-onset severe retinal dystrophy with significant macular involvement. Hypomorphic alleles of this gene cause relatively mild retinopathy with predominant macular involvement. This phenotype demonstrates the vulnerability of the macular photoreceptors to certain perturbations of .
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http://dx.doi.org/10.1080/13816810.2020.1802763DOI Listing
December 2020

A genetic and clinical study of individuals with nonsyndromic retinopathy consequent upon sequence variants in HGSNAT, the gene associated with Sanfilippo C mucopolysaccharidosis.

Am J Med Genet C Semin Med Genet 2020 09 7;184(3):631-643. Epub 2020 Aug 7.

Genetics Service, Moorfields Eye Hospital, London, UK.

Pathogenic variants in the gene HGSNAT (heparan-α-glucosaminide N-acetyltransferase) have been reported to underlie two distinct recessive conditions, depending on the specific genotype, mucopolysaccharidosis type IIIC (MPSIIIC)-a severe childhood-onset lysosomal storage disorder, and adult-onset nonsyndromic retinitis pigmentosa (RP). Here we describe the largest cohort to-date of HGSNAT-associated nonsyndromic RP patients, and describe their retinal phenotype, leukocyte enzymatic activity, and likely pathogenic genotypes. We identified biallelic HGSNAT variants in 17 individuals (15 families) as the likely cause of their RP. None showed any other symptoms of MPSIIIC. All had a mild but significant reduction of HGSNAT enzyme activity in leukocytes. The retinal condition was generally of late-onset, showing progressive degeneration of a concentric area of paramacular retina, with preservation but reduced electroretinogram responses. Symptoms, electrophysiology, and imaging suggest the rod photoreceptor to be the cell initially compromised. HGSNAT enzymatic testing was useful in resolving diagnostic dilemmas in compatible patients. We identified seven novel sequence variants [p.(Arg239Cys); p.(Ser296Leu); p.(Phe428Cys); p.(Gly248Ala); p.(Gly418Arg), c.1543-2A>C; c.1708delA], three of which were considered to be retina-disease-specific alleles. The most prevalent retina-disease-specific allele p.(Ala615Thr) was observed heterozygously or homozygously in 8 and 5 individuals respectively (7 and 4 families). Two siblings in one family, while identical for the HGSNAT locus, but discordant for retinal disease, suggest the influence of trans-acting genetic or environmental modifying factors.
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http://dx.doi.org/10.1002/ajmg.c.31822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125330PMC
September 2020

DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration.

Genet Med 2020 12 5;22(12):2041-2051. Epub 2020 Aug 5.

Department of Biological Sciences, Birbeck, University of London, London, UK.

Purpose: Determining the role of DYNC2H1 variants in nonsyndromic inherited retinal disease (IRD).

Methods: Genome and exome sequencing were performed for five unrelated cases of IRD with no identified variant. In vitro assays were developed to validate the variants identified (fibroblast assay, induced pluripotent stem cell [iPSC] derived retinal organoids, and a dynein motility assay).

Results: Four novel DYNC2H1 variants (V1, g.103327020_103327021dup; V2, g.103055779A>T; V3, g.103112272C>G; V4, g.103070104A>C) and one previously reported variant (V5, g.103339363T>G) were identified. In proband 1 (V1/V2), V1 was predicted to introduce a premature termination codon (PTC), whereas V2 disrupted the exon 41 splice donor site causing incomplete skipping of exon 41. V1 and V2 impaired dynein-2 motility in vitro and perturbed IFT88 distribution within cilia. V3, homozygous in probands 2-4, is predicted to cause a PTC in a retina-predominant transcript. Analysis of retinal organoids showed that this new transcript expression increased with organoid differentiation. V4, a novel missense variant, was in trans with V5, previously associated with Jeune asphyxiating thoracic dystrophy (JATD).

Conclusion: The DYNC2H1 variants discussed herein were either hypomorphic or affecting a retina-predominant transcript and caused nonsyndromic IRD. Dynein variants, specifically DYNC2H1 variants are reported as a cause of non syndromic IRD.
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http://dx.doi.org/10.1038/s41436-020-0915-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708302PMC
December 2020

Spatial Functional Characteristics of East Asian Patients With Occult Macular Dystrophy (Miyake Disease); EAOMD Report No. 2.

Am J Ophthalmol 2021 01 21;221:169-180. Epub 2020 Jul 21.

Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan; Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan; UCL Institute of Ophthalmology, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom. Electronic address:

Purpose: To describe the functional phenotypic features of East Asian patients with RP1L1-associated occult macular dystrophy (ie, Miyake disease).

Design: An international multicenter retrospective cohort study.

Methods: Twenty-eight participants (53 eyes) with Miyake disease were enrolled at 3 centers (in Japan, China, and South Korea). Ophthalmologic examinations including spectral-domain optical coherence tomography (SDOCT) and multifocal electroretinogram (mfERG) were performed. Patients were classified into 3 functional groups based on mfERG: Group 1, paracentral dysfunction with relatively preserved central/peripheral function; Group 2, homogeneous central dysfunction with preserved peripheral function; and Group 3, widespread dysfunction over the recorded area. Three functional phenotypes were compared in clinical parameters and SDOCT morphologic classification (severe phenotype, blurred/flat ellipsoid zone and absence of the interdigitation zone; mild phenotype, preserved ellipsoid zone).

Results: There were 8 eyes in Group 1, 40 eyes in Group 2, and 5 eyes in Group 3. The patients in Group 1 showed significantly later onset (P = .005) and shorter disease duration (P = .002), compared with those in Group 2. All 8 eyes in Group 1 showed the mild morphologic phenotype, while 43 of 45 eyes in Groups 2 and 3 presented the severe phenotype, which identified a significant association between the functional grouping and the morphologic classification (P < .001).

Conclusions: A spectrum of functional phenotypes of Miyake disease was first documented with identification of 3 functional subtypes. Patients with paracentral dysfunction had the mildest phenotype, and those with homogeneous central or widespread dysfunction showed overlapping clinical findings with severe photoreceptor changes, suggesting various extents of visual impairment.
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http://dx.doi.org/10.1016/j.ajo.2020.07.025DOI Listing
January 2021

A clinical study of patients with novel CDHR1 genotypes associated with late-onset macular dystrophy.

Eye (Lond) 2021 May 17;35(5):1482-1489. Epub 2020 Jul 17.

Moorfields Eye Hospital, London, UK.

Purpose: To describe the clinical and electrophysiological features of adult-onset macular dystrophy, due to novel combinations of CDHR1 alleles, and compare the associated phenotypes with previous reports.

Methods: The clinical records of patients with macular dystrophy and biallelic variants in CDHR1 were reviewed. Data analysed included best corrected visual acuity (BCVA), fundus images: autofluorescence (AF) and optical coherence tomography (OCT); full field electroretinography (ERG) and pattern ERG (PERG).

Results: Seven patients from six pedigrees were ascertained. One patient was homozygous for a known synonymous variant p.(Pro261=), four were compound heterozygous for the p.(Pro261=) variant and a novel allele of CDHR1: p.(Gly188Ser), p.(Met1?), or p.(Val458Asp); one patient was compound heterozygous for two previously unreported variants: c.297+1G>T in trans with p.(Pro735Thr). The range of BCVA at the last clinic review was (6/5-6/60). Autofluorescence showed macular flecks of increased AF in mild cases and patches of reduced AF in severe cases. The OCT showed attenuation of the ellipsoid zone (EZ) in mild cases and loss of the EZ and the outer nuclear layer in severe cases; one patient had subfoveal hyporeflective region between the EZ and the retinal pigment epithelium. The full field ERG was normal or borderline subnormal in all cases, and the PERG was subnormal in mild cases or undetectable in severe cases.

Conclusions: This report corroborates previous observations that genotypes distinct from those causing pan-retinal dystrophy can cause a milder phenotype, predominantly affecting the macula, and expands the spectrum of these genotypes. The findings in this cohort suggest a potential macular susceptibility to mild perturbations of the photoreceptor cadherin.
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http://dx.doi.org/10.1038/s41433-020-1045-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182786PMC
May 2021

Enhanced S-Cone Syndrome: Spectrum of Clinical, Imaging, Electrophysiologic, and Genetic Findings in a Retrospective Case Series of 56 Patients.

Ophthalmol Retina 2021 02 15;5(2):195-214. Epub 2020 Jul 15.

Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom. Electronic address:

Purpose: To describe the detailed phenotype, long-term clinical course, clinical variability, and genotype of patients with enhanced S-cone syndrome (ESCS).

Design: Retrospective case series.

Participants: Fifty-six patients with ESCS.

Methods: Clinical history, examination, imaging, and electrophysiologic findings of 56 patients (age range, 1-75 years) diagnosed with ESCS were reviewed. Diagnosis was established by molecular confirmation of disease-causing variants in the NR2E3 gene (n = 38) or by diagnostic full-field electroretinography findings (n = 18).

Main Outcome Measures: Age at onset of visual symptoms, best-corrected visual acuity (BCVA), quantitative age-related electrophysiologic decline, and imaging findings.

Results: Mean age at onset of visual symptoms was 4.0 years, and median age at presentation was 20.5 years, with mean follow-up interval being 6.1 years. Six patients were assessed once. Disease-causing variants in NR2E3 were identified in 38 patients. Mean BCVA of the better-seeing eye was 0.32 logarithm of the minimum angle of resolution (logMAR) at baseline and 0.39 logMAR at follow-up. In most eyes (76% [76/100]), BCVA remained stable, with a mean BCVA change of 0.07 logMAR during follow-up. Nyctalopia was the most common initial symptom, reported in 92.9% of patients (52/56). Clinical findings were highly variable and included foveomacular schisis (41.1% [26/56]), yellow-white dots (57.1% [32/56]), nummular pigmentation (85.7% [48/56]), torpedo-like lesions (10.7% [6/56]), and circumferential subretinal fibrosis (7.1% [4/56]). Macular and peripheral patterns of autofluorescence were classified as (1) minimal change, (2) hypoautofluorescent (mild diffuse, moderate speckled, moderate diffuse, or advanced), or (3) hyperautofluorescent flecks. One patient showed undetectable electroretinography findings; quantification of main electroretinography components in all other patients revealed amplitude and peak time variability but with pathognomonic electroretinography features. The main electroretinography components showed evidence of age-related worsening over 6.7 decades, at a rate indistinguishable from that seen in unaffected control participants. Eighteen sequence variants in NR2E3 were identified, including 4 novel missense changes.

Conclusions: Enhanced S-cone syndrome has a highly variable phenotype with relative clinical and imaging stability over time. Most electroretinography findings have pathognomonic features, but quantitative assessment reveals variability and a normal mean rate of age-related decline, consistent with largely nonprogressive peripheral retinal dysfunction.
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http://dx.doi.org/10.1016/j.oret.2020.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861019PMC
February 2021

Detailed Phenotyping and Therapeutic Strategies for Intronic ABCA4 Variants in Stargardt Disease.

Mol Ther Nucleic Acids 2020 Sep 12;21:412-427. Epub 2020 Jun 12.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address:

Stargardt disease is a progressive retinal disorder caused by bi-allelic mutations in the ABCA4 gene that encodes the ATP-binding cassette, subfamily A, member 4 transporter protein. Over the past few years, we and others have identified several pathogenic variants that reside within the introns of ABCA4, including a recurrent variant in intron 36 (c.5196+1137G>A) of which the pathogenicity so far remained controversial. Detailed clinical characterization of this variant confirmed its pathogenic nature, and classified it as an allele of intermediate severity. Moreover, we discovered several additional ABCA4 variants clustering in intron 36. Several of these variants resulted in aberrant splicing of ABCA4, i.e., the inclusion of pseudoexons, while the splicing defects caused by the recurrent c.5196+1137G>A variant strongly increased upon differentiation of patient-derived induced pluripotent stem cells into retina-like cells. Finally, all splicing defects could be rescued by the administration of antisense oligonucleotides that were designed to specifically block the pseudoexon insertion, including rescue in 3D retinal organoids harboring the c.5196+1137G>A variant. Our data illustrate the importance of intronic variants in ABCA4 and expand the therapeutic possibilities for overcoming splicing defects in Stargardt disease.
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http://dx.doi.org/10.1016/j.omtn.2020.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352060PMC
September 2020
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