Publications by authors named "Andrew R Webster"

259 Publications

Characterization of Retinal Function using Microperimetry-Derived Metrics in both Adults and Children with RPGR-Associated Retinopathy.

Am J Ophthalmol 2021 Jul 22. Epub 2021 Jul 22.

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

Purpose: To investigate microperimetry testing of RPGR-associated retinopathy in a cohort of children and adults.

Study Design: Prospective observational case series.

Methods: The coefficient of repeatability and intraclass correlation coefficient (ICC) of mean sensitivity (MS) were calculated for mesopic microperimetry. Best-corrected visual acuity (BCVA), contrast sensitivity (CS), MS, total volume (V), and central 3-degree field volume (V) from volumetric and topographic analyses were acquired.

Results: Seventy-six RPGR subjects (53 adults, 23 children) were recruited. The mean follow-up period was 2.8 years. The ICC values for MS, V and V were 0.982 dB (95% confidence intervals, CI 0.969 to 0.989), 0.970 dB-sr (95% CI -0.02658 to 0.03691) and 0.986 dB-sr (95% CI 0.978 to 0.991), respectively. The r values for interocular MS, V and V, were 0.97 (P<0.01), 0.97 (P<0.01) and 0.98 (P<0.01) respectively, indicating strong inter-ocular correlation. The interocular correlation of progression for MS, V and V was 0.81 (P<0.01), 0.64 (P<0.01) and 0.81 (P<0.01), respectively. There was no statistically significant difference in the interocular progression rates for MS or V. V did show a statistically significant difference. Most patients lost retinal sensitivity rapidly during their second and third decades of life.

Conclusions: The high degree of reproducibility of results and the good interocular correlation lends this modality to accurately monitoring disease progression, as well as supporting validation of the use of MP in assessing the outcomes of gene therapy clinical treatment trials.
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http://dx.doi.org/10.1016/j.ajo.2021.07.018DOI Listing
July 2021

Foveal structure and visual function in nanophthalmos and posterior microphthalmos.

Br J Ophthalmol 2021 Jul 22. Epub 2021 Jul 22.

Moorfields Eye Hospital NHS Foundation Trust, London, UK

Background/aims: The reason for visual impairment in patients with nanophthalmos and posterior microphthalmos is not completely understood. Therefore, this study aims to investigate foveal structure, and the impact of demographic, clinical and imaging parameters on best-corrected visual acuity (BCVA) in these conditions.

Methods: Sixty-two eyes of 33 patients with nanophthalmos (n=40) or posterior microphthalmos (n=22), and 114 eyes of healthy controls with high-resolution retinal imaging including spectral-domain or swept-source optical coherence tomography images were included in this cross-sectional case-control study. Foveal retinal layer thickness was determined by two independent readers. A mixed-effect model was used to perform structure-function correlations and predict the BCVA based on subject-specific variables.

Results: Most patients (28/33) had altered foveal structure associated with loss of foveal avascular zone and impaired BCVA. However, widening of outer nuclear layer, lengthening of photoreceptor outer segments, normal distribution of macular pigment and presence of Henle fibres were consistently found. Apart from the presence of choroidal effusion, which had significant impact on BCVA, the features age, refractive error, axial length and retinal layer thickness at the foveal centre explained 61.7% of the variability of BCVA.

Conclusion: This study demonstrates that choroidal effusion, age, refractive error, axial length and retinal layer thickness are responsible for the majority of interindividual variability of BCVA as well as the morphological foveal heterogeneity in patients with nanophthalmos or posterior microphthalmos. This might give further insights into the physiology of foveal development and the process of emmetropisation, and support clinicians in the assessment of these disease entities.
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http://dx.doi.org/10.1136/bjophthalmol-2020-318717DOI Listing
July 2021

A Novel Pathogenic Variant in a Mother and Daughter with Blau Syndrome.

Ophthalmic Genet 2021 Jul 12:1-12. Epub 2021 Jul 12.

Uveitis and Scleritis Service, Moorfields Eye Hospital NHS Foundation Trust, London, UK.

Background: Blau syndrome (BS) is a rare dominantly-inherited autoinflammatory disorder characterized by the triad of arthritis, uveitis and dermatitis that is consequence of gain-of-function mutations. We describe the clinical features and genetic basis of a family with two affected members in consecutive generations affected with childhood onset arthritis and uveitis.

Materials And Methods: Clinical features were retrospectively collected from clinical records. Genetic studies were performed using the Sanger method of DNA sequencing.

Results: The proband is a 44 years-old female, who was diagnosed with juvenile onset arthritis at the age of 9 years. She subsequently developed uveitis at age 12 and since then she was managed between the uveitis and rheumatology services. The proband's daughter developed episcleritis at the age of 7 years, and arthritis with bilateral intermediate uveitis two years later. analyses revealed in both patients the heterozygous c.1494A>C transversion, predicted to lead the novel, missense p.E498D variant in the protein. Additional studies including databases searches and in silico bioinformatic predictions strongly support the "likely pathogenic" classification for this novel variant.

Conclusions: We report a novel pathogenic variant in a multiplex family with clinical features compatible with the BS diagnosis. This condition is inherited as a dominant trait in its familial form and should be considered in patients with granulomatous uveitis in association with arthritis and/or dermatitis. Further insight into variants and their downstream effects may have implications in the treatment of BS and other inflammatory granulomatous diseases.
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http://dx.doi.org/10.1080/13816810.2021.1946701DOI Listing
July 2021

Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome.

Ophthalmic Genet 2021 Jul 5:1-10. Epub 2021 Jul 5.

Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA.

Atypical Usher syndrome (USH) is poorly defined with a broad clinical spectrum. Here, we characterize the clinical phenotype of disease caused by variants in , and .Chart review evaluating demographic, clinical, imaging, and genetic findings of 19 patients from 18 families with a clinical diagnosis of retinal disease and confirmed disease-causing variants in , or .-related disease included sensorineural hearing loss (SNHL) in 6/7 patients and demonstrated a broad phenotypic spectrum including: vascular attenuation, pallor of the optic disc, intraretinal pigment, retinal pigment epithelium mottling, areas of mid-peripheral hypo-autofluorescence, outer retinal atrophy, mild pigmentary changes in the macula, foveal hypo-autofluorescence, and granularity of the ellipsoid zone. Nonsense and frameshift variants in showed mild retinal disease with progressive, non-congenital SNHL. variants resulted in a characteristic pericentral pattern of hypo-autofluorescence with one patient reporting non-congenital SNHL. -related disease showed rod-cone dystrophy with macular involvement, early and severe decreased best corrected visual acuity, and non-congenital SNHL ranging from unreported to severe.This study serves to expand the clinical phenotypes of atypical USH. Given the variable findings, atypical USH should be considered in patients with peripheral and macular retinal disease even without the typical RP phenotype especially when SNHL is noted. Additionally, genetic screening may be useful in patients who have clinical symptoms and retinal findings even in the absence of known SNHL given the variability of atypical USH.
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http://dx.doi.org/10.1080/13816810.2021.1946704DOI Listing
July 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

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

Invest Ophthalmol Vis Sci 2021 May;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

CNGB1-related rod-cone dystrophy: A mutation review and update.

Hum Mutat 2021 Jun 16;42(6):641-666. Epub 2021 May 16.

Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Institut de la Vision, Paris, France.

Cyclic nucleotide-gated channel β1 (CNGB1) encodes the 240-kDa β subunit of the rod photoreceptor cyclic nucleotide-gated ion channel. Disease-causing sequence variants in CNGB1 lead to autosomal recessive rod-cone dystrophy/retinitis pigmentosa (RP). We herein present a comprehensive review and analysis of all previously reported CNGB1 sequence variants, and add 22 novel variants, thereby enlarging the spectrum to 84 variants in total, including 24 missense variants (two of which may also affect splicing), 21 nonsense, 19 splicing defects (7 at noncanonical positions), 10 small deletions, 1 small insertion, 1 small insertion-deletion, 7 small duplications, and 1 gross deletion. According to the American College of Medical Genetics and Genomics classification criteria, 59 variants were considered pathogenic or likely pathogenic and 25 were variants of uncertain significance. In addition, we provide further phenotypic data from 34 CNGB1-related RP cases, which, overall, are in line with previous findings suggesting that this form of RP has long-term retention of useful central vision despite the early onset of night blindness, which is valuable for patient counseling, but also has implications for it being considered a priority target for gene therapy trials.
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http://dx.doi.org/10.1002/humu.24205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218941PMC
June 2021

An association between stellate nonhereditary idiopathic foveomacular retinoschisis, peripheral retinoschisis and posterior hyaloid attachment.

Retina 2021 Apr 8. Epub 2021 Apr 8.

Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom Institute of Ophthalmology, University College London, United Kingdom Wellcome EPSRC Centre for Interventional and Surgical Sciences, University College London, United Kingdom Department of Ophthalmology, Luton and Dunstable University Hospital, United Kingdom.

Purpose: Stellate nonhereditary idiopathic foveomacular retinoschisis (SNIFR) is a disorder characterized by splitting of the retina at the macula, without a known underlying mechanical or inherited cause. This study investigates demographic, anatomical and functional characteristics of subjects with SNIFR, to explore potential underlying mechanisms.

Methods: In this single-site, retrospective and cross-sectional, observational study, data were collected from 28 eyes from 24 subjects with SNIFR. Descriptive statistics were reported, based on the observed anatomico-functional features.

Results: Visual acuity remained stable (median 20/20) in all subjects over a median follow-up of 17 months. All cases demonstrated foveomacular retinoschisis within Henle's fiber layer, at the junction of the outer plexiform and outer nuclear layers. This schisis cavity extended beyond the limits of the macular OCT temporally in all eyes. In the majority of affected eyes, there were documented features of peripheral retinoschisis and broad attachment of the posterior hyaloid at the macula. Functional testing in a cross-sectional subset demonstrated normal retinal sensitivity centrally but an absolute scotoma peripherally.

Conclusions: Stellate nonhereditary idiopathic foveomacular retinoschisis appears to be associated with peripheral retinoschisis and anomalous or incomplete posterior hyaloid detachment. Despite chronic manifestation, this does not significantly affect central visual function, but can manifest with profound loss of peripheral visual function.
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http://dx.doi.org/10.1097/IAE.0000000000003191DOI Listing
April 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

Novel Biallelic Variants and Phenotypic Features in Patients with -Related Foveal Hypoplasia.

Int J Mol Sci 2021 Jan 24;22(3). Epub 2021 Jan 24.

Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK.

Biallelic pathogenic variants in solute carrier family 38 member 8, , cause a pan-ocular autosomal recessive condition known as foveal hypoplasia 2, FVH2, characterised by foveal hypoplasia, nystagmus and optic nerve chiasmal misrouting. Patients are often clinically diagnosed with ocular albinism, but foveal hypoplasia can occur in several other ocular disorders. Here we describe nine patients from seven families who had molecularly confirmed biallelic recessive variants in identified through whole genome sequencing or targeted gene panel testing. We identified four novel sequence variants (p.(Tyr88*), p.(Trp145*), p.(Glu233Gly) and c.632+1G>A). All patients presented with foveal hypoplasia, nystagmus and reduced visual acuity; however, one patient did not exhibit any signs of chiasmal misrouting, and three patients had features of anterior segment dysgenesis. We highlight these findings in the context of 30 other families reported to date. This study reinforces the importance of obtaining a molecular diagnosis in patients whose phenotype overlap with other inherited ocular conditions, in order to support genetic counselling, clinical prognosis and family planning. We expand the spectrum of mutations which will be relevant for treatment through future genetic-based therapies.
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http://dx.doi.org/10.3390/ijms22031130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866073PMC
January 2021

Longitudinal Study to Assess the Quantitative Use of Fundus Autofluorescence for Monitoring Disease Progression in Choroideremia.

J Clin Med 2021 Jan 11;10(2). Epub 2021 Jan 11.

NIHR Biomedical Resource Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, London EC1V 9EL, UK.

Background: Characterisation of preserved autofluorescence (PAF) area in choroideremia (CHM) and its validity for monitoring disease progression in clinical trials is of importance.

Methods: Eighty patients with molecularly confirmed CHM were recruited. PAF area was measured manually by 2 graders and half-life was calculated based on exponential decay model.

Results: Mean age at baseline and follow-up examination was 38.1 (range, 10-69) and 40.7 (range, 11-70) years. Mean follow-up interval was 29 months (range, 6-104). The median LogMAR visual acuity was 0.10 (OD) and 0.18 (OS). Interobserver repeatability for PAF area was -0.99 to 1.03 mm (-6.46 to 6.49% of area). There was a statistically significant relationship between age and rate of PAF area loss (r = 0.28, = 0.012). The half-life for PAF area was 13.7 years (range, 1.7-216.0 years). The correlation between half-life and age was stronger than between half-life and log transformed baseline PAF area, although neither was statistically significant.

Conclusions: The intra- and inter-observer PAF area measurement variability provides a baseline change, which must be overcome in a clinical trial if this metric were to be used. Treatments must slow progression to alter the exponential decay in a timely manner accounting for naturally slow progression patterns.
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http://dx.doi.org/10.3390/jcm10020232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826764PMC
January 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

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

Ophthalmology 2021 Jun 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

Autosomal Recessive Bestrophinopathy: Clinical Features, Natural History, and Genetic Findings in Preparation for Clinical Trials.

Ophthalmology 2021 May 8;128(5):706-718. Epub 2020 Oct 8.

Moorfields Eye Hospital NHS Foundation Trust, and UCL Institute of Ophthalmology, University College London, London, United Kingdom. Electronic address:

Purpose: To investigate the clinical course, genetic findings, and phenotypic spectrum of autosomal recessive bestrophinopathy (ARB) in a large cohort of children and adults.

Design: Retrospective case series.

Participants: Patients with a detailed clinical phenotype consistent with ARB, biallelic likely disease-causing sequence variants in the BEST1 gene, or both identified at a single tertiary referral center.

Methods: Review of case notes, retinal imaging (color fundus photography, fundus autofluorescence, OCT), electrophysiologic assessment, and molecular genetic testing.

Main Outcome Measures: Visual acuity (VA), retinal imaging, and electrophysiologic changes over time.

Results: Fifty-six eyes of 28 unrelated patients were included. Compound heterozygous variants were detected in most patients (19/27), with 6 alleles recurring in apparently unrelated individuals, the most common of which was c.422G→A, p.(Arg141His; n = 4 patients). Mean presenting VA was 0.52 ± 0.36 logarithm of the minimum angle of resolution (logMAR), and final VA was 0.81 ± 0.75 logMAR (P = 0.06). The mean rate of change in VA was 0.05 ± 0.13 logMAR/year. A significant change in VA was detected in patients with a follow-up of 5 years or more (n = 18) compared with patients with a follow-up of 5 years or less (n = 10; P = 0.001). Presence of subretinal fluid and vitelliform material were early findings in most patients, and this did not change substantially over time. A reduction in central retinal thickness was detected in most eyes (80.4%) over the course of follow-up. Many patients (10/26) showed evidence of generalized rod and cone system dysfunction. These patients were older (P < 0.001) and had worse VA (P = 0.02) than those with normal full-field electroretinography results.

Conclusions: Although patients with ARB are presumed to have no functioning bestrophin channels, significant phenotypic heterogeneity is evident. The clinical course is characterized by a progressive loss of vision with a slow rate of decline, providing a wide therapeutic window for anticipated future treatment strategies.
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http://dx.doi.org/10.1016/j.ophtha.2020.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062850PMC
May 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

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

Prog Retin Eye Res 2021 May 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

Quantifying the Separation Between the Retinal Pigment Epithelium and Bruch's Membrane using Optical Coherence Tomography in Patients with Inherited Macular Degeneration.

Transl Vis Sci Technol 2020 05 23;9(6):26. Epub 2020 May 23.

Medical Retina Service, Moorfields Eye Hospital, London, UK.

Purpose: To describe and quantify Bruch's membrane (BM) and retinal pigment epithelium (RPE) separation using spectral-domain (SD) optical coherence tomography (OCT) in patients affected by inherited macular degenerations associated with BM thickening.

Methods: Patients with molecularly confirmed Sorsby fundus dystrophy (SFD), dominant drusen (DD), and late-onset retinal degeneration (L-ORD) were included in this retrospective study. Each disease was classed as early stage if subjects were asymptomatic, intermediate stage if they had nyctalopia alone, and late stage if they described loss of central vision. The main outcome was measurement of BM-RPE separation on SD-OCT. The BM-RPE separation measurements were compared against those in normal age-matched controls.

Results: Seventeen patients with SFD, 22 with DD, and eight with L-ORD were included. BM-RPE separation on SD-OCT demonstrated a high test-retest and interobserver reproducibility (intraclass correlation coefficients >0.9). BM-RPE separation was not identified in normal subjects. In SFD, there was greater BM-RPE separation in late-stage disease compared with intermediate-stage patients both at subfoveal ( < 0.05) and juxtafoveal ( < 0.01) locations. In DD, there was increased BM-RPE separation in late-stage disease compared with early stage at subfoveal ( < 0.001) and juxtafoveal ( < 0.05) topographies. There was no significant difference in BM-RPE separation between disease stages in L-ORD.

Conclusions: BM-RPE separation is a novel, quantifiable phenotype in the three monogenic macular dystrophies studied, and may be an optical correlate of the histopathological thickening in BM that is known to occur. BM-RPE separation, as measured by OCT, varies with stage of disease in SFD and DD, but not in L-ORD.

Translational Relevance: SFD, DD, and L-ORD are associated with BM thickening. In this group of patients, OCT assessment of macular structure identifies a separation of the usually single, hyperreflective line thought to represent BM and the overlying RPE. This separation is a novel and quantifiable feature of disease staging in SFD and DD.
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http://dx.doi.org/10.1167/tvst.9.6.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409156PMC
May 2020

Long-term follow-up of a case of posterior microphthalmos (PRSS56) with hyperautofluorescent retinal pigment epithelial deposits.

Eur J Ophthalmol 2020 Aug 17:1120672120949756. Epub 2020 Aug 17.

National Institute for Health Research Moorfields Biomedical Research Centre, Moorfields Eye Hospital, London, UK.

Purpose: To report a case of posterior microphthalomos (PM) related to PRSS56 gene mutation with long term follow up with multimodal imaging findings.

Methods: Single retrospective case report.

Results: A 43-year old male patient presented in 2009 with bilateral reduced vision. Clinical examination and multimodal imaging showed features consistent with posterior microphthalmos with prominent bilateral horizontal papillomacular retinal folds. Posterior pole hyperautofluorescent RPE deposits were present. Gradual worsening of visual acuity and rod and cone photoreceptor function more so on the left was demonstrated during the 8 years of follow up.

Conclusion: Hyperautofluorescent RPE deposits may occur in patients with posterior microphthalmos and such patient's may experience only gradual disease progression over long term follow up.
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http://dx.doi.org/10.1177/1120672120949756DOI Listing
August 2020

Sector Retinitis Pigmentosa: Extending the Molecular Genetics Basis and Elucidating the Natural History.

Am J Ophthalmol 2021 01 12;221:299-310. Epub 2020 Aug 12.

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

Purpose: To determine the genetic background of sector retinitis pigmentosa (RP) natural history to better inform patient counseling.

Design: Retrospective case series.

Methods: Review of clinical notes, retinal imaging including color fundus photography (CFP), fundus autofluorescence (FAF), optical coherence tomography (OCT), electrophysiological assessment (ERG), and molecular genetic testing were performed in patients with sector RP from a single tertiary referral center. Main outcomes measured were demographic data, signs and symptoms, visual acuity, molecular genetics; and ERG, FAF, and OCT findings.

Results: Twenty-six molecularly confirmed patients from 23 different families were identified harboring likely disease-causing variants in 9 genes. The modes of inheritance were autosomal recessive (AR, n=6: USH1C, n=2; MYO7A, n=2; CDH3, n=1; EYS, n=1), X-linked (XL, n=4: PRPS1, n=1; RPGR, n=3), and autosomal dominant (AD, n=16: IMPDH1, n=3; RP1, n=3; RHO, n=10), with a mean age of disease onset of 38.5, 30.5, and 39.0 years old, respectively. Five of these genes have not previously been reported to cause sector RP (PRPS1, MYO7A, EYS, IMPDH1, and RP1). Inferior and nasal predilection was common across the different genotypes, and patients tended to maintain good central vision. Progression on serial FAF was observed in RPGR, MYO7A, CDH23, EYS, IMPDH1, RP1, and RHO-associated sector RP.

Conclusions: The genotypic spectrum of the disease is broader than previously reported. The longitudinal data provided will help to make accurate patient prognoses and counseling as well as inform patients' potential participation in the increasing numbers of trials of novel therapeutics and access to future treatments.
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http://dx.doi.org/10.1016/j.ajo.2020.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772805PMC
January 2021

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

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

Retinal detachment in retinitis pigmentosa.

BMJ Open Ophthalmol 2020 9;5(1):e000454. Epub 2020 Jul 9.

Vitreoretinal Service, Moorfields Eye Hospital NHS Foundation Trust, London, UK.

Objective: Retinitis pigmentosa-related retinal detachment (RPRD) is rare, and the full spectrum of retinal complications is not well defined. To describe the types of retinal detachment in patients with retinitis pigmentosa and the surgical outcomes of RPRD.

Methods: This is a non-comparative, retrospective case series. An electronic database search was performed using Moorfields OpenEyes electronic health records. We identified 90 patients with RPRD between January 2000 and August 2017. Main outcome and measures are visual acuity (VA), surgical outcomes and classification of RPRD.

Results: Of the 90 patients/detachments, 61 (67.8%) were rhegmatogenous retinal detachment (RRD), 19 (21.1%) were exudative, 3 (3.3%) were tractional retinal detachment (TRD) and 7 (7.8%) had combined. 37.5% (9/24) of patients with exudative retinal detachment were treated with either cryotherapy or laser, and one patient underwent vitrectomy for vitreous haemorrhage. 56/90 patients underwent surgical intervention. Nine patients presented late and were deemed inoperable (two exudative and seven RRD). Of the RRD patients with full operative record, the primary attachment rate was 76.2% (16/21) and final reattachment rate was 85.7% (18/21) over a mean 15.4-year follow-up period. Mean VA for RRD surgery improved from 6/190 (1.51 logMAR) to 6/120 (1.31 logMAR) (p=0.194). In the TRD group, the mean VA was 6/300 (1.66 logMAR) at baseline and improved after surgery to 6/48 (0.90 logMAR) (p=0.421).

Conclusions: We demonstrated a final reattachment rate of 85.7% with a trend toward better vision following intervention for patients with RPRD. However, the final long-term vision may be poor due to the natural progression of retinitis pigmentosa-associated macular degeneration.
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http://dx.doi.org/10.1136/bmjophth-2020-000454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351280PMC
July 2020

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

Whole-genome sequencing of patients with rare diseases in a national health system.

Nature 2020 07 24;583(7814):96-102. Epub 2020 Jun 24.

Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.
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http://dx.doi.org/10.1038/s41586-020-2434-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610553PMC
July 2020

Monozygotic twins discordant for asymmetric pigmented paravenous chorioretinal atrophy.

Retin Cases Brief Rep 2020 Jun 8. Epub 2020 Jun 8.

Moorfields Eye Hospital, London, United Kingdom.

Purpose: To demonstrate phenotypic discordance between a monozygotic twin pair, one of whom exhibited pigmented paravenous chorioretinal atrophy (PPCRA).

Methods: A patient and his identical twin brother, attending Moorfields Eye Hospital, were reviewed. Clinical assessment included visual acuity and color vision testing, fundus imaging including autofluorescence, spectral-domain optical coherence tomography and static perimetry. In addition, the affected sibling underwent pattern and full field electroretinography (PERG and ERG) according to ISCEV standards. Zygosity testing was performed using short tandem repeat (STR) analysis.

Results: The 48-year old proband was referred with abnormal visual fields and difficulty reading at near. Examination revealed 20/20 Snellen visual acuity bilaterally, normal colour vision and bilateral asymmetric outer retinal atrophy with intra-retinal pigment migration along the course of the retinal veins, consistent with PPCRA. The visual field defects were contiguous with the blind spot and mirrored the retinal involvement in both eyes. Pattern ERG showed mild macular dysfunction and full field ERG was within normal limits. Blood testing for common uveitic entities was non-contributory. The proband's twin brother's clinical assessment and retinal imaging showed no abnormality. Zygosity testing showed the twins to be identical for 24 short tandem repeat (STR) microsatellite markers, indicative of monozygosity.

Conclusion: Some cases of PPCRA, without an obvious inflammatory etiology, do not have a clear Mendelian inheritance pattern and may represent an acquired disorder.
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http://dx.doi.org/10.1097/ICB.0000000000001018DOI Listing
June 2020

Prospective deep phenotyping of choroideremia patients using multimodal structure-function approaches.

Eye (Lond) 2021 Mar 28;35(3):838-852. Epub 2020 May 28.

Moorfields Eye Hospital NHS Foundation Trust, London, UK.

Objective: To investigate the retinal changes in choroideremia (CHM) patients to determine correlations between age, structure and function.

Subjects/methods: Twenty-six eyes from 13 male CHM patients were included in this prospective longitudinal study. Participants were divided into <50-year (n = 8) and ≥50-year (n = 5) old groups. Patients were seen at baseline, 6-month, and 1-year visits. Optical coherence tomography (OCT), OCT angiography, and fundus autofluorescence were performed to measure central foveal (CFT) and subfoveal choroidal thickness (SCT), as well as areas of preserved choriocapillaris (CC), ellipsoid zone (EZ), and autofluorescence (PAF). Patients also underwent functional investigations including visual acuity (VA), contrast sensitivity (CS), colour testing, microperimetry, dark adaptometry, and handheld electroretinogram (ERG). Vision-related quality-of-life was assessed by using the NEI-VFQ-25 questionnaire.

Results: Over the 1-year follow-up period, progressive loss was detected in SCT, EZ, CC, PAF, and CFT. Those ≥50-years exhibited more structural and functional defects with SCT, EZ, CC, and PAF showing strong correlation with patient age (rho ≤ -0.47, p ≤ 0.02). CS and VA did not change over the year, but CS was significantly correlated with age (rho = -0.63, p = 0.001). Delayed to unmeasurable dark adaptation, decreased colour discrimination and no detectable ERG activity were observed in all patients. Minimal functional deterioration was observed over one year with a general trend of slower progression in the ≥50-years group.

Conclusions: Quantitative structural parameters including SCT, CC, EZ, and PAF are most useful for disease monitoring in CHM. Extended follow-up studies are required to determine longitudinal functional changes.
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http://dx.doi.org/10.1038/s41433-020-0974-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027673PMC
March 2021
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