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Article ; Online: Typical best vitelliform dystrophy secondary to biallelic variants in BEST1.

Dhoble, Pankaja / Robson, Anthony G / Webster, Andrew R / Michaelides, Michel

2023 Volume 45, Issue 1, Page(s) 38–43

Abstract: Background: Pathogenic variants in : Materials and methods: Detailed ophthalmic workup included comprehensive ophthalmologic examination, multimodal retinal imaging, full-field and pattern electroretinography (ERG; PERG), and electrooculogram (EOG). ... ...

Abstract	Background: Pathogenic variants in Materials and methods: Detailed ophthalmic workup included comprehensive ophthalmologic examination, multimodal retinal imaging, full-field and pattern electroretinography (ERG; PERG), and electrooculogram (EOG). Genetic analysis of probands and segregation testing and fundus examination of proband relatives was performed where possible. Results: Three unrelated cases presented with a clinical phenotype typical for BVMD and were found to have biallelic disease-causing variants in Conclusions: Individuals with biallelic variants in
MeSH term(s)	Humans ; Vitelliform Macular Dystrophy/diagnosis ; Vitelliform Macular Dystrophy/genetics ; Vitelliform Macular Dystrophy/pathology ; Angiotensin Receptor Antagonists ; Chloride Channels/genetics ; Eye Proteins/genetics ; Pedigree ; DNA Mutational Analysis ; Angiotensin-Converting Enzyme Inhibitors ; Bestrophins/genetics ; Phenotype ; Retinal Dystrophies ; Mutation ; Tomography, Optical Coherence
Chemical Substances	Angiotensin Receptor Antagonists ; Chloride Channels ; Eye Proteins ; Angiotensin-Converting Enzyme Inhibitors ; Bestrophins ; BEST1 protein, human
Language	English
Publishing date	2023-03-13
Publishing country	England
Document type	Journal Article
ZDB-ID	1199279-7
ISSN	1744-5094 ; 0167-6784 ; 1381-6810
ISSN (online)	1744-5094
ISSN	0167-6784 ; 1381-6810
DOI	10.1080/13816810.2023.2188227
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Article ; Online: PHYH c.678+5G>T Leads to In-Frame Exon Skipping and Is Associated With Attenuated Refsum Disease.

Daich Varela, Malena / Schiff, Elena / Malka, Samantha / Wright, Genevieve / Mahroo, Omar A / Webster, Andrew R / Michaelides, Michel / Arno, Gavin

Investigative ophthalmology & visual science

2024 Volume 65, Issue 2, Page(s) 38

Abstract: Purpose: To investigate the molecular effect of the variant PHYH:c.678+5G>T. This variant has conflicting interpretations in the ClinVar database and a maximum allele frequency of 0.0045 in the South Asian population in gnomAD.: Methods: We recruited ...

Abstract	Purpose: To investigate the molecular effect of the variant PHYH:c.678+5G>T. This variant has conflicting interpretations in the ClinVar database and a maximum allele frequency of 0.0045 in the South Asian population in gnomAD. Methods: We recruited patients from Moorfields Eye Hospital (London, UK) and Buenos Aires, Argentina, who were diagnosed with retinitis pigmentosa and found to have biallelic variants in PHYH, with at least one being c.678+5G>T. Total RNA was purified from PaxGene RNA-stabilized whole-blood samples, followed by reverse transcription to cDNA, PCR amplification of the canonical PHYH transcript, Oxford Nanopore Technologies library preparation, and single-molecule amplicon sequencing. Results: Four patients provided a blood sample. One patient had isolated retinitis pigmentosa and three had mild extraocular findings. Blood phytanic acid levels were normal in two patients, mildly elevated in one, and markedly high in the fourth. Retinal evaluation showed an intact ellipsoid zone as well as preserved autofluorescence in the macular region in three of the four patients. In all patients, we observed in-frame skipping of exons 5 and 6 in 31.1% to 88.4% of the amplicons and a smaller proportion (0% to 11.3% of amplicons) skipping exon 6 only. Conclusions: We demonstrate a significant effect of PHYH:c.678+5G>T on splicing of the canonical transcript. The in-frame nature of this may be in keeping with a mild presentation and higher prevalence in the general population. These data support the classification of the variant as pathogenic, and patients harboring a biallelic genotype should undergo phytanic acid testing.
MeSH term(s)	Humans ; Refsum Disease ; Phytanic Acid ; Retinitis Pigmentosa/diagnosis ; Retinitis Pigmentosa/genetics ; Exons/genetics ; RNA/genetics ; Mixed Function Oxygenases
Chemical Substances	Phytanic Acid (14721-66-5) ; RNA (63231-63-0) ; PHYH protein, human (EC 1.14.-) ; Mixed Function Oxygenases (EC 1.-)
Language	English
Publishing date	2024-02-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.65.2.38
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Article ; Online: Congenital Stationary Night Blindness Structure, Function and Genotype-Phenotype Correlations in a Cohort of 122 Patients.

Katta, Mohamed / de Guimaraes, Thales A C / Fujinami-Yokokawa, Yu / Fujinami, Kaoru / Georgiou, Michalis / Mahroo, Omar A / Webster, Andrew R / Michaelides, Michel

Ophthalmology. Retina

2024

Abstract: Objective: To examine the molecular causes of Schubert-Bornschein (S-B) congenital stationary night blindness (CSNB), clinically characterize in detail, and assess genotype-phenotype correlations for retinal function and structure.: Design: ... ...

Abstract	Objective: To examine the molecular causes of Schubert-Bornschein (S-B) congenital stationary night blindness (CSNB), clinically characterize in detail, and assess genotype-phenotype correlations for retinal function and structure. Design: Retrospective, longitudinal, single-center case series. Participants: One hundred twenty-two patients with S-B CSNB attending Moorfields Eye Hospital, United Kingdom. Methods: All case notes, results of molecular genetic testing, and OCT were reviewed. Main outcome measures: Molecular genetics, presenting complaints, rates of nystagmus, nyctalopia, photophobia, strabismus, color vision defects and spherical equivalent refraction (SER). Retinal thickness, outer nuclear layer (ONL) thickness, and ganglion cell layer + inner plexiform layer (GCL+IPL) thickness from OCT imaging. Results: X-linked (CACNA1F and NYX) and autosomal recessive (TRPM1, GRM6, GPR179 and CABP4) genotypes were identified. The mean (± standard deviation) reported age of onset was 4.94 ± 8.99 years. Over the follow-up period, 95.9% of patients reported reduced visual acuity (VA), half had nystagmus, and 64.7% reported nyctalopia. Incomplete CSNB (iCSNB) patients more frequently had nystagmus and photophobia. Nyctalopia was similar for iCSNB and complete CSNB (cCSNB). Color vision data were limited but more defects were found in iCSNB. None of these clinical differences met statistical significance. There was no significant difference between groups in VA, with a mean of 0.46 logarithm of the minimum angle of resolution, and VA remained stable over the course of follow-up. Complete congenital stationary night blindness patients, specifically those with NYX and TRPM1 variants, were more myopic. CACNA1F patients showed the largest refractive variability, and the CABP4 patient was hyperopic. No significant differences were found in OCT structural analysis during the follow-up period. Conclusions: Retinal structure in CSNB is stationary and no specific genotype-structure correlates were identified. Visual acuity seems to be relatively stable, with rare instances of progression. Financial disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Language	English
Publishing date	2024-03-24
Publishing country	United States
Document type	Journal Article
ISSN	2468-6530
ISSN (online)	2468-6530
DOI	10.1016/j.oret.2024.03.017
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Article ; Online: Clinical, Ophthalmic and Genetic Characterization of RPGRIP1-Associated Leber Congenital Amaurosis/Early Onset Severe Retinal Dystrophy.

Daich Varela, Malena / Jeste, Mrunmayi / de Guimaraes, Thales A C / Mahroo, Omar A / Arno, Gavin / Webster, Andrew R / Michaelides, Michel

American journal of ophthalmology

2024

Abstract: Purpose: To present the clinical characteristics, retinal features, natural history, and genetics of RPGRIP1-Associated Early Onset Severe Retinal Dystrophy (EOSRD)/Leber Congenital Amaurosis (LCA).: Design: Retrospective case series.: Methods: ... ...

Abstract	Purpose: To present the clinical characteristics, retinal features, natural history, and genetics of RPGRIP1-Associated Early Onset Severe Retinal Dystrophy (EOSRD)/Leber Congenital Amaurosis (LCA). Design: Retrospective case series. Methods: Review of clinical notes, multi-modal retinal imaging, and molecular diagnosis of 18 patients (17 families) with EOSRD/LCA and disease-causing variants in RPGRIP1. Results: The mean age of visual symptoms onset was 0.87 ± 1 year (birth-3 years) and the mean age at baseline visit was 11.4 ± 10.2 years (1-39 years). At the baseline visit, 44% of patients were legally blind (range= 2-39 years) and there was no significant association found between age and best corrected visual acuity (BCVA) in cross sectional analysis. Retinal evaluation showed an abolished electroretinogram or a cone-rod dystrophy pattern, none or minimal pigment deposits, a hyperautofluorescent ring at the posterior pole, and a largely preserved central macular architecture, with retained outer nuclear layer and ellipsoid zone island into adulthood. Eleven variants (48%) were previously unreported, and 13 families (76%) had a double null genotype (DN). Twelve patients (67%) had follow up assessments over a 15.7 ± 9.5 year period. The rate of BCVA decline was 0.02 LogMAR (1 letter)/year. Conclusions: RPGRIP1-EOSRD/LCA often presents at birth or early infancy, with nystagmus, decreased VA, hyperopia, and photophobia. Patients with a DN genotype may develop symptoms earlier and have worse vision. Multimodal imaging may show a hyperautofluorescent posterior pole ring, and relatively preserved central macular architecture, suggesting that the condition is a promising candidate for gene supplementation.
Language	English
Publishing date	2024-05-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	80030-2
ISSN	1879-1891 ; 0002-9394
ISSN (online)	1879-1891
ISSN	0002-9394
DOI	10.1016/j.ajo.2024.05.007
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Article ; Online: A rare canonical splice-site variant in VPS13B causes attenuated Cohen syndrome.

Daich Varela, Malena / Motta, Fabiana Louise / Webster, Andrew R / Arno, Gavin

Ophthalmic genetics

2021 Volume 43, Issue 1, Page(s) 110–115

Abstract: 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 ... ...

Abstract	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 Conclusions: Exon 31 skipping in
MeSH term(s)	Developmental Disabilities ; Diabetes Mellitus, Type 2/complications ; Electroretinography ; Fingers/abnormalities ; Humans ; Intellectual Disability ; Male ; Microcephaly ; Muscle Hypotonia/genetics ; Myopia ; Obesity/complications ; Obesity/genetics ; Retinal Degeneration ; Retinal Dystrophies ; Tomography, Optical Coherence ; Vesicular Transport Proteins/genetics
Chemical Substances	VPS13B protein, human ; Vesicular Transport Proteins
Language	English
Publishing date	2021-08-23
Publishing country	England
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1199279-7
ISSN	1744-5094 ; 0167-6784 ; 1381-6810
ISSN (online)	1744-5094
ISSN	0167-6784 ; 1381-6810
DOI	10.1080/13816810.2021.1970194
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Article ; Online: Whole Genome Sequencing Identifies a Partial Deletion of RTN4IP1 in a Patient With Isolated Optic Atrophy.

Jurkute, Neringa / Arno, Gavin / Webster, Andrew R / Yu-Wai-Man, Patrick

Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society

2022 Volume 43, Issue 4, Page(s) e142–e145

MeSH term(s)	Humans ; Carrier Proteins/genetics ; Mitochondrial Proteins/genetics ; Mutation ; Optic Atrophy/diagnosis ; Optic Atrophy/genetics ; Optic Atrophy, Autosomal Dominant/genetics ; Whole Genome Sequencing
Chemical Substances	Carrier Proteins ; Mitochondrial Proteins ; RTN4IP1 protein, human
Language	English
Publishing date	2022-04-19
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	1189901-3
ISSN	1536-5166 ; 1070-8022
ISSN (online)	1536-5166
ISSN	1070-8022
DOI	10.1097/WNO.0000000000001589
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Article ; Online: No strong evidence to date for an association between RIMS1 and retinal dystrophy.

Mahroo, Omar A / Martin-Gutierrez, Maria Pilar / Michaelides, Michel / Webster, Andrew R / Arno, Gavin

Documenta ophthalmologica. Advances in ophthalmology

2022 Volume 146, Issue 1, Page(s) 93–94

MeSH term(s)	Humans ; Electroretinography ; Retinal Dystrophies/diagnosis ; Retinal Dystrophies/genetics ; Mutation
Language	English
Publishing date	2022-11-02
Publishing country	Netherlands
Document type	Letter ; Comment
ZDB-ID	212594-8
ISSN	1573-2622 ; 0012-4486
ISSN (online)	1573-2622
ISSN	0012-4486
DOI	10.1007/s10633-022-09905-8
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Article ; Online: Visual Acuity by Decade in 139 Males with

De Silva, Samantha R / Chan, Hwei Wuen / Agarwal, Aditi / Webster, Andrew R / Michaelides, Michel / Mahroo, Omar A

Ophthalmology science

2023 Volume 4, Issue 2, Page(s) 100375

Language	English
Publishing date	2023-07-24
Publishing country	Netherlands
Document type	Journal Article
ISSN	2666-9145
ISSN (online)	2666-9145
DOI	10.1016/j.xops.2023.100375
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Article ; Online: Sub-cellular level resolution of common genetic variation in the photoreceptor layer identifies continuum between rare disease and common variation.

Currant, Hannah / Fitzgerald, Tomas W / Patel, Praveen J / Khawaja, Anthony P / Webster, Andrew R / Mahroo, Omar A / Birney, Ewan

PLoS genetics

2023 Volume 19, Issue 2, Page(s) e1010587

Abstract: Photoreceptor cells (PRCs) are the light-detecting cells of the retina. Such cells can be non-invasively imaged using optical coherence tomography (OCT) which is used in clinical settings to diagnose and monitor ocular diseases. Here we present the ... ...

Abstract	Photoreceptor cells (PRCs) are the light-detecting cells of the retina. Such cells can be non-invasively imaged using optical coherence tomography (OCT) which is used in clinical settings to diagnose and monitor ocular diseases. Here we present the largest genome-wide association study of PRC morphology to date utilising quantitative phenotypes extracted from OCT images within the UK Biobank. We discovered 111 loci associated with the thickness of one or more of the PRC layers, many of which had prior associations to ocular phenotypes and pathologies, and 27 with no prior associations. We further identified 10 genes associated with PRC thickness through gene burden testing using exome data. In both cases there was a significant enrichment for genes involved in rare eye pathologies, in particular retinitis pigmentosa. There was evidence for an interaction effect between common genetic variants, VSX2 involved in eye development and PRPH2 known to be involved in retinal dystrophies. We further identified a number of genetic variants with a differential effect across the macular spatial field. Our results suggest a continuum between common and rare variation which impacts retinal structure, sometimes leading to disease.
MeSH term(s)	Humans ; Rare Diseases/pathology ; Genome-Wide Association Study ; Retina/pathology ; Photoreceptor Cells ; Genetic Variation
Language	English
Publishing date	2023-02-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1010587
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Article ; Online: Prognostication in Stargardt Disease Using Fundus Autofluorescence: Improving Patient Care.

Daich Varela, Malena / Laich, Yannik / Hashem, Shaima Awadh / Mahroo, Omar A / Webster, Andrew R / Michaelides, Michel

Ophthalmology

2023 Volume 130, Issue 11, Page(s) 1182–1190

Abstract: Purpose: To explore fundus autofluorescence (FAF) imaging as an alternative to electroretinography as a noninvasive, quick, and readily interpretable method to predict disease progression in Stargardt disease (STGD).: Design: Retrospective case ... ...

Abstract	Purpose: To explore fundus autofluorescence (FAF) imaging as an alternative to electroretinography as a noninvasive, quick, and readily interpretable method to predict disease progression in Stargardt disease (STGD). Design: Retrospective case series of patients who attended Moorfields Eye Hospital (London, United Kingdom). Participants: Patients with STGD who met the following criteria were included: (1) biallelic disease-causing variants in ABCA4, (2) electroretinography testing performed in house with an unequivocal electroretinography group classification, and (3) ultrawidefield (UWF) FAF imaging performed up to 2 years before or after the electroretinography. Methods: Patients were divided into 3 electroretinography groups based on retinal function and 3 FAF groups according to the extent of hypoautofluorescence and retinal background appearance. Fundus autofluorescence images of 30° and 55° were reviewed subsequently. Main outcome measures: Electroretinography and FAF concordance and its association with baseline visual acuity (VA) and genetics. Results: Two hundred thirty-four patients were included in the cohort. One hundred seventy patients (73%) were in electroretinography and FAF groups of the same severity, 33 (14%) were in a milder FAF than electroretinography group, and 31 (13%) were in a more severe FAF than electroretinography group. Children < 10 years of age (n = 23) showed the lowest electroretinography and FAF concordance at 57% (9 of the 10 with discordant electroretinography and FAF showed milder FAF than electroretinography), and adults with adult onset showed the highest (80%). In 97% and 98% of patients, 30° and 55° FAF imaging, respectively, matched with the group defined by UWF FAF. Conclusions: We demonstrated that FAF imaging is an effective method to determine the extent of retinal involvement and thereby inform prognostication by comparing FAF with the current gold standard of electroretinography. In 80% of patients in our large molecularly proven cohort, we were able to predict if the disease was confined to the macula or also affected the peripheral retina. Children assessed at a young age, with at least 1 null variant, early disease onset, poor initial VA, or a combination thereof may have wider retinal involvement than predicted by FAF alone, may progress to a more severe FAF phenotype over time, or both. Financial disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Language	English
Publishing date	2023-06-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	392083-5
ISSN	1549-4713 ; 0161-6420
ISSN (online)	1549-4713
ISSN	0161-6420
DOI	10.1016/j.ophtha.2023.06.010
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