Genome-Wide Insights Into the Genes and Pathways Shaping Human Foveal Development: Redefining the Genetic Landscape of Foveal Hypoplasia.

Purpose: To define the genetic architecture of foveal morphology and explore its relevance to foveal hypoplasia (FH), a hallmark of developmental macular disorders.

Methods: We applied deep-learning algorithms to quantify foveal pit depth from central optical coherence tomography (OCT) B-scans in 61,269 UK Biobank participants. A genome-wide association study (GWAS) was conducted using REGENIE, adjusting for age, sex, height, and ancestry.

Sex Distributions in the Most Frequent Autosomal Genetic Causes of Retinitis Pigmentosa.

Purpose: The purpose of this study was to explore whether sex imbalances are detectable in the most frequent genetic causes of retinitis pigmentosa (RP).

Methods: Databases from centers in three countries (Moorfields Eye Hospital, London; Hospital for Sick Children, Toronto; and Australian Inherited Retinal Disease Registry, Perth, Australia) were searched, quantifying numbers of male and female patients with disease attributed to variants in the six most frequently involved autosomal RP genes. Proportions of female patients (with 95% confidence intervals [CIs]) were calculated for each gene.

SNRNP200- associated Retinopathy: In-depth Clinical Phenotyping and Genetic Characterization.

Purpose: To analyze the clinical spectrum and natural history of SNRNP200-associated retinopathy.

Design: Multi-center retrospective, observational cohort study.

Patients: Molecularly confirmed patients with at least one disease-causing variant in SNRNP200.

Retinograd-AI: An Open-Source Automated Fundus Autofluorescence Retinal Image Gradability Assessment for Inherited Retinal Diseases.

Purpose: To develop an automated system for assessing the quality of fundus autofluorescence (FAF) images in patients with inherited retinal diseases (IRDs).

Design: A retrospective study of imaging data.

Participants: Patients with a confirmed molecular diagnosis of IRD who have undergone FAF imaging at Moorfields Eye Hospital.

RHO-Associated Retinitis Pigmentosa: Genetics, Phenotype, Natural History, Functional Assays, and Animal Model - In Preparation for Clinical Trials.

Purpose: The purpose of this study was to describe the largest cohort of RHO-associated retinitis pigmentosa (RP) to date, analyzing the spectrum of phenotypes, variants, disease natural history, and genotype-phenotype correlations.

Methods: Variants were classified using functional assays, animal models, and published data. Clinical assessments involved visual acuity (LogMAR), dilated fundus examinations, multimodal imaging (spectral-domain optical coherence tomography [SD-OCT] and fundus autofluorescence [FAF]), and international-standard electrophysiology.

Quantification of Optical Coherence Tomography Features in >3500 Patients with Inherited Retinal Disease Reveals Novel Genotype-Phenotype Associations.

Purpose: To quantify spectral-domain optical coherence tomography (SD-OCT) images cross-sectionally and longitudinally in a large cohort of molecularly characterized patients with inherited retinal disease (IRDs) from the UK.

Design: Retrospective study of imaging data.

Participants: Patients with a clinical and molecularly confirmed diagnosis of IRD who have undergone macular SD-OCT imaging at Moorfields Eye Hospital (MEH) between 2011 and 2019.

A Phenotypic Study of CRB1 Retinopathy Secondary to the Variant p.(Pro836Thr) Prevalent in Those of Black African Ancestry.

Purpose: To comprehensively characterize the clinical consequences of the CRB1 variant p.(Pro836Thr). In African populations, this variant has an allele frequency of 0.

Next-generation phenotyping of inherited retinal diseases from multimodal imaging with Eye2Gene.

Rare eye diseases such as inherited retinal diseases (IRDs) are challenging to diagnose genetically. IRDs are typically monogenic disorders and represent a leading cause of blindness in children and working-age adults worldwide. A growing number are now being targeted in clinical trials, with approved treatments increasingly available.

Natural History of Autosomal Recessive IMPG2-Associated Retinal Dystrophy.

Purpose: To describe the natural history of autosomal recessive IMPG2-associated retinal dystrophy.

Design: Multicenter international retrospective case series.

Methods: Review of clinical notes, retinal imaging including fundus autofluorescence (FAF) and optical coherence tomography (OCT), and molecular genetic testing, of sixty patients with molecularly confirmed IMPG2-associated retinal dystrophy from 14 tertiary eye centers.

Clinical and Biochemical Characterization of Specific GUCY2D Alleles Associated With a Rare Form of Night Blindness.

Purpose: To clinically and biochemically characterize a rare autosomal recessive rod-cone dysfunction, with electroretinographic similarities to some forms of stationary night blindness (SNB), associated with biallelic variants in GUCY2D.

Methods: Six patients from five families with a history of longstanding night blindness, no fundus features suggestive of retinitis pigmentosa, and an unusual electroretinographic phenotype were ascertained. Clinical examination and genotyping were performed.

Biallelic NSUN3 Variants Cause Diverse Phenotypic Spectrum Disease: From Isolated Optic Atrophy to Severe Early-Onset Mitochondrial Disorder.

Purpose: Primary mitochondrial disorders (PMDs) are a clinically heterogeneous group of genetic disorders that can affect many tissues, with a broad phenotypic spectrum ranging from isolated organ involvement to severe early-onset multisystem disease. Visual loss from optic atrophy is a frequent clinical manifestation of mitochondrial cytopathies. This study aimed to identify the missing heritability in previously unsolved cases of suspected isolated or syndromic optic neuropathy.

Discrepancies Between Autofluorescence Imaging Modalities in CNGB3-Associated Achromatopsia and Correlation With Ellipsoid Zone Continuity.

Purpose: To explore discrepancies on fundus autofluorescence (FAF) obtained with two widely used devices in patients with CNGB3-associated achromatopsia, with respect to the central foveal signal. Secondly, to explore continuity of the foveal ellipsoid zone (EZ) in these patients.

Methods: Patients who had undergone blue (488 nm; Heidelberg Spectralis) and green (532 nm; Optos) FAF imaging during the same visit were included.

syndrome presenting with a familial exudative vitreoretinopathy (FEVR)-like retinovascular phenotype.

Introduction: The DYRK1A gene plays a crucial role in central nervous system development, with haploinsufficiency leading to DYRK1A-related intellectual disability syndrome. Ocular manifestations are common in DYRK1A syndrome and include refractive error, strabismus and optic nerve hypoplasia. Retinal involvement, however is less frequently reported and remains uncharacterised.

Inherited retinal disease pathway in the UK: a patient perspective and the potential of AI.

Background: Inherited retinal diseases (IRDs) are the leading cause of blindness in young people in the UK. Despite significant improvements in genomics medicine, the diagnosis of these conditions remains challenging, and around 40% do not receive a definite genetic diagnosis after extensive genetic testing. This survey aims to investigate the experience of individuals affected by IRDs, their relatives, friends and caregivers, focusing on their care and diagnostic journey.

Detailed Clinical, Ophthalmic, and Genetic Characterization of MYO7A-Associated Usher Syndrome.

Purpose: To analyze the clinical spectrum and natural history of MYO7A-associated Usher syndrome type I (USH1).

Methods: Patients with molecularly confirmed MYO7A-associated USH1 in a single tertiary referral center. Data was extracted from physical and electronic case notes, including imaging and electrophysiology.

Variants in CFAP410 cause a range of retinal and skeletal phenotypes.

Ciliopathies are associated with a range of phenotypes including retinal degeneration and skeletal abnormalities. We present a retrospective study of 49 patients with variants in Cilia and Flagella Associated Protein 410 (CFAP410) from multiple ophthalmic centers across the world. Common clinical features included early-onset reduced visual acuity, photophobia, and delayed light-to-dark adaptation.

Best Vitelliform Macular Dystrophy Natural History Study Report 2: Fundus Autofluorescence and OCT.

Purpose: To analyze the retinal imaging findings and natural history of Best vitelliform macular dystrophy (BVMD).

Design: Single-center retrospective, consecutive, observational study.

Participants: Patients with a clinical diagnosis of BVMD, from pedigrees with a likely disease-causing monoallelic variant in BEST1.

Bi-allelic variants in three genes encoding distinct subunits of the vesicular AP-5 complex cause hereditary macular dystrophy.

Inherited retinal diseases (IRDs) are a genetically heterogeneous group of Mendelian disorders that often lead to progressive vision loss and involve approximately 300 distinct genes. Although variants in these loci account for the majority of molecular diagnoses, other genes associated with IRD await molecular identification. In this study, we uncover bi-allelic assortments of 23 different (22 loss-of-function) variants in AP5Z1, AP5M1, and AP5B1 as independent causes of recessive IRD in members of 19 families from nine countries.

Biallelic null variants in C19orf44 cause a unique late-onset retinal dystrophy phenotype characterized by patchy perifoveal chorioretinal atrophy.

Purpose: To identify the genetic cause for disease in individuals affected with inherited retinal disease and to characterize their retinal phenotype and the properties of the underlying gene.

Methods: Participants underwent a comprehensive ophthalmological evaluation, including best-corrected visual acuity, visual field testing, fundus autofluorescence, optical coherence tomography, and electroretinography. Genetic analyses included exome, genome, and Sanger sequencing.

Rare disease gene association discovery in the 100,000 Genomes Project.

Up to 80% of rare disease patients remain undiagnosed after genomic sequencing, with many probably involving pathogenic variants in yet to be discovered disease-gene associations. To search for such associations, we developed a rare variant gene burden analytical framework for Mendelian diseases, and applied it to protein-coding variants from whole-genome sequencing of 34,851 cases and their family members recruited to the 100,000 Genomes Project. A total of 141 new associations were identified, including five for which independent disease-gene evidence was recently published.

Clinical, Genetic, Imaging and Electrophysiological Findings in a Cohort of Patients With GUCA1A-Associated Retinopathy.

Purpose: To report findings in GUCA1A-associated retinopathy, a rare autosomal-dominant retinopathy.

Methods: Clinical features and investigations from molecularly confirmed patients at a large referral center were analyzed (retrospective cohort study).

Results: Nineteen patients (14 families), with five different variants, were included: p.

Quantification of Fundus Autofluorescence Features in a Molecularly Characterized Cohort of >3500 Patients with Inherited Retinal Disease from the United Kingdom.

Purpose: To quantify relevant fundus autofluorescence (FAF) features cross-sectionally and longitudinally in a large cohort of patients with inherited retinal diseases (IRDs).

Design: Retrospective study of imaging data.

Participants: Patients with a clinical and molecularly confirmed diagnosis of IRD who have undergone 55° FAF imaging at Moorfields Eye Hospital (MEH) and the Royal Liverpool Hospital between 2004 and 2019.

De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa.

The U4 small nuclear RNA (snRNA) forms a duplex with the U6 snRNA and, together with U5 and ~30 proteins, is part of the U4/U6.U5 tri-snRNP complex, located at the core of the major spliceosome. Recently, recurrent variants in the U4 RNA, transcribed from the gene, and in at least two other genes were discovered to cause neurodevelopmental disorder.