Autoencoder-based phenotyping of ophthalmic images highlights genetic loci influencing retinal morphology and provides informative biomarkers.

Motivation: Genome-wide association studies (GWAS) have been remarkably successful in identifying associations between genetic variants and imaging-derived phenotypes. To date, the main focus of these analyses has been on established, clinically-used imaging features. We sought to investigate if deep learning approaches can detect more nuanced patterns of image variability.

THE FIGHT INHERITED RETINAL BLINDNESS! PROJECT: A NEW TREATMENT OUTCOME AND NATURAL HISTORY REGISTRY FOR INHERITED RETINAL DISEASE.

Purpose: To design and build a new disease registry to track the natural history and outcomes of approved gene therapy in patients with inherited retinal diseases (IRDs).

Methods: A core committee of 6 members was convened to oversee the construction of the FIRB! module. A further 11 experts formed a steering committee, which discussed disease classification and variables to form minimum datasets via a consensus approach.

Genome-wide association testing beyond SNPs.

Decades of genetic association testing in human cohorts have provided important insights into the genetic architecture and biological underpinnings of complex traits and diseases. However, for certain traits, genome-wide association studies (GWAS) for common SNPs are approaching signal saturation, which underscores the need to explore other types of genetic variation to understand the genetic basis of traits and diseases. Copy number variation (CNV) is an important source of heritability that is well known to functionally affect human traits.

Using computational approaches to enhance the interpretation of missense variants in the PAX6 gene.

The PAX6 gene encodes a highly-conserved transcription factor involved in eye development. Heterozygous loss-of-function variants in PAX6 can cause a range of ophthalmic disorders including aniridia. A key molecular diagnostic challenge is that many PAX6 missense changes are presently classified as variants of uncertain significance.

Retinal imaging for the assessment of stroke risk: a systematic review.

Background: Stroke is a leading cause of morbidity and mortality. Retinal imaging allows non-invasive assessment of the microvasculature. Consequently, retinal imaging is a technology which is garnering increasing attention as a means of assessing cardiovascular health and stroke risk.

Recommendations for risk allele evidence curation, classification, and reporting from the ClinGen Low Penetrance/Risk Allele Working Group.

Purpose: Genetic variants at the low end of the penetrance spectrum have historically been challenging to interpret because their high population frequencies exceed the disease prevalence of the associated condition, leading to a lack of clear segregation between the variant and disease. There is currently substantial variation in the classification of these variants, and no formal classification framework has been widely adopted. The Clinical Genome Resource Low Penetrance/Risk Allele Working Group was formed to address these challenges and promote harmonization within the clinical community.

Clinical, biochemical and molecular analysis in a cohort of individuals with gyrate atrophy.

Background: Gyrate atrophy of the choroid and retina is a rare autosomal recessive metabolic disorder caused by biallelic variants in the OAT gene, encoding the enzyme ornithine δ-aminotransferase. Impaired enzymatic activity leads to systemic hyperornithinaemia, which in turn underlies progressive chorioretinal degeneration. In this study, we describe the clinical and molecular findings in a cohort of individuals with gyrate atrophy.

A multilayered approach to the analysis of genetic data from individuals with suspected albinism.

Albinism is a clinically and genetically heterogeneous group of conditions characterised by visual abnormalities and variable degrees of hypopigmentation. Multiple studies have demonstrated the clinical utility of genetic investigations in individuals with suspected albinism. Despite this, the variation in the provision of genetic testing for albinism remains significant.

Causal factors in primary open angle glaucoma: a phenome-wide Mendelian randomisation study.

Primary open angle glaucoma (POAG) is a chronic, adult-onset optic neuropathy associated with characteristic optic disc and/or visual field changes. With a view to identifying modifiable risk factors for this common neurodegenerative condition, we performed a 'phenome-wide' univariable Mendelian randomisation (MR) study that involved analysing the relationship between 9661 traits and POAG. Utilised analytical approaches included weighted mode based estimation, the weighted median method, the MR Egger method and the inverse variance weighted (IVW) approach.

The Role of Genetic Testing in Children Requiring Surgery for Ectopia Lentis.

Non-traumatic ectopia lentis can be isolated or herald an underlying multisystemic disorder. Technological advances have revolutionized genetic testing for many ophthalmic disorders, and this study aims to provide insights into the clinical utility of genetic analysis in paediatric ectopia lentis. Children that underwent lens extraction for ectopia lentis between 2013 and 2017 were identified, and gene panel testing findings and surgical outcomes were collected.

Phenome-wide Mendelian randomisation analysis identifies causal factors for age-related macular degeneration.

Background: Age-related macular degeneration (AMD) is a leading cause of blindness in the industrialised world and is projected to affect >280 million people worldwide by 2040. Aiming to identify causal factors and potential therapeutic targets for this common condition, we designed and undertook a phenome-wide Mendelian randomisation (MR) study.

Methods: We evaluated the effect of 4591 exposure traits on early AMD using univariable MR.

From genetic variation to precision medicine.

Genetics has been an important tool for discovering new aspects of biology across life. In humans, there is growing momentum behind the application of this knowledge to drive innovation in clinical care, most notably through developments in precision medicine. Nowhere has the impact of genetics on clinical practice been more striking than in the field of rare disorders.

EyeG2P: an automated variant filtering approach improves efficiency of diagnostic genomic testing for inherited ophthalmic disorders.

Background: Genomic variant prioritisation is one of the most significant bottlenecks to mainstream genomic testing in healthcare. Tools to improve precision while ensuring high recall are critical to successful mainstream clinical genomic testing, in particular for whole genome sequencing where millions of variants must be considered for each patient.

Methods: We developed EyeG2P, a publicly available database and web application using the Ensembl Variant Effect Predictor.

Assessing the Pathogenicity of In-Frame CACNA1F Indel Variants Using Structural Modeling.

Small in-frame insertion-deletion (indel) variants are a common form of genomic variation whose impact on rare disease phenotypes has been understudied. The prediction of the pathogenicity of such variants remains challenging. X-linked incomplete congenital stationary night blindness type 2 (CSNB2) is a nonprogressive, inherited retinal disorder caused by variants in CACNA1F, encoding the Ca1.

LASER PROPHYLAXIS IN STICKLER SYNDROME: The Manchester Protocol.

Purpose: Patients with Stickler syndrome are at high risk of giant retinal tears (GRTs) and detachments. Vitreoretinal interventions can reduce this risk, but there is presently no consensus about the optimal prophylactic approach. The aim of our study was to determine whether 360° laser prophylaxis is a safe and effective procedure to prevent GRT detachments in patients with Stickler syndrome.

Generation of a human induced pluripotent stem cell line carrying the TYR c.575C>A (p.Ser192Tyr) and c.1205G>A (p.Arg402Gln) variants in homozygous state using CRISPR-Cas9 genome editing.

TYR encodes tyrosinase, the enzyme catalysing the first steps of melanin biosynthesis in melanocytes and retinal pigment epithelia (RPE). The TYR c.575C>A (p.

The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism.

Genetic diseases have been historically segregated into rare Mendelian disorders and common complex conditions. Large-scale studies using genome sequencing are eroding this distinction and are gradually unmasking the underlying complexity of human traits. Here, we analysed data from the Genomics England 100,000 Genomes Project and from a cohort of 1313 individuals with albinism aiming to gain insights into the genetic architecture of this archetypal rare disorder.

Clinical and genetic findings in TRPM1-related congenital stationary night blindness.

Purpose: Congenital stationary night blindness (CSNB) is a heterogeneous group of Mendelian retinal disorders that present in childhood. Biallelic variants altering the protein-coding region of the TRPM1 gene are one of the commonest causes of CSNB. Here, we report the clinical and genetic findings in 10 unrelated individuals with TRPM1-retinopathy.

Mast cell infiltration of the choroid and protease release are early events in age-related macular degeneration associated with genetic risk at both chromosomes 1q32 and 10q26.

Age-related macular degeneration (AMD) is a leading cause of visual loss. It has a strong genetic basis, and common haplotypes on chromosome (Chr) 1 (CFH Y402H variant) and on Chr10 (near HTRA1/ARMS2) contribute the most risk. Little is known about the early molecular and cellular processes in AMD, and we hypothesized that analyzing submacular tissue from older donors with genetic risk but without clinical features of AMD would provide biological insights.

Beyond factor H: The impact of genetic-risk variants for age-related macular degeneration on circulating factor-H-like 1 and factor-H-related protein concentrations.

Age-related macular degeneration (AMD) is a leading cause of vision loss; there is strong genetic susceptibility at the complement factor H (CFH) locus. This locus encodes a series of complement regulators: factor H (FH), a splice variant factor-H-like 1 (FHL-1), and five factor-H-related proteins (FHR-1 to FHR-5), all involved in the regulation of complement factor C3b turnover. Little is known about how AMD-associated variants at this locus might influence FHL-1 and FHR protein concentrations.

North Carolina Macular Dystrophy: Phenotypic Variability and Computational Analysis of Disease-Associated Noncoding Variants.

Purpose: North Carolina macular dystrophy (NCMD) is an autosomal dominant, congenital disorder affecting the central retina. Here, we report clinical and genetic findings in three families segregating NCMD and use epigenomic datasets from human tissues to gain insights into the effect of NCMD-implicated variants.

Methods: Clinical assessment and genetic testing were performed.