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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. We investigated the contribution of protein-coding and regulatory variants both rare and common. We focused on TYR , the gene encoding tyrosinase, and found that a high-frequency promoter variant, TYR c.−301C>T [rs4547091], modulates the penetrance of a prevalent, albinism-associated missense change, TYR c.1205G>A (p.Arg402Gln) [rs1126809]. We also found that homozygosity for a haplotype formed by three common, functionally-relevant variants, TYR c.[−301C;575C>A;1205G>A], is associated with a high probability of receiving an albinism diagnosis (OR>82). This genotype is also associated with reduced visual acuity and with increased central retinal thickness in UK Biobank participants. Finally, we report how the combined analysis of rare and common variants can increase diagnostic yield and can help inform genetic counselling in families with albinism. Albinism is a rare disorder often caused by high-effect rare variants in the TYR gene. Here, the authors study a large albinism cohort and find that a common variant in the TYR  promoter contributes to albinism by modifying the penetrance of other common variants, demonstrating a complex genetic architecture.

Although rare genetic conditions are mostly caused by DNA sequence alterations that functionally disrupt individual genes, large-scale studies using genome sequencing have started to unmask additional complexity. Understanding how combinations of variants in different genes shape human phenotypes is expected to provide important insights into the clinical and genetic heterogeneity of rare disorders. Here, we use albinism, an archetypal rare condition associated with hypopigmentation, as an exemplar for the study of genetic interactions. We analyse data from the Genomics England 100,000 Genomes Project alongside a cohort of 1120 individuals with albinism, and investigate the effect of dual heterozygosity for the combination of two established albinism-related variants: TYR :c.1205 G > A (p.Arg402Gln) [rs1126809] and OCA2 :c.1327 G > A (p.Val443Ile) [rs74653330]. As each of these changes alone is insufficient to cause disease when present in the heterozygous state, we sought evidence of synergistic effects. We show that, when both variants are present, the probability of receiving a diagnosis of albinism is significantly increased (odds ratio 12.8; 95% confidence interval 6.0 – 24.7; p -value 2.1 ×10 −8 ). Further analyses in an independent cohort, the UK Biobank, support this finding and highlight that heterozygosity for the TYR :c.1205 G > A and OCA2 :c.1327 G > A variant combination is associated with statistically significant alterations in visual acuity and central retinal thickness (traits that are considered albinism endophenotypes). The approach discussed in this report opens up new avenues for the investigation of oligogenic patterns in apparently Mendelian disorders. This study demonstrates that the co-occurrence of two specific variants in the TYR and OCA2 genes significantly increases the likelihood of having albinism. The outlined approach could help to elucidate digenic/oligogenic patterns in other rare conditions.

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. We evaluated the effect of 4591 exposure traits on early AMD using univariable MR. Statistically significant results were explored further using: validation in an advanced AMD cohort; MR Bayesian model averaging (MR-BMA); and multivariable MR. Overall, 44 traits were found to be putatively causal for early AMD in univariable analysis. Serum proteins that were found to have significant relationships with AMD included S100-A5 (odds ratio [OR] = 1.07, p-value = 6.80E-06), cathepsin F (OR = 1.10, p-value = 7.16E-05), and serine palmitoyltransferase 2 (OR = 0.86, p-value = 1.00E-03). Univariable MR analysis also supported roles for complement and immune cell traits. Although numerous lipid traits were found to be significantly related to AMD, MR-BMA suggested a driving causal role for serum sphingomyelin (marginal inclusion probability [MIP] = 0.76; model-averaged causal estimate [MACE] = 0.29). The results of this MR study support several putative causal factors for AMD and highlight avenues for future translational research. This project was funded by the Wellcome Trust (224643/Z/21/Z; 200990/Z/16/Z); the University of Manchester's Wellcome Institutional Strategic Support Fund (Wellcome ISSF) grant (204796/Z/16/Z); the UK National Institute for Health Research (NIHR) Academic Clinical Fellow and Clinical Lecturer Programmes; Retina UK and Fight for Sight (GR586); the Australian National Health and Medical Research Council (NHMRC) (1150144).

Pathogenic variants in the OCA2 gene result in oculocutaneous albinism. In humans and several other mammalian species, OCA2 is transcribed into two coding mRNAs, a major transcript that encodes the full-length protein and a minor transcript that skips in-frame exon 10 and has no identified function. By contrast, rodents and non-mammalian vertebrates only express the major transcript. Several rare variants of human OCA2 have been reported to be pathogenic due to increased exon 10 skipping. To understand the vulnerability of human OCA2 to exon 10 skipping and its impact on pigmentation, we first functionally tested a series of rare missense variants spread across exon 10. We found that each variant significantly influences the skipping ratio either positively or negatively. By combining human and murine sequences in functional assays, we found that the skipping ratio depends on particular exonic and intronic combinations. Next, we focused on the most frequent exonic single nucleotide variant of human OCA2 , rs1800404-T (c.1065G > A/p.Ala355=), located in exon 10. We show that this variant significantly promotes exon 10 skipping on its own and exhibits an additive effect in cis to previously identified splicing variants likely contributing to their pathogenicity. Association studies reveal that rs1800404-T is tightly associated with lighter skin and hair pigmentation in a representative European population, as has been observed in other populations around the world. Our structural models of the skipped transcript-derived protein support causality by predicting that it could exert a dominant-negative effect, which is consistent with a dose-dependent hypopigmentation response in both pathological and physiological contexts. Overall, the modulation of OCA2 exon 10 skipping by both benign and pathogenic variants provides a basis for improving the genetic diagnosis of albinism, and paves the way for research into the molecular and evolutionary mechanisms behind human pigmentation diversity.

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. Eleven traits related to POAG risk were identified including: serum levels of the angiopoietin-1 receptor (OR [odds ratio] = 1.11, IVW p  = 2.34E-06) and the cadherin 5 protein (OR = 1.06, IVW p  = 1.31E-06); intraocular pressure (OR = 2.46–3.79, IVW p  = 8.94E-44–3.00E-27); diabetes (OR = 5.17, beta = 1.64, IVW p  = 9.68E-04); and waist circumference (OR = 0.79, IVW p  = 1.66E-05). Future research focussing on the effects of adiposity, cadherin 5 and angiopoietin-1 receptor on POAG development and progression is expected to provide key insights that might inform the provision of lifestyle modification advice and/or the development of novel therapies.

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. Methods Study participants were recruited through a tertiary UK clinical ophthalmic genetic service. All cases had a biochemical and molecular diagnosis of gyrate atrophy. Retrospective phenotypic and biochemical data were collected using electronic healthcare records. Results 18 affected individuals from 12 families (8 male, 10 female) met the study inclusion criteria. The median age at diagnosis was 8 years (range 10 months – 33 years) and all cases had hyperornithinaemia (median: 800 micromoles/L; range: 458–1244 micromoles/L). Common features at presentation included high myopia (10/18) and nyctalopia (5/18). Ophthalmic findings were present in all study participants who were above the age of 6 years. One third of patients had co-existing macular oedema and two thirds developed pre-senile cataracts. Compliance with dietary modifications was suboptimal in most cases. A subset of participants had extraocular features including a trend towards reduced fat-free mass and developmental delay. Conclusions Our findings highlight the importance of multidisciplinary care in families with gyrate atrophy. Secondary ophthalmic complications such as macular oedema and cataract formation are common. Management of affected individuals remains challenging due to the highly restrictive nature of the recommended diet and the limited evidence-base for current strategies.

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. Overall, 10/11 cases received a probable molecular diagnosis. Genetic variants were identified in four genes: FBN1 (associated with Marfan syndrome and cardiovascular complications; n = 6), ADAMTSL4 (associated with non-syndromic ectopia lentis; n = 2), LTBP2 (n = 1) and ASPH (n = 1). Parents appeared unaffected in 6/11 cases; the initial presentation of all six of these children was to an ophthalmologist, and only 2/6 had FBN1 variants. Notably, 4/11 cases required surgery before the age of 4 years, and only one of these children carried an FBN1 variant. In summary, in this retrospective cohort study, panel-based genetic testing pointed to a molecular diagnosis in >90% of paediatric ectopia lentis cases requiring surgery. In a subset of study participants, genetic analysis revealed changes in genes that have not been linked to extraocular manifestations and highlighted that extensive systemic investigations were not required in these individuals. We propose the introduction of genetic testing early in the diagnostic pathway in children with ectopia lentis.

More than 20 genes have been linked with infantile-onset retinal dystrophy.1 In 2012, testing of multiple genes in parallel became possible in the NHS clinical setting.2 We tested the proband's DNA for mutations in genes previously associated with retinal dystrophy (appendix) but did not identify disease-causing genetic alterations.

Background The optical accessibility of the eye and technological advances in ophthalmic diagnostics have put ophthalmology at the forefront of data-driven medicine. The focus of this study is rare eye disorders, a group of conditions whose clinical heterogeneity and geographic dispersion make data-driven, evidence-based practice particularly challenging. Inter-institutional collaboration and information sharing is crucial but the lack of standardised terminology poses an important barrier. Ontologies are computational tools that include sets of vocabulary terms arranged in hierarchical structures. They can be used to provide robust terminology standards and to enhance data interoperability. Here, we discuss the development of the ophthalmology-related component of two well-established biomedical ontologies, the Human Phenotype Ontology (HPO; includes signs, symptoms and investigation findings) and the Orphanet Rare Disease Ontology (ORDO; includes rare disease nomenclature/nosology). Methods A variety of approaches were used including automated matching to existing resources and extensive manual curation. To achieve the latter, a study group including clinicians, patient representatives and ontology developers from 17 countries was formed. A broad range of terms was discussed and validated during a dedicated workshop attended by 60 members of the group. Results A comprehensive, structured and well-defined set of terms has been agreed on including 1106 terms relating to ocular phenotypes (HPO) and 1202 terms relating to rare eye disease nomenclature (ORDO). These terms and their relevant annotations can be accessed in http://www.human-phenotype-ontology.org/ and http://www.orpha.net/ ; comments, corrections, suggestions and requests for new terms can be made through these websites. This is an ongoing, community-driven endeavour and both HPO and ORDO are regularly updated. Conclusions To our knowledge, this is the first effort of such scale to provide terminology standards for the rare eye disease community. We hope that this work will not only improve coding and standardise information exchange in clinical care and research, but also it will catalyse the transition to an evidence-based precision ophthalmology paradigm.

Background/Objectives: Age-related macular degeneration (AMD) is the leading cause of visual impairment among the elderly. Optical coherence tomography angiography (OCTA) is a non-invasive imaging modality that enables detailed visualisation of retinal vascular layers. However, clinical assessment of OCTA images is often challenging due to high data volume, pattern variability, and subtle abnormalities. This study aimed to develop automated algorithms to detect and quantify AMD in OCTA images, thereby reducing ophthalmologists’ workload and enhancing diagnostic accuracy. Methods: Two texture-based algorithms were developed to classify OCTA images without relying on segmentation. The first algorithm used whole local texture features, while the second applied principal component analysis (PCA) to decorrelate and reduce texture features. Local texture descriptors, including rotation-invariant uniform local binary patterns (LBP2riu), local binary patterns (LBP), and binary robust independent elementary features (BRIEF), were combined with machine learning classifiers such as support vector machine (SVM) and K-nearest neighbour (KNN). OCTA datasets from Manchester Royal Eye Hospital and Moorfields Eye Hospital, covering healthy, dry AMD, and wet AMD eyes, were used for evaluation. Results: The first algorithm achieved a mean area under the receiver operating characteristic curve (AUC) of 1.00±0.00 for distinguishing healthy eyes from wet AMD. The second algorithm showed superior performance in differentiating dry AMD from wet AMD (AUC 0.85±0.02). Conclusions: The proposed algorithms demonstrate strong potential for rapid and accurate AMD diagnosis in OCTA workflows. By reducing manual image evaluation and associated variability, they may support improved clinical decision-making and patient care.