Healthcare professionals' knowledge and attitudes towards polygenic risk testing for glaucoma.

Background: Effective clinical implementation of polygenic risk testing for glaucoma relies on healthcare professionals' attitudes and knowledge of the test. Given the emerging applications of the test, it will likely impact a range of healthcare professionals and will require competency in polygenic risk scores concepts for all those involved in patient care. To our knowledge, this is the first study to assess healthcare professionals' views towards polygenic testing for glaucoma.

Deep Learning-Based Identification of Intraocular Pressure-Associated Genes Influencing Trabecular Meshwork Cell Morphology.

Purpose: Genome-wide association studies have recently uncovered many loci associated with variation in intraocular pressure (IOP). Artificial intelligence (AI) can be used to interrogate the effect of specific genetic knockouts on the morphology of trabecular meshwork cells (TMCs) and thus, IOP regulation.

Design: Experimental study.

Polygenic Risk Scores Driving Clinical Change in Glaucoma.

Glaucoma is a clinically heterogeneous disease and the world's leading cause of irreversible blindness. Therapeutic intervention can prevent blindness but relies on early diagnosis, and current clinical risk factors are limited in their ability to predict who will develop sight-threatening glaucoma. The high heritability of glaucoma makes it an ideal substrate for genetic risk prediction, with the bulk of risk being polygenic in nature.

The landscape of genomic structural variation in Indigenous Australians.

Indigenous Australians harbour rich and unique genomic diversity. However, Aboriginal and Torres Strait Islander ancestries are historically under-represented in genomics research and almost completely missing from reference datasets. Addressing this representation gap is critical, both to advance our understanding of global human genomic diversity and as a prerequisite for ensuring equitable outcomes in genomic medicine.

Genetic Risk Assessment of Degenerative Eye Disease (GRADE): study protocol of a prospective assessment of polygenic risk scores to predict diagnosis of glaucoma and age-related macular degeneration.

Background: Glaucoma and age-related macular degeneration (AMD) account for a substantial portion of global blindness. Both conditions are highly heritable, with recognised monogenic and polygenic inheritance patterns. Current screening guidelines lack decisive recommendations.

Neuroimaging Findings in Axenfeld-Rieger Syndrome: A Case Series.

Axenfeld-Rieger syndrome is an autosomal dominant condition associated with multisystemic features including developmental anomalies of the anterior segment of the eye. Single nucleotide and copy number variants in the paired-like homeodomain transcription factor 2 () and forkhead box C1 () genes are associated with Axenfeld-Rieger syndrome as well as other CNS malformations. We determined the association between Axenfeld-Rieger syndrome and specific brain MR imaging neuroradiologic anomalies in cases with or without a genetic diagnosis.

Phenotypic consequences of a nanophthalmos-associated TMEM98 variant in human and mouse.

Nanophthalmos is characterised by shorter posterior and anterior segments of the eye, with a predisposition towards high hyperopia and primary angle-closure glaucoma. Variants in TMEM98 have been associated with autosomal dominant nanophthalmos in multiple kindreds, but definitive evidence for causation has been limited. Here we used CRISPR/Cas9 mutagenesis to recreate the human nanophthalmos-associated TMEM98 p.

Physical Activity Is Associated With Macular Thickness: A Multi-Cohort Observational Study.

Purpose: To assess the association between physical activity and spectral-domain optical coherence tomography (SD-OCT)-measured rates of macular thinning in an adult population with primary open-angle glaucoma.

Methods: The correlation between accelerometer-measured physical activity and rates of macular ganglion cell-inner plexiform layer (GCIPL) thinning was measured in 735 eyes from 388 participants of the Progression Risk of Glaucoma: RElevant SNPs with Significant Association (PROGRESSA) study. The association between accelerometer-measured physical activity and cross-sectional SD-OCT macular thickness was then assessed in 8862 eyes from 6152 participants available for analysis in the UK Biobank who had SD-OCT, ophthalmic, comorbidity, and demographic data.

Thrombospondin 1 missense alleles induce extracellular matrix protein aggregation and TM dysfunction in congenital glaucoma.

Glaucoma is a highly heritable disease that is a leading cause of blindness worldwide. Here, we identified heterozygous thrombospondin 1 (THBS1) missense alleles altering p.Arg1034, a highly evolutionarily conserved amino acid, in 3 unrelated and ethnically diverse families affected by congenital glaucoma, a severe form of glaucoma affecting children.

Association of High Polygenic Risk With Visual Field Worsening Despite Treatment in Early Primary Open-Angle Glaucoma.

Importance: Irreversible vision loss from primary open-angle glaucoma (POAG) can be prevented through timely diagnosis and treatment, although definitive diagnosis can be difficult in early-stage disease. As a consequence, large numbers of individuals with suspected glaucoma require regular monitoring, even though many of these may never develop disease and other high-risk individuals with suspected glaucoma may have delayed or inadequate treatment. POAG is one of the most heritable common diseases, and this provides an opportunity to use genetic instruments in risk-stratified screening, diagnosis, and treatment of early glaucoma.

Attitudes Toward Glaucoma Genetic Risk Assessment in Unaffected Individuals.

Purpose: Integrating polygenic risk scores (PRS) into healthcare has the potential to stratify an individual's risk of glaucoma across a broad population. Glaucoma is the most common cause of irreversible blindness worldwide, therefore effective screening for glaucoma endorsed by the population is highly important. This study assessed the attitude of unaffected individuals toward PRS testing for glaucoma, and sought to identify factors associated with interest in testing.

The phenotypic spectrum of associated ectopia lentis: Additional cases, complications, and review of literature.

Purpose: associated ectopia lentis is a rare autosomal recessive condition that is primarily associated with crystalline lens displacement. However, the prevalence of other ocular and systemic manifestations of this condition is poorly understood. In this study, we summarize the ocular and systemic phenotypic spectrum of this condition.

The E4 Allele Is Associated with Faster Rates of Neuroretinal Thinning in a Prospective Cohort Study of Suspect and Early Glaucoma.

Purpose: To investigate the association between the apolipoprotein E () E4 dementia-risk allele and prospective longitudinal retinal thinning in a cohort study of suspect and early manifest glaucoma.

Design: Retrospective analysis of prospective cohort data.

Participants: This study included all available eyes from participants recruited to the Progression Risk of Glaucoma: Relevant SNPs [single nucleotide polymorphisms] with Significant Association (PROGRESSA) study with genotyping data from which genotypes could be determined.

Genetic Risk of Cardiovascular Disease Is Associated with Macular Ganglion Cell-Inner Plexiform Layer Thinning in an Early Glaucoma Cohort.

Purpose: To evaluate the association between genetic risk for cardiovascular disease and retinal thinning in early glaucoma.

Design: Prospective, observational genetic association study.

Participants: Multicohort study combining a cohort of patients with suspect and early manifest primary open-angle glaucoma (POAG), a cohort of patients with perimetric POAG, and an external normative control cohort.

Specifications of the ACMG/AMP variant curation guidelines for myocilin: Recommendations from the clingen glaucoma expert panel.

The standardization of variant curation criteria is essential for accurate interpretation of genetic results and clinical care of patients. The variant curation guidelines developed by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) in 2015 are widely used but are not gene specific. To address this issue, the Clinical Genome Resource (ClinGen) Variant Curation Expert Panels (VCEP) have been tasked with developing gene-specific variant curation guidelines.

Association Between Body Mass Index and Primary Open Angle Glaucoma in Three Cohorts.

Purpose: To evaluate the relationship between body mass index (BMI) and glaucoma progression.

Design: Multicohort observational study.

Methods: This study combined a retrospective longitudinal analysis of suspect and early manifest primary open angle glaucoma cases from the Progression Risk of Glaucoma: RElevant SNPs with Significant Association (PROGRESSA) study with 2 replication cohorts from the UK Biobank and the Canadian Longitudinal Study of Ageing (CLSA).

High Polygenic Risk Is Associated with Earlier Trabeculectomy in Patients with Primary Open-Angle Glaucoma.

Purpose: To evaluate the association between a polygenic risk score (PRS) for primary open-angle glaucoma (POAG) and the age at the first trabeculectomy and the need for bilateral trabeculectomy.

Design: Retrospective observational cohort study.

Participants: Nine hundred and three genotyped participants with POAG from the Australian and New Zealand Registry of Advanced Glaucoma.

Infliximab Reverses Symptoms and May Protect from Developing Chronic Restrictive Ophthalmopathy in Children with Familial Orbital Myositis: A Case Report.

Background: Orbital myositis is a rare sporadic eye disease associated with extraocular eye muscle inflammation. To date, there have been two reports of familial orbital myositis (FOM), which demonstrate partially penetrant autosomal dominant inheritance.

Cases: We report six new Australian cases of FOM, four of whom extend one of the reported pedigrees, as well as a separate mother and daughter manifesting orbital myositis, which constitutes a third report of familial occurrence.

Comparison of Anterior Segment Abnormalities in Individuals With FOXC1 and PITX2 Variants.

Purpose: Axenfeld-Rieger syndrome encompasses a group of developmental disorders affecting the anterior chamber structures of the eye, with associated systemic features in some cases. This study aims to compare the difference in anterior segment phenotypes such as those involving the cornea, iris, lens, and anterior chamber angle between cases with disease-causing sequence variations in FOXC1 and PITX2 .

Methods: This cross-sectional study involved 61 individuals, from 32 families with pathogenic FOXC1 or PITX2 variants, who were registered with the Australian and New Zealand Registry of Advanced Glaucoma.

RNA Sequencing of Lens Capsular Epithelium Implicates Novel Pathways in Pseudoexfoliation Syndrome.

Purpose: Pseudoexfoliation syndrome (PEX) is a common systemic disease that results in severe and often irreversible vision loss. Despite considerable research effort, PEX remains incompletely understood. This study sought to perform the first RNAseq study in elucidate the pathophysiology of PEX, and contribute a publicly available transcriptomic data resource for future research.

Attitudes Towards Polygenic Risk Testing in Individuals with Glaucoma.

Purpose: Glaucoma is the leading cause of irreversible blindness worldwide; however, vision loss resulting from glaucoma generally can be prevented through early identification and timely implementation of treatment. Recently, polygenic risk scores (PRSs) have shown promise in stratifying individual risk and prognostication for primary open-angle glaucoma (POAG) to reduce disease burden. Integrating PRS testing into clinical practice is becoming increasingly realistic; however, little is known about the attitudes of patients toward such testing.