Jamie E. Craig

Pathogenic variants in the myocilin ( MYOC ) gene are the most common cause of Mendelian open-angle glaucoma. In 2022, the Clinical Genome Resource (ClinGen) Glaucoma Variant Curation Expert Panel (VCEP) published rule specifications for MYOC variant interpretation, including a pilot study of 81 variants. Here, we present the results of curating 271 MYOC variants reported in people with open-angle glaucoma using updated specification rules. Of all the variants, 11 were classified as benign (B), 45 as likely benign (LB), 166 as variants of uncertain significance (VUS), 35 as likely pathogenic (LP), and 14 as pathogenic (P). All LP/P variants were located within the conserved olfactomedin domain encoded by exon 3. The updated variant curation guidelines from the Glaucoma VCEP increased the number of clinically definitive classifications from 28% (74/265) to 39% (105/271), with 95% (41/43) of reclassified variants moving to greater clinical relevance. Functional evidence was lacking for 93% (154/166) of VUS. Additional functional evidence could further enhance classification by halving (85/166) the proportion of those classified as VUS. These findings highlight the role of rule calibration and rigorous functional evidence assessment toward improving variant classification with clinical utility for patients.

Early glaucoma detection and treatment are critical to prevent irreversible blindness. Glaucoma polygenic risk scores (PRS) offer an effective approach for stratifying disease risk and are increasingly available in clinical practice. However, the psychosocial impact of receiving glaucoma PRS results is currently unknown. As such, this study investigated short-term psychosocial outcomes of disclosing glaucoma PRS to individuals over 50 years from the general population. Individuals from the bottom 10%, middle 45-55%, and top 10% of PRS scores were invited to receive their results and complete surveys before and 2 weeks after receiving results to assess anxiety, test-related distress, decisional regret, recall and understanding. Of invited participants, 51.7% (136/263) enrolled with 133 completing both surveys. Two weeks after disclosure, PRS recall was high (78.2%), although PRS knowledge remained limited. Privacy concerns were moderate, not differing across PRS groups ( Χ ² = 4.17, p = .124). Small reductions in glaucoma-related anxiety ( z = –2.93, p = .003), generalised anxiety ( z = −3.75, p < .001) and stress ( z = −2.49, p = .013) were observed following disclosure. While scores remained within normal ranges, higher glaucoma-related anxiety ( t = –2.36, p = .020), higher negative emotions ( Χ ² = 20.80, p < .001), and lower positive experience ( F = 5.70, p = .004) were seen for high-risk participants compared to lower-risk participants. Decisional regret was low and didn’t differ across PRS groups ( Χ ² = 0.28, p = .869). These findings support the psychosocial safety of glaucoma PRS testing while highlighting the need for improved education and longer-term follow-up to support clinical implementation.

Axenfeld–Rieger Syndrome (ARS) is an autosomal dominant condition with both ocular and non-ocular manifestations. ARS is primarily caused by coding variants at the PITX2 or FOXC1 loci, yet many cases still remain undiagnosed. Here we used whole-genome sequencing to identify two families with non-coding structural variants associated with a typical presentation of PITX2 -associated ARS: one family with a 450 kb deletion removing a series of conserved enhancer elements distal to PITX2 , and the second family with a 12.54 Mb inversion displacing the PITX2 gene from these same enhancer elements. Neither variant disrupted the PITX2 gene itself, and therefore both were expected to reduce PITX2 expression by disrupting its proximity or access to enhancer elements. PITX2 enhancer-disrupting inversions are an emerging genetic mechanism for the development of ARS, which should be carefully considered in the context of ARS and other conditions without a conclusive genetic diagnosis.

Background: The visual field (VF) test results of many eyes with glaucoma progress despite treatment. This suggests that some eyes are either untreated or that the management of intraocular pressure (IOP) does not influence the outcome. In this work, we explore whether future VF parameters can be predicted from a baseline optical coherence retinal nerve fibre layer (OCT-RNFL) scan using a deep learning model. Methods: The model was developed using 1792 eyes from 1610 patients, and externally validated on 151 eyes from a second centre using the same Zeiss Cirrus machine and 281 eyes from a third centre using scans obtained from a different (Heidelberg Spectralis) machine. The Vision Transformers (ViT)-based regression model was trained on baseline OCT-RNFL scans to predict three key VF indices (follow-up interval: 4.74 ± 2.59 years). Model performance was evaluated using Mean Absolute Error (MAE) and Root Mean Square Error (RMSE), with 95% confidence intervals (CI). Results: The model achieved an overall MAE of 2.07 (95% CI: 1.91-2.22) and RMSE of 2.87 (95% CI: 2.60-3.14) on the internal validation set. On external validation, the model showed comparable performance with an MAE of 2.07 (95% CI: 1.8-2.35) for the external validation (Zeiss OCT) cohort and 2.11 (95% CI: 1.93-2.31) for the external validation (Heidelberg OCT) cohort. Saliency maps revealed that the inner and outer RNFL layers were key structures in driving the model’s predictions. Conclusions: Our ViT-based regression model effectively predicts key VF indices objectively from a single OCT-RNFL scan, with strong performance across two OCT devices, offering a novel tool for predicting glaucoma progression.

SUMMARY: Glaucoma is the leading cause of irreversible blindness; vision loss is preventable with timely treatment, but early detection is challenging, leaving ∼50% undiagnosed, highlighting the need for improved risk assessment tools. We developed a polygenic risk score (PRS) using data from >6 million individuals. PRS performance was exceptional in European ancestries; top 10% PRS individuals had 10-fold increased risk (OR=10.0) relative to the remainder. Performance remained good across all major ancestry groups; high-PRS individuals were at high absolute risk, especially Africans. High-risk individuals (top 10% PRS) developed glaucoma up to 25 years earlier than those in the lowest 10% and were at 100 times the risk. The PRS also predicted need for treatment escalation in early glaucoma and both prevalent and incident surgery. Risk profiling with this PRS which is clinically available, enables earlier identification and more timely treatment of high-risk individuals for preventable vision loss, with a reduced screening and monitoring burden for those at low-risk. Research in Context: Evidence before this study: Glaucoma is the leading cause of irreversible blindness worldwide. Early detection is essential because current treatments cannot restore lost vision. Population-wide screening using conventional risk factors for glaucoma (such as elevated intraocular pressure) is not currently cost-effective, though a better stratification method could improve early diagnosis rates and reduce over-monitoring of lower risk cases. Glaucoma is one of the most heritable common complex diseases, suggesting that genetics-based approaches could revolutionize risk stratification. Previous polygenic risk scores (PRS) indexing glaucoma genetic risk were limited by restricted applicability outside European ancestry populations, small discovery sample sizes, modest predictive power, poor clinical availability. The inability to cover a broad range of ancestries limited the practical clinical application of earlier versions of glaucoma PRS for risk stratification and patient management. Added value of this study: A novel PRS, trained on >6 million individuals, has significantly improved glaucoma risk prediction across major ancestry groups, identifying high-risk individuals (top 10% of risk versus remainder) with odds ratios up to 10 in Europeans and 3.4–7.5 in non-Europeans (larger than for any other common complex disease). The excellent PRS risk stratification remained after adjusting for intraocular pressure; adding PRS to a prediction model with age, sex and intraocular pressure increased the Area Under the Curve for predicting glaucoma status from 0.63 to 0.82. High-risk individuals (top 10% PRS) developed glaucoma up to 25 years earlier than those in the lowest 10% and were at 100 times greater risk. The PRS also predicted structural progression, the need for treatment initiation and escalation in early glaucoma, both prevalent and incident incisional surgery for glaucoma, and the likelihood of glaucoma being present in first-degree relatives. These improvements impart strong clinical utility for population risk stratification, and the personalised management of individuals with clinical features suggestive of early stage glaucoma. Implications of all the available evidence: This clinically available, enhanced PRS enables accurate identification of both high- and low-risk individuals across diverse populations, supporting earlier diagnosis, targeted monitoring, and timely treatment. It provides a clinical tool which can be applied for precision prevention and management of glaucoma, enabling cost-effective, equitable, genetically-informed glaucoma risk stratification across the entire population.

GWAS of primary angle-closure glaucoma have identified eight loci conferring risk in Asian populations. However, it remains unclear whether the genetic risk factors for the disease are consistent across different populations. Here, we present a discovery GWAS for primary angle-closure glaucoma in Europeans using the UK Biobank. We replicate our findings in six independent European populations and compare these results with results from 14 Asian cohorts. Five genomic regions in the discovery cohort are associated at genome-wide significance, including two loci previously identified in Asian cohorts. We next meta-analyse the discovery and replication cohorts to identify six additional novel loci, all previously associated with refractive error. Mendelian randomisation provides evidence for a causal role of shorter axial length and hypermetropic refractive error on primary angle-closure glaucoma. A polygenic risk score derived from the European ancestry meta-analysis demonstrates significant associations with quantitative ocular traits – including a shallower anterior chamber and higher intraocular pressure – in the independent EPIC-Norfolk cohort. Finally, a multi-ancestry meta-analysis of all 21 European and Asian cohorts identifies 12 further novel loci. This work shows that genetic factors associated with a darker iris and hypermetropia confer risk for primary angle-closure glaucoma.

Precision medicine is paving the way for personalised risk assessment, and its translation into glaucoma clinics holds potential to change current management paradigms. Our understanding of glaucoma's genetic architecture has expanded in recent years, recognising both monogenic and polygenic contributions. Genetic testing within glaucoma populations can provide additional information for clinicians to support decision‐making. Here, we review the evidence base for genetic variants strongly associated with glaucoma and outline a vision for translating these learnings into the clinic. Integrating clinical and genetic information will provide clinicians and patients with the strongest evidence to deliver personalised glaucoma management.