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. Here, we summarize the foundations of glaucoma genetic risk, the development of polygenic risk prediction instruments, and emerging opportunities for genetic risk stratification. Although challenges remain, genetic risk stratification will significantly improve glaucoma screening and management.

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. Polygenic risk scores (PRS) allow for cost-effective broad population risk stratification for these conditions. The predictive potential of PRS could facilitate earlier diagnosis and treatment, and prevent unnecessary vision loss. METHODS: The Genetic Risk Assessment of Degenerative Eye disease (GRADE) study is a prospective study designed to generate high-quality evidence about the feasibility of PRS to stratify individuals from the general population, enabling identification of those at highest risk of developing glaucoma or AMD. The targeted recruitment is 1000 individuals aged over 50 years, from which blood or saliva samples will be used for genotyping and an individual PRS for glaucoma and AMD will be derived. Individuals with PRS values in the bottom decile (n = 100), top decile (n = 100) and middle 80% (n = 100) for both glaucoma and AMD will undergo a detailed eye examination for glaucoma and/or AMD. DISCUSSION: The primary objective will be to compare the prevalence of glaucoma and AMD cases between low, intermediate, and high PRS risk groups. We expect to find a higher prevalence of both diseases in the high PRS risk group, as compared to the middle and low risk groups. This prospective study will assess the clinical validity of a PRS for glaucoma and AMD in the general Australian population. Positive findings will support the implementation of PRS into clinical practice.

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 (PITX2) and forkhead box C1 (FOXC1) 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. This case series included 8 individuals with pathogenic variants in FOXC1; 2, in PITX2; and 2 without a genetic diagnosis. The most common observation was vertebrobasilar artery dolichoectasia, with 46% prevalence. Other prevalent abnormalities included WM hyperintensities, cerebellar hypoplasia, and ventriculomegaly. Vertebrobasilar artery dolichoectasia and absent/hypoplastic olfactory bulbs were reported in >50% of individuals with FOXC1 variants compared with 0% of PITX2 variants. Notwithstanding the small sample size, neuroimaging abnormalities were more prevalent in individuals with FOXC1 variants compared those with PITX2 variants.

No Strong Association between the Apolipoprotein E E4 Allele and Glaucoma: A Multicohort Study.

Purpose: To elucidate a potential association between the apolipoprotein E (APOE) E4 allele and glaucoma prevalence in large cohorts. Design: A cross-sectional analysis of baseline and prospectively collected cohort data. Participants: UK Biobank (UKBB) participants of genetically determined European ancestry (n = 438 711). Replication analyses were performed using clinical and genotyping data collected from European participants recruited to the Canadian Longitudinal Study of Aging (CLSA; n = 18 199), the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG; n = 1970), and the Blue Mountains Eye Study (BMES; n = 2440). Methods: Apolipoprotein E alleles and genotypes were determined, and their distributions were compared on the basis of glaucoma status. Similar analyses were performed using positive control outcomes associated with the APOE E4 allele (death, dementia, age-related macular degeneration) and negative control outcomes not associated with the APOE E4 allele (cataract, diabetic eye disease). Outcome phenotypes were also correlated with Alzheimer's dementia (AD), a clinical outcome highly associated with the APOE E4 allele. Main Outcome Measures: Results of APOE E4 genotype-phenotype comparisons were reported as odds ratios (ORs) with 95% confidence intervals (CIs). Replication analyses investigated APOE E4 associations in 2 replication cohorts (CLSA and ANZRAG/BMES). Results: The APOE E4 allele was inversely associated with glaucoma (OR, 0.96; 95% CI, 0.93-0.99; P = 0.016) and both negative controls (cataract: OR, 0.98; 95% CI, 0.96-0.99; P = 0.015; diabetic eye disease: OR, 0.92; 95% CI, 0.87-0.97; P = 0.003) in the UKBB cohort. A paradoxical positive association was observed between AD and both glaucoma (OR, 1.30; 95% CI, 1.08-1.54; P < 0.01) and cataract (OR, 1.15; 1.04-1.28; P = 0.018). No association between the APOE E4 allele and glaucoma was observed in either replication cohort (CLSA: OR, 1.03; 95% CI, 0.89-1.19; P = 0.66; ANZRAG/BMES: OR, 0.97; 95% CI, 0.84-1.12; P = 0.65). Conclusions: A small negative association observed between APOE E4 and glaucoma within the UKBB was not evident in either replication cohort and may represent an artifact of glaucoma underdiagnosis in APOE E4 carriers. Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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. METHODS: The ocular surgical history of these participants was reviewed and the following parameters were recorded: age at diagnosis, age at trabeculectomy, and lateraly of trabeculectomy. Multivariate linear regression analyses correlated glaucoma PRSs with age at trabeculectomy, and laterality of trabeculectomy. For descriptive purposes, the participants were stratified into the top decile, intermediate group (10th-89th percentile), and bottom decile. MAIN OUTCOME MEASURES: Age at trabeculectomy, and laterality of trabeculectomy. RESULTS: Higher PRS was associated with younger age at the first trabeculectomy (ß, -1.94 years/standard deviation; 95% confidence interval [CI], - 0.41 to -3.47; P = 0.014). Participants in the top decile underwent their first trabeculectomy approximately 7 years earlier than participants in the lowest decile (mean difference, -7.04 years; 95% CI, 2.82-11.26). Participants in the top decile were 1.41-fold more likely to require bilateral trabeculectomy than participants in the bottom decile (odds ratio, 1.41; 95% CI, 1.06-1.91; P = 0.021). CONCLUSIONS: This report identified clinically relevant correlations between glaucoma PRS and the need for surgical intervention in patients with glaucoma. Further work is required to investigate the association between PRS and other clinical end points such as treatment initiation.

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. Objective: To assess the association of glaucoma polygenic risk with glaucoma progression in early-stage disease. Design, Setting, and Participants: This cohort study used clinical and genetic data obtained from a longitudinal cohort study, Progression Risk of Glaucoma: Relevant SNPs With Significant Association (PROGRESSA). Participants of European ancestry with characteristic optic nerve head changes suggestive of glaucoma were included. Data were collected between February 2012 and June 2020. Analysis took place between July 2020 and April 2022. Main Outcomes and Measures: The association of a glaucoma polygenic risk score (PRS) (2673 uncorrelated variants) with rate of peripapillary retinal nerve fiber layer thinning on optical coherence tomography and progression of visual field loss on 24-2 Humphrey visual fields. Results: A total of 1777 eyes from 896 individuals had sufficient data for structural progression analyses and 1563 eyes from 808 individuals for functional progression analyses. The mean (SD) age was 62.1 (9.9) years, 488 (44%) were male, and 1087 of 1103 individuals (98.5%) had European ancestry. An ancestrally matched normative population cohort (n = 17 642) was used for PRS reference. Individuals in the top 5% PRS risk group were at a higher risk of visual field progression compared with the remaining 95% after 5 years (hazard ratio, 1.5; 95% CI, 1.13-1.97; P = .005). Conversely, those in the bottom 20% PRS risk group were at a lower risk of visual field progression compared with an intermediate risk group over 3 years (hazard ratio, 0.52; 95% CI, 0.28-0.96; P = .04). Conclusions and Relevance: In this study, high polygenic risk was associated with more rapid structural and functional progression in early POAG, despite more intensive treatment. A PRS may serve as a valuable adjunct to identify individuals who stand to benefit the most from more frequent surveillance and earlier or more intensive treatment.

The APOE 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 (APOE) 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 APOE genotypes could be determined. Methods: Apolipoprotein E alleles and genotypes were determined in PROGRESSA, and their distributions were compared with an age-matched and ancestrally matched normative cohort, the Blue Mountains Eye Study. Structural parameters of neuroretinal atrophy measured using spectral-domain OCT were compared within the PROGRESSA cohort on the basis of APOE E4 allele status. Main Outcome Measures: Longitudinal rates of thinning in the macular ganglion cell-inner plexiform layer (mGCIPL) complex and the peripapillary retinal nerve fiber layer (pRNFL). Results: Rates of mGCIPL complex thinning were faster in participants harboring ≥1 copies of the APOE E4 allele (ß = -0.13 µm/year; P ≤0.001). This finding was strongest in eyes affected by normal-tension glaucoma (NTG; ß = -0.20 µm/year; P = 0.003). Apolipoprotein E E4 allele carriers were also more likely to be lost to follow-up (P = 0.01) and to demonstrate a thinner average mGCIPL complex (70.9 µm vs. 71.9 µm; P = 0.011) and pRNFL (77.6 µm vs. 79.2 µm; P = 0.045) after a minimum of 3 years of monitoring. Conclusions: The APOE E4 allele was associated with faster rates of mCGIPL complex thinning, particularly in eyes with NTG. These results suggest that the APOE E4 allele may be a risk factor for retinal ganglion cell degeneration in glaucoma.

The phenotypic spectrum of ADAMTSL4-associated ectopia lentis: Additional cases, complications, and review of literature.

Purpose: ADAMTSL4-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. Methods: A cross-sectional case study series of four individuals with biallelic pathogenic or likely pathogenic ADAMTSL4 variants was performed alongside a literature review of individuals with ADAMTSL4-associated ectopia lentis on September 29, 2021. Ocular and systemic findings, complications, and genetic findings of all four individuals were collected and summarized. Results: The phenotypic spectrum across 91 individuals sourced from literature and four individuals from this case study series was highly variable. The main ocular phenotypes included ectopia lentis (95/95, 100%), ectopia lentis et pupillae (18/95, 19%), iris transillumination (13/95, 14%), iridodonesis (12/95, 13%), persistent pupillary membrane (12/95, 13%), and early-onset cataract or lens opacities (12/95, 13%). Anterior segment features other than ectopia lentis appeared to be exclusively associated with biallelic loss of function variants (p<0.001). Pupillary block glaucoma had a prevalence of 1%. Post-lensectomy complications included retinal detachment (6/41, 15%), elevated intraocular pressure (4/41, 10%), and aphakic glaucoma (1/41, 2%). Most individuals were not reported to have had systemic features (69/95, 73%). Conclusions: The clinical phenotype of ADAMTSL4-associated ectopia lentis was summarized and expanded. Clinicians should be aware of the varied ocular phenotype and the risks of retinal detachment, ocular hypertension, and glaucoma in the diagnosis and management of this condition.

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. Methods: We surveyed 418 unaffected individuals including 193 with a first-degree relative with glaucoma, 117 who had a recent eye examination, and 108 general members of the community. Results: Overall, 71.3% of the individuals indicated an interest in taking a polygenic risk test for glaucoma. Interest was more likely in those who believed glaucoma to be a severe medical condition (odds ratio [OR] = 14.58, 95% confidence interval [CI] = 1.15-185.50, P = 0.039), those concerned about developing glaucoma (OR = 4.37, 95% CI = 2.32-8.25, P < 0.001), those with an intention to take appropriate measures regarding eye health (OR = 2.39, 95% CI = 1.16-4.95, P = 0.019), and those preferring to know if considered to be at-risk or not (OR = 4.52, 95% CI = 2.32-8.83, P < 0.001). Conclusions: Our results show strong interest in genetic risk assessment for glaucoma among unaffected individuals in Australia. Translational Relevance: These findings represent a valuable assessment of interest in glaucoma polygenic risk testing among potential target populations, which will be integral to the implementation and uptake of novel PRS-based tests into clinical practice.

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. The Glaucoma VCEP was created to develop rule specifications for genes associated with primary glaucoma, including myocilin (MYOC), the most common cause of Mendelian glaucoma. Of the 28 ACMG/AMP criteria, the Glaucoma VCEP adapted 15 rules to MYOC and determined 13 rules not applicable. Key specifications included determining minor allele frequency thresholds, developing an approach to counting probands and segregations, and reviewing functional assays. The rules were piloted on 81 variants and led to a change in classification in 40% of those that were classified in ClinVar, with functional evidence influencing the classification of 18 variants. The standardized variant curation guidelines for MYOC provide a framework for the consistent application of the rules between laboratories, to improve MYOC genetic testing in the management of glaucoma.

Pathogenic genetic variants identified in Australian families with paediatric cataract.

OBJECTIVE: Paediatric (childhood or congenital) cataract is an opacification of the normally clear lens of the eye and has a genetic basis in at least 18% of cases in Australia. This study aimed to replicate clinical gene screening to identify variants likely to be causative of disease in an Australian patient cohort. METHODS AND ANALYSIS: Sixty-three reported isolated cataract genes were screened for rare coding variants in 37 Australian families using genome sequencing. RESULTS: Disease-causing variants were confirmed in eight families with variant classification as 'likely pathogenic'. This included novel variants PITX3 p.(Ter303LeuextTer100), BFSP1 p.(Glu375GlyfsTer2), and GJA8 p.(Pro189Ser), as well as, previously described variants identified in genes GJA3, GJA8, CRYAA, BFSP1, PITX3, COL4A1 and HSF4. Additionally, eight variants of uncertain significance with evidence towards pathogenicity were identified in genes: GJA3, GJA8, LEMD2, PRX, CRYBB1, BFSP2, and MIP. CONCLUSION: These findings expand the genotype-phenotype correlations of both pathogenic and benign variation in cataract-associated genes. They further emphasise the need to develop additional evidence such as functional assays and variant classification criteria specific to paediatric cataract genes to improve interpretation of variants and molecular diagnosis in patients.

Diagnostic yield of candidate genes in an Australian corneal dystrophy cohort.

Corneal dystrophies describe a clinically and genetically heterogeneous group of inherited disorders. The International Classification of Corneal Dystrophies (IC3D) lists 22 types of corneal dystrophy, 17 of which have been demonstrated to result from pathogenic variants in 19 identified genes. In this study, we investigated the diagnostic yield of genetic testing in a well-characterised cohort of 58 individuals from 44 families with different types of corneal dystrophy. Individuals diagnosed solely with Fuchs endothelial corneal dystrophy were excluded. Clinical details were obtained from the treating ophthalmologist. Participants and their family members were tested using a gene candidate and exome sequencing approach. We identified a likely molecular diagnosis in 70.5% families (31/44). The detection rate was significantly higher among probands with a family history of corneal dystrophy (15/16, 93.8%) than those without (16/28, 57.1%, p = .015), and among those who had undergone corneal graft surgery (9/9, 100.0%) compared to those who had not (22/35, 62.9%, p = .041). We identified eight novel variants in five genes and identified five families with syndromes associated with corneal dystrophies. Our findings highlight the genetic heterogeneity of corneal dystrophies and the clinical utility of genetic testing in reaching an accurate clinical diagnosis.

Quality of life in children with glaucoma: a qualitative interview study in Australia.

OBJECTIVE: Childhood glaucoma is a chronic vision-threatening condition that may significantly impact an individual's psychosocial well-being. There is a paucity of literature investigating the quality of life (QoL) in children with glaucoma. The aim of this study was to investigate and report on the QoL issues encountered by children with glaucoma. DESIGN: This is a qualitative interview study. Data were collected through semistructured interviews. NVivo V.12 software (QSR International Pty Ltd, Melbourne, Australia) was used to analyse and code data to identify QoL themes. The prominence of QoL themes was determined by the number of children who raised issues connected to the corresponding theme. SETTING: Interviews were conducted via telephone or videoconferencing between April 2020 and July 2021. PARTICIPANTS: Eighteen children with glaucoma, aged 8-17 years, who resided in Australia, were recruited from the Australian and New Zealand Registry of Advanced Glaucoma. RESULTS: Median child age was 12.1 years (IQR: 9.7-14.5 years) and 33% were female. Seven QoL themes were identified: 'coping', 'inconveniences' and 'emotional well-being' were more prominent themes than 'symptoms', 'ocular health concerns', 'social well-being' and 'autonomy'. Adaptive coping strategies included resilience throughout clinical examinations and establishing positive relationships with ophthalmologists. These minimised inconveniences related to clinic waiting times and pupillary dilatation. External to the clinical setting, children often dissociated from their glaucoma but struggled with glare symptoms and feeling misunderstood by fellow peers. Older children aged 13-17 years commonly disengaged from their glaucoma care and expressed an unwillingness to attend ophthalmic appointments. Older children further raised issues with career options, obtaining a driver's licence and family planning under the theme of autonomy. CONCLUSIONS: The psychosocial impact of childhood glaucoma extends beyond the clinical environment and was minimised using coping strategies. Older children may require additional social and ophthalmic support as they transition into adulthood.

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. RESULTS: The median age of the cohort was 39 years at the time of last assessment (range 3-85 years; females, 54%). Thirty-two patients had pathogenic variants in the FOXC1 gene, and 29 patients had pathogenic variants in the PITX2 gene. Corneal abnormalities were more common in individuals with FOXC1 variants (18/36, 50%) than those with PITX2 variants (4/25, 16%; P = 0.007). Iris abnormalities such as hypoplasia ( P = 0.008) and pseudopolycoria ( P = 0.001) were more common in individuals with PITX2 variants than those with FOXC1 variants. Glaucoma was present in 72% of participants. Corneal decompensation was positively associated with corneal abnormalities ( P < 0.001), glaucoma surgery ( P = 0.025), and cataract surgery ( P = 0.002). CONCLUSIONS: Corneal abnormalities were more common in individuals with FOXC1 than in those with PITX2 variants and were often associated with early onset glaucoma. These findings highlight that patients with FOXC1 variations require close follow-up and monitoring throughout infancy and into adulthood.

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. Methods: Human ocular lens capsular epithelium samples were collected from 25 patients with PEX and 39 non-PEX controls undergoing cataract surgery. RNA extracted from these specimens was subjected to polyadenylated (mRNA) selection and deep bulk RNA sequencing. Differential expression analysis investigated protein-coding gene transcripts. Exploratory analyses used pathway analysis tools, and curated class- and disease-specific gene sets. Results: Differential expression analysis demonstrated that 2882 genes were differentially expressed according to PEX status. Genes associated with viral gene expression pathways were among the most upregulated, alongside genes encoding ribosomal and mitochondrial respiratory transport chain proteins. Cell adhesion protein transcripts including type 4 collagen subunits were downregulated. Conclusions: This comparative transcriptomic dataset highlights novel and previously recognized pathogenic pathways in PEX and provides the first comprehensive transcriptomic resource, adding an additional layer to build further understanding of PEX pathophysiology.

The Caregiver Experience in Childhood Glaucoma: An Interview Study.

PURPOSE: To investigate and report on the quality-of-life (QoL) issues experienced by caregivers of individuals with childhood glaucoma. DESIGN: Exploratory, qualitative study. PARTICIPANTS: Thirty-five caregivers of individuals with childhood glaucoma (defined as disease onset before 18 years of age) recruited from the Australian and New Zealand Registry of Advanced Glaucoma. METHODS: A qualitative research methodology (interpretive phenomenology) was applied. Data were collected through semistructured in-depth interviews. NVivo-12 software (QSR International Pty Ltd) was used to analyze, code, and organize data into QoL themes inductively. MAIN OUTCOME MEASURES: Quality-of-life themes and their subthemes. RESULTS: The mean caregiver age was 50.2 ± 13.6 years, and 27 of 35 caregivers (77%) were mothers of an individual with childhood glaucoma. A total of 6 QoL themes were identified. Coping strategies and emotional well-being were the most prominent themes. Caregivers frequently adopted problem-focused adaptive coping strategies including partner or peer support, and normalization. A caregiver's psychosocial well-being was often impacted by feelings of guilt and regret regarding their child's delayed diagnosis, fear and anxiety related to medical and social support, and loss of control as their child developed medical autonomy. The effect of family planning from the perspective of the caregiver formed a novel QoL theme and was associated with normalization and parental confidence in management of the condition. CONCLUSIONS: Childhood glaucoma poses a substantial threat to a caregiver's psychosocial well-being. Strategies that promote normalization, peer support, psychotherapeutic intervention, and genetic counseling may be indicated and, indeed, critical to the caregiver as they adapt to supporting their child with glaucoma.

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. DESIGN: Cross-sectional, questionnaire-based study. PARTICIPANTS: Among the participants in the Australian and New Zealand Registry of Advanced Glaucoma, 2369 were invited to participate who fit the inclusion criteria of adults with a diagnosis of POAG who had not received genetic results that explain their condition, were not known to be deceased, resided in Australia, and had agreed to receive correspondence. METHODS: One thousand one hundred sixty-nine individuals (response rate, 49%) with POAG completed the survey evaluating their attitudes towards polygenic risk testing for glaucoma. MAIN OUTCOME MEASURES: Sociodemographic, health, perception, and emotional factors were examined to assess associations with interest in PRS testing. Interest in PRS testing was evaluated through assessing likelihood to take the test to predict personal risk of disease and disease severity, and whether the individual would recommend the test to family members or others. RESULTS: Our results show strong interest in the test, with 69.4% of individuals (798 of 1150) indicating a keenness in testing before diagnosis, had it been available. In particular, interest was seen in those from an urban area (odds ratio [OR], 1.70; 95% confidence interval [CI], 1.15-2.49; P = 0.007), those who perceived their risk of developing glaucoma as higher (OR, 2.05; 95% CI, 1.28-3.29; P = 0.003), and those who were worried about developing glaucoma (OR, 2.07; 95% CI, 1.27-3.37; P = 0.004). People who were interested in testing were more likely to change their eye health-seeking intentions and to recommend testing to family members and others, as well as to undergo testing for prognostication. CONCLUSIONS: These findings will help to facilitate the clinical implementation of PRS testing for glaucoma to reduce irreversible vision loss.

Quality of Life in Adults with Childhood Glaucoma: An Interview Study.

PURPOSE: To explore and report on the quality-of-life (QoL) issues encountered by adults with childhood glaucoma. DESIGN: Exploratory qualitative study. PARTICIPANTS: Forty-seven participants with childhood glaucoma (defined as disease onset <18 years) recruited from the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG). METHODS: A qualitative research methodology (interpretive phenomenology) was applied, and data were collected through semistructured in-depth interviews. NVivo-12 software (QSR International Pty Ltd) was used to inductively analyze and code data to identify QoL themes pertinent to the cohort studied. MAIN OUTCOME MEASURES: Quality-of-life themes and subthemes. RESULTS: Mean participant age was 40.0 ± 15.3 years, and 55% of participants were female. We identified 10 QoL themes pertinent to adults living with childhood glaucoma. Coping strategies and emotional well-being were the most prominent themes. Maladaptive coping strategies, including treatment nonadherence, were observed more commonly in individuals aged <40 years and those without a vision impairment or reviewed less regularly. Emotional well-being was affected by feelings of being misunderstood because of the rarity of the condition, being self-conscious of physical manifestations of the disease, and anxiety related to possible disease progression and vision loss. The effect of childhood glaucoma on family planning formed a novel QoL theme and included worry for their child to inherit the condition and an inability to fulfill parental duties. This often led to genetic counseling-seeking behaviors. Mobility issues were infrequently experienced. CONCLUSIONS: Childhood glaucoma poses a substantial impact to the emotional well-being of adults with the condition, which is mediated by the use of coping strategies. Genetic counseling and family planning options may be important. This study supports the development of a childhood glaucoma-specific patient-reported outcome measure for assessment of the psychosocial impact of childhood glaucoma in adults.

Retinal ganglion cell-specific genetic regulation in primary open-angle glaucoma.

To assess the transcriptomic profile of disease-specific cell populations, fibroblasts from patients with primary open-angle glaucoma (POAG) were reprogrammed into induced pluripotent stem cells (iPSCs) before being differentiated into retinal organoids and compared with those from healthy individuals. We performed single-cell RNA sequencing of a total of 247,520 cells and identified cluster-specific molecular signatures. Comparing the gene expression profile between cases and controls, we identified novel genetic associations for this blinding disease. Expression quantitative trait mapping identified a total of 4,443 significant loci across all cell types, 312 of which are specific to the retinal ganglion cell subpopulations, which ultimately degenerate in POAG. Transcriptome-wide association analysis identified genes at loci previously associated with POAG, and analysis, conditional on disease status, implicated 97 statistically significant retinal ganglion cell-specific expression quantitative trait loci. This work highlights the power of large-scale iPSC studies to uncover context-specific profiles for a genetically complex disease.

Normal-tension glaucoma is associated with cognitive impairment.

BACKGROUND/AIMS: Recent research suggests an association between normal-tension glaucoma (NTG) and dementia. This study investigated whether cognitive impairment is more strongly associated with NTG than high tension glaucoma (HTG) using cognitive screening within an Australiasian Glaucoma Disease Registry. METHODS: The authors completed a case-control cross-sectional cognitive screening involving 290 age-matched and sex-matched NTG participants and HTG controls aged ≥65 randomly sampled from the Australian and New Zealand Registry of Advanced Glaucoma. Cognitive screening was performed using the Telephone Version of the Montreal Cognitive Assessment (T-MoCA). The T-MoCA omits points requiring visual interpretation, accounting for confounding factors related to vision loss in visually impaired participants. Cognitive impairment was defined by a T-MoCA score of <11/22. Cognition was compared between NTG and HTG participants using predetermined thresholds and absolute screening scores. RESULTS: A total of 290 participants completed cognitive assessment. There were no differences in NTG (n=144) and HTG (n=146) cohort demographics or ocular parameters at baseline. Cognitive impairment was more prevalent in the NTG cohort than the HTG cohort (OR=2.2; 95% CI 1.1 to 6.7, p=0.030). Though a linear trend was also observed between lower absolute T-MoCA scores in the NTG cohort when compared with the HTG cohort, this association was not statistically significant (p=0.108). CONCLUSION: This study demonstrated an association between NTG status and poor cognition, supporting the hypothesis that there exists a disease association and shared pathoaetiological features between NTG and dementia.