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Background: Polygenic risk scores (PRS), which provide an individual probabilistic estimate of genetic susceptibility to develop a disease, have shown effective risk stratification for glaucoma onset. However, there is limited best practice evidence for reporting PRS and patient-friendly reports for communicating PRS effectively are lacking. Here we developed patient-centred PRS reports for glaucoma screening based on the literature, and evaluated them with participants using a qualitative research approach. Methods: We first reviewed existing PRS reports and literature on probabilistic risk communication. This informed the development of a draft glaucoma screening PRS report for a hypothetical high risk individual from the general population. We designed three versions of the report to illustrate risk using a pictograph, a pie chart and a bell curve. We then conducted semi-structured interviews to assess preference of visual risk communication aids, understanding of risk, content, format and structure of the reports. Participants were invited from an existing study, which aims to evaluate the clinical validity of glaucoma PRS among individuals > 50 years from the general population. Numeracy and literacy levels were assessed. Results: We interviewed 12 individuals. The cohort was highly educated (42% university education), all were European and 50% were female. Numeracy (mean 2.1 ± 0.9, range 0 to 3), graph literacy (mean 2.8 ± 0.8, range 0 to 4) and genetic literacy (mean 24.2 ± 6.2, range − 20 to + 46) showed a range of levels. We analysed the reports under three main themes: visual preferences, understanding risk and reports formatting. The visual component was deemed important to understanding risk, with the pictograph being the preferred visual risk representation, followed by the pie chart and the bell curve. Participants expressed preference for absolute risk in understanding risk, along with the written content explaining the results. The importance of follow-up recommendations and time to glaucoma onset were deemed important. Participants expressed varied opinions in the level of information and the colours used, which informed revisions of the report. Conclusions: Our study revealed preferences for reporting PRS information in the context of glaucoma screening, to support the development of clinical PRS reporting. Further research is needed to assess PRS communication in other groups representative of target populations and with other target audiences (e.g. referring clinicians), and its potential psychosocial impact in the wider community. [ABSTRACT FROM AUTHOR]

Glaucoma is the leading cause of irreversible blindness with early detection and intervention critical to slowing disease progression. However, half of those affected are undiagnosed. This is largely due to the early stages of disease being asymptomatic; current population-based screening measures being unsupported; and a lack of current efficient prediction models. Research investigating polygenic risk scores (PRS) for glaucoma have shown predictive ability to identify individuals at higher risk. Potential clinical applications include identification of high-risk individuals, resulting in earlier diagnosis and treatment to prevent glaucoma blindness, and adjusted monitoring for low-risk individuals. However, the psychological impact of receiving glaucoma PRS is unknown. There is a critical need to evaluate risk information communication and assess the impact of receiving results, to support clinical implementation of glaucoma PRS testing. In this prospective study, 300 individuals from the GRADE (Genetic Risk Assessment of Degenerative Eye disease) study will be recruited to investigate the psychosocial impact of disclosing polygenic risk results for glaucoma. GRADE aimed to apply PRS testing on 1,000 unexamined individuals aged 50 years or older from the general population and examine a subset of these individuals to assess the clinical validity of PRS to detect glaucoma. In this study, individuals each from the bottom decile (10%), top decile (10%), and middle (45–55%) of the PRS distributions will be invited to receive research glaucoma PRS results. Participants who choose to receive their results will complete up to four questionnaires (prior to receiving their results, and subsequently two-weeks, six- and 12-months after receiving their result). The questionnaires will include health belief model measures and assess glaucoma anxiety, general anxiety and depression, test-related distress, decisional regret, and recall and understanding of results. This research will provide guidance for the implementation of polygenic risk testing into clinical practice and inform delivery strategies. [ABSTRACT FROM AUTHOR]

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. Methods: An online cross‐sectional questionnaire was distributed to healthcare professionals via relevant professional organisations in Australia. The questionnaire assessed experience and confidence with genetic testing, glaucoma and genetic knowledge, recommendations for the tests, and factors affecting the decision. Results: A total of 94 participants completed the questionnaire. The sample was composed of ophthalmologists (36%), optometrists (21%), orthoptists (17%), general practitioners (16%) and clinical geneticists/genetic counsellors (10%). Although familiarity with polygenic risk scores for glaucoma was low overall (11%), the majority reported a positive attitude towards recommending testing based on known risk factors such as family history (91%) and older age (57%). Over 95% indicated that ophthalmologists would be the most appropriate group to order polygenic risk testing and communicate results. The majority felt they would benefit from more training on polygenic risk scores (93%). Conclusions: Our findings indicated that multiple groups of healthcare professionals were neither familiar nor confident with the concept of glaucoma polygenic risk testing, and identified training and education needs to support the implementation of testing into clinical practice. [ABSTRACT FROM AUTHOR]

Childhood glaucoma is a heterogeneous group of ocular disorders defined by an age of onset from birth to 18 years. These vision‐threatening disorders require early diagnosis, timely treatment, and lifelong management to maintain vision and minimise irreversible blindness. The genetics of childhood glaucoma is complex with both phenotypic and genetic heterogeneity. The purpose of this review is to summarise the different types of childhood glaucoma and their genetic architecture to aid in the genetic counselling process with patients and their families. We provide an overview of associated syndromes and discuss implications for genetic counselling, including genetic testing strategies, cascade genetic testing, and reproductive options. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction Afflicting more than 60 million individuals worldwide and leaving 8 million blind, glaucoma is a devastating disease with no cure (1). Current therapy slows disease progression but cannot repair [...], Primary congenital glaucoma (PCG) is a leading cause of blindness in children worldwide and is caused by developmental defects in 2 aqueous humor outflow structures, Schlemm's canal (SC) and the trabecular meshwork. We previously identified loss-of-function mutations in the angiopoietin (ANGPT) receptor TEK in families with PCG and showed that ANGPT/TEK signaling is essential for SC development. Here, we describe roles for the major ANGPT ligands in the development of the aqueous outflow pathway. We determined that ANGPT1 is essential for SC development, and that Angpt1-knockout mice form a severely hypomorphic canal with elevated intraocular pressure. By contrast, ANGPT2 was dispensable, although mice deficient in both Angpt1 and Angpt2 completely lacked SC, indicating that ANGPT2 compensates for the loss of ANGPT1. In addition, we identified 3 human subjects with rare ANGPT1 variants within an international cohort of 284 PCG patients. Loss of function in 2 of the 3 patient alleles was observed by functional analysis of ANGPT1 variants in a combined in silico, in vitro, and in vivo approach, supporting a causative role for ANGPT1 in disease. By linking ANGPT1 with PCG, these results highlight the importance of ANGPT/TEK signaling in glaucoma pathogenesis and identify a candidate target for therapeutic development.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In adult rats, elongation of cardiac myocytes (CMs) correlates with dilatation (and sometimes dysfunction) of cardiac ventricles. Although sex steroids may constitute one possible factor that affects the dimensions of CMs, studies on their effects in rodents is complicated by the fact that most commercial soy-based diets also contain abundant phytoestrogens. We report that feeding Wistar-Kyoto rat dams during gestation and lactation with a phytoestrogen-rich soy-based diet caused the CMs of their adult offspring to be shorter than in counterparts originating from mothers fed with a phytoestrogen-free casein-based diet. The soy-based diet had no such effects when given to rats after 6 wk of age, and its effects were replicated when supplementing the maternal casein-based diet with the isoflavones daidzein and genistein (the most abundant phytoestrogens in soy-based diets). In contrast to rats whose mothers had been fed with a soy-based diet, the hearts of adult rats raised with a casein-based diet only featured dilated eccentric hypertrophy and progressed toward congestive heart failure when further challenged. Thus the presence of isoflavones in the maternal diet provides cardioprotection to the hearts of their offspring during adulthood. phytoestrogen; dilated ventricular hypertrophy; neonatal exposure; congestive heart failure; isolated adult rat cardiomyocytes

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. [ABSTRACT FROM AUTHOR]