Whole exome sequence analysis in 51 624 participants identifies novel genes and variants associated with refractive error and myopia.

Refractive errors are associated with a range of pathological conditions, such as myopic maculopathy and glaucoma, and are highly heritable. Studies of missense and putative loss of function (pLOF) variants identified via whole exome sequencing (WES) offer the prospect of directly implicating potentially causative disease genes. We performed a genome-wide association study for refractive error in 51 624 unrelated adults, of European ancestry, aged 40-69 years from the UK and genotyped using WES. After testing 29 179 pLOF and 495 263 missense variants, 1 pLOF and 18 missense variants in 14 distinct genomic regions were taken forward for fine-mapping analysis. This yielded 19 putative causal variants of which 18 had a posterior inclusion probability >0.5. Of the 19 putative causal variants, 12 were novel discoveries. Specific variants were associated with a more myopic refractive error, while others were associated with a more hyperopic refractive error. Association with age of onset of spectacle wear (AOSW) was examined in an independent validation sample (38 100 early AOSW cases and 74 243 controls). Of 11 novel variants that could be tested, 8 (73%) showed evidence of association with AOSW status. This work identified COL4A4 and ATM as novel candidate genes associated with refractive error. In addition, novel putative causal variants were identified in the genes RASGEF1, ARMS2, BMP4, SIX6, GSDMA, GNGT2, ZNF652 and CRX. Despite these successes, the study also highlighted the limitations of community-based WES studies compared with high myopia case-control WES studies.

Whole exome sequencing of known eye genes reveals genetic causes for high myopia.

High myopia [refractive error ≤ -6 diopters (D)] is a heterogeneous condition, and without clear accompanying features, it can be difficult to pinpoint a genetic cause. This observational study aimed to evaluate the utility of whole exome sequencing (WES) using an eye disorder gene panel in European patients with high myopia. Patients with high myopia were recruited by ophthalmologists and clinical geneticists. Clinical features were categorized into isolated high myopia, high myopia with other ocular involvement or with systemic involvement. WES was performed and an eye disorder gene panel of ~500 genes was evaluated. Hundred and thirteen patients with high myopia [mean (SD) refractive error - 11.8D (5.2)] were included. Of these, 53% were children younger than 12 years of age (53%), 13.3% were aged 12-18 years and 34% were adults (aged > 18 years). Twenty-three out of 113 patients (20%) received a genetic diagnosis of which 11 patients displayed additional ocular or systemic involvement. Pathogenic variants were identified in retinal dystrophy genes (e.g. GUCY2D and CACNA1F), connective tissue disease genes (e.g. COL18A1 and COL2A1), non-syndromic high myopia genes (ARR3), ocular development genes (e.g. PAX6) and other genes (ASPH and CNNM4). In 20% of our high myopic study population, WES using an eye gene panel enabled us to diagnose the genetic cause for this disorder. Eye genes known to cause retinal dystrophy, developmental or syndromic disorders can cause high myopia without apparent clinical features of other pathology.

Genetic architecture of orbital telorism.

The interocular distance, or orbital telorism, is a distinctive craniofacial trait that also serves as a clinically informative measure. While its extremes, hypo- and hypertelorism, have been linked to monogenic disorders and are often syndromic, little is known about the genetic determinants of interocular distance within the general population. We derived orbital telorism measures from cranial magnetic resonance imaging by calculating the distance between the eyeballs' centre of gravity, which showed a good reproducibility with an intraclass correlation coefficient of 0.991 (95% confidence interval 0.985-0.994). Heritability estimates were 76% (standard error = 12%) with a family-based method (N = 364) and 39% (standard error = 2.4%) with a single nucleotide polymorphism-based method (N = 34 130) and were unaffected by adjustment for height (model II) and intracranial volume (model III) or head width (model IV). Genome-wide association studies in 34 130 European individuals identified 56 significantly associated genomic loci (P < 5 × 10-8) across four different models of which 46 were novel for facial morphology, and overall these findings replicated in an independent sample (N = 10 115) with telorism-related horizontal facial distance measures. Genes located nearby these 56 identified genetic loci were 4.9-fold enriched for Mendelian hypotelorism and hypertelorism genes, underlining their biological relevance. This study provides novel insights into the genetic architecture underlying interocular distance in particular, and the face in general, and explores its potential for applications in a clinical setting.

The Clinical Usefulness of a Glaucoma Polygenic Risk Score in 4 Population-Based European Ancestry Cohorts.

PURPOSE: We used a polygenic risk score (PRS) to identify high-risk groups for primary open-angle glaucoma (POAG) within population-based cohorts. DESIGN: Secondary analysis of 4 prospective population-based studies. PARTICIPANTS: We included four European-ancestry cohorts: the United States-based Nurses' Health Study, Nurses' Health Study 2, and the Health Professionals Follow-up Study and the Rotterdam Study (RS) in The Netherlands. The United States cohorts included female nurses and male health professionals ≤ 55 years of age. The RS included residents ≤ 45 years of age living in Rotterdam, The Netherlands. METHODS: Polygenic risk score weights were estimated by applying the lassosum method on imputed genotype and phenotype data from the UK Biobank. This resulted in 144 020 variants, single nucleotide polymorphism and insertions or deletions, with nonzero ßs that we used to calculate a PRS in the target populations. Using multivariable Cox proportional hazard models, we estimated the relationship between the standardized PRS and relative risk for POAG. Additionally, POAG prediction was tested by calculating these models' concordance (Harrell's C statistic). Finally, we assessed the association between PRS tertiles and glaucoma-related traits. MAIN OUTCOME MEASURES: The relative risk for POAG and Harrell's C statistic. RESULTS: Among 1046 patients and 38 809‬ control participants, the relative risk (95% confidence interval) for POAG for participants in the highest PRS quintile was 3.99 (3.08-5.18) times higher in the United States cohorts and 4.89 (2.93-8.17) times higher in the RS, compared with participants with median genetic risk (third quintile). Combining age, sex, intraocular pressure of more than 25 mmHg, and family history resulted in a meta-analyzed concordance of 0.75 (95% CI, 0.73-0.75). Adding the PRS to this model improved the concordance to 0.82 (95% CI, 0.80-0.84). In a meta-analysis of all cohorts, patients in the highest tertile showed a larger cup-to-disc ratio at diagnosis, by 0.10 (95% CI, 0.06 0.14), and a 2.07-fold increased risk of requiring glaucoma surgery (95% CI, 1.19-3.60). CONCLUSIONS: Incorporating a PRS into a POAG predictive model improves identification concordance from 0.75 up to 0.82, supporting its potential for guiding more cost-effective screening strategies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Evaluating a web-based visual acuity and refractive error self-assessment tool in myopic children.

INTRODUCTION: Demands for myopia management are rising. A web-based tool that allows home-performed self-assessments of visual acuity (VA) and refractive error may enable hybrid care pathways and aid in identifying those with deteriorating visual performance. The tool has been validated in adult populations, but has yet to be evaluated in children. This study compared home-performed VA and refraction self-assessments to conventional measurements obtained at the clinic in a population of myopic children. METHODS: Myopic children aged ≥6 years old were invited to perform web-based eye tests at home, assisted by a parent. At two myopia control clinics, they also underwent measurements of VA using a Snellen chart and refractive error using cycloplegic autorefraction. Agreement between the tests, repeatability of the web-based test and associations between clinical characteristics and web-based test accuracy were evaluated. RESULTS: A total of 147 children were enrolled, of whom 116 (51% male; mean age 13 ± 3 years; mean spherical equivalent refraction (SEQ) -5.58 ± 3.05) performed the web-based tests at home. Overall, the home-performed VA self-assessment and the Snellen chart assessment at the clinic agreed well (mean difference 0.03 ± 0.11 logMAR). A significant proportional bias was identified (ß 0.65, p < 0.001), indicating underestimated web-based VA scores when the child's vision declined. The sensitivity to detect VA poorer than 0.10 logMAR was 94%; the specificity was 71%. The web-based refractive error algorithm measured more myopia progression compared to clinic observations (mean difference SEQ 0.40 ± 0.51 dioptres). Age, sex or use of atropine drops were not significantly associated with test accuracy. CONCLUSIONS: The web-based test for self-assessing vision, performed at home by children with assistance from their parents, yielded VA scores with a precision similar to Snellen chart testing conducted in a clinical setting. However, the web-based refractive error algorithm overestimated myopia progression and requires recalibration for this specific age group.

Deep learning predicted perceived age is a reliable approach for analysis of facial ageing: A proof of principle study.

BACKGROUND: Perceived age (PA) has been associated with mortality, genetic variants linked to ageing and several age-related morbidities. However, estimating PA in large datasets is laborious and costly to generate, limiting its practical applicability. OBJECTIVES: To determine if estimating PA using deep learning-based algorithms results in the same associations with morbidities and genetic variants as human-estimated perceived age. METHODS: Self-supervised learning (SSL) and deep feature transfer (DFT) deep learning (DL) approaches were trained and tested on human-estimated PAs and their corresponding frontal face images of middle-aged to elderly Dutch participants (n = 2679) from a population-based study in the Netherlands. We compared the DL-estimated PAs with morbidities previously associated with human-estimated PA as well as genetic variants in the gene MC1R; we additionally tested the PA associations with MC1R in a new validation cohort (n = 1158). RESULTS: The DL approaches predicted PA in this population with a mean absolute error of 2.84 years (DFT) and 2.39 years (SSL). In the training-test dataset, we found the same significant (p < 0.05) associations for DL PA with osteoporosis, ARHL, cognition, COPD and cataracts and MC1R, as with human PA. We also found a similar but less significant association for SSL and DFT PAs (0.69 and 0.71 years per allele, p = 0.008 and 0.011, respectively) with MC1R variants in the validation dataset as that found with human, SSL and DFT PAs in the training-test dataset (0.79, 0.78 and 0.71 years per allele respectively; all p < 0.0001). CONCLUSIONS: Deep learning methods can automatically estimate PA from facial images with enough accuracy to replicate known links between human-estimated perceived age and several age-related morbidities. Furthermore, DL predicted perceived age associated with MC1R gene variants in a validation cohort. Hence, such DL PA techniques may be used instead of human estimations in perceived age studies thereby reducing time and costs.

Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images.

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.

Correction: Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images.

[This corrects the article DOI: 10.1371/journal.pgen.1009497.].

Association of Systemic Medication Use with Glaucoma and Intraocular Pressure: The European Eye Epidemiology Consortium.

PURPOSE: To investigate the association of commonly used systemic medications with glaucoma and intraocular pressure (IOP) in the European population. DESIGN: Meta-analysis of 11 population-based cohort studies of the European Eye Epidemiology Consortium. PARTICIPANTS: The glaucoma analyses included 143 240 participants and the IOP analyses included 47 177 participants. METHODS: We examined associations of 4 categories of systemic medications-antihypertensive medications (ß-blockers, diuretics, calcium channel blockers [CCBs], α-agonists, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers), lipid-lowering medications, antidepressants, and antidiabetic medications-with glaucoma prevalence and IOP. Glaucoma ascertainment and IOP measurement method were according to individual study protocols. Results of multivariable regression analyses of each study were pooled using random effects meta-analyses. Associations with antidiabetic medications were examined in participants with diabetes only. MAIN OUTCOME MEASURES: Glaucoma prevalence and IOP. RESULTS: In the meta-analyses of our maximally adjusted multivariable models, use of CCBs was associated with a higher prevalence of glaucoma (odds ratio [OR], 1.23; 95% confidence interval [CI], 1.08 to 1.39). This association was stronger for monotherapy of CCBs with direct cardiac effects (OR, 1.96; 95% CI, 1.23 to 3.12). No other antihypertensive medications, lipid-lowering medications, antidepressants, or antidiabetic medications were associated with glaucoma. Use of systemic ß-blockers was associated with a lower IOP (ß coefficient, -0.33 mmHg; 95% CI, -0.57 to -0.08 mmHg). Monotherapy of both selective systemic ß-blockers (ß coefficient, -0.45 mmHg; 95% CI -0.74 to -0.16 mmHg) and nonselective systemic ß-blockers (ß coefficient, -0.54 mmHg; 95% CI, -0.94 to -0.15 mmHg) was associated with lower IOP. A suggestive association was found between use of high-ceiling diuretics and lower IOP (ß coefficient, -0.30 mmHg; 95% CI, -0.47 to -0.14 mmHg) but not when used as monotherapy. No other antihypertensive medications, lipid-lowering medications, antidepressants, or antidiabetic medications were associated with IOP. CONCLUSIONS: We identified a potentially harmful association between use of CCBs and glaucoma prevalence. Additionally, we observed and quantified the association of lower IOP with systemic ß-blocker use. Both findings potentially are important, given that patients with glaucoma frequently use systemic antihypertensive medications. Determining causality of the CCB association should be a research priority. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Exposure to cyan or red light inhibits the axial growth of zebrafish eyes.

Myopia, or nearsightedness, is the most common type of refractive error and is characterized by a mismatch between the optical power and ocular axial length. Light, and more specifically the spectral composition of light, has been known to influence myopic axial growth. In this pilot study, we exposed zebrafish to illuminations that vary in spectral composition and screened for changes in axial length. The illumination spectra included narrow band ultra-violet A (UVA) (peak wavelength 369 nm), violet (425 nm), cyan (483 nm), green/yellow (557 nm), and red (633 nm) light, as well as broad band white light (2700 K and 6500 K), dim white light and broad spectrum (day) light. We found that rearing zebrafish in cyan or red light leads to a reduction of the ocular axial length. The results of this pilot study may contribute to new perspectives on the role of light and lighting as an intervention strategy for myopia control.

Younger facial looks are associate with a lower likelihood of several age-related morbidities in the middle-aged to elderly.

BACKGROUND: Looking older for one's chronological age is associated with a higher mortality rate. Yet it remains unclear how perceived facial age relates to morbidity and the degree to which facial ageing reflects systemic ageing of the human body. OBJECTIVES: To investigate the association between ΔPA and age-related morbidities of different organ systems, where ΔPA represents the difference between perceived age (PA) and chronological age. METHODS: We performed a cross-sectional analysis on data from the Rotterdam Study, a population-based cohort study in the Netherlands. High-resolution facial photographs of 2679 men and women aged 51.5-87.8 years of European descent were used to assess PA. PA was estimated and scored in 5-year categories using these photographs by a panel of men and women who were blinded for chronological age and medical history. A linear mixed model was used to generate the mean PAs. The difference between the mean PA and chronological age was calculated (ΔPA), where a higher (positive) ΔPA means that the person looks younger for their age and a lower (negative) ΔPA that the person looks older. ΔPA was tested as a continuous variable for association with ageing-related morbidities including cardiovascular, pulmonary, ophthalmological, neurocognitive, renal, skeletal and auditory morbidities in separate regression analyses, adjusted for age and sex (model 1) and additionally for body mass index, smoking and sun exposure (model 2). RESULTS: We observed 5-year higher ΔPA (i.e. looking younger by 5 years for one's age) to be associated with less osteoporosis [odds ratio (OR) 0.76, 95% confidence interval (CI) 0.62-0.93], less chronic obstructive pulmonary disease (OR 0.85, 95% CI 0.77-0.95), less age-related hearing loss (model 2; B = -0.76, 95% CI -1.35 to -0.17) and fewer cataracts (OR 0.84, 95% CI 0.73-0.97), but with better global cognitive functioning (g-factor; model 2; B = 0.07, 95% CI 0.04-0.10). CONCLUSIONS: PA is associated with multiple morbidities and better cognitive function, suggesting that systemic ageing and cognitive ageing are, to an extent, externally visible in the human face.

MIND diet lowers risk of open-angle glaucoma: the Rotterdam Study.

PURPOSE: To assess the association between the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet and the incidence of open-angle glaucoma (iOAG), as well as the association between iOAG and two other well-established diets in the Netherlands, i.e., the Mediterranean diet and Dutch dietary guidelines. METHODS: In the Rotterdam Study, participants were followed for iOAG since 1991, with intervals of approximately 5 years. A total of 170 participants developed iOAG during follow-up. Participants with iOAG were matched with healthy controls on age and sex in a case:control ratio of 1:5. The associations between food frequency questionnaire-derived diet adherences (baseline) and iOAG were analyzed using multivariable conditional logistic regression analyses. The associations between the diet adherences and intraocular pressure (IOP; a risk factor for OAG) were assessed using multivariable linear regression analyses. RESULTS: Greater adherence to the MIND diet was associated with a decreased iOAG risk (odds ratio [95% confidence interval]: 0.80 [0.66 to 0.96], for each 10-percent increase in adherence). Food component analyses showed that, in particular a higher intake of green leafy vegetables, berries and fish tended to be protective for iOAG. No significant associations were observed between adherence to the Mediterranean diet or Dutch dietary guidelines and iOAG. Moreover, none of the three examined diets were associated with IOP. CONCLUSION: Adherence to the MIND diet was significantly associated with a lower incidence of OAG in contrast to adherence to the Mediterranean diet or the Dutch dietary guidelines. As this association was IOP-independent, the MIND diet may be particularly relevant for the prevention of neurodegeneration in the eye.

LONG-TERM TREATMENT OUTCOMES AFTER BEVACIZUMAB THERAPY FOR MACULAR NEOVASCULARIZATION IN WHITE PATIENTS WITH HIGH MYOPIA.

PURPOSE: To report long-term treatment outcomes of intravitreal bevacizumab in myopic macular neovascularization (MNV). METHODS: Retrospective analysis of longitudinal, clinical data of patients with high myopic MNV treated with intravitreal bevacizumab. One-hundred and seventeen eyes of 106 patients were followed from first injection up to 12 years. Outcome measures were best-corrected visual acuity change during follow-up and myopic MNV recurrence. RESULTS: Mean (±SD) baseline best-corrected visual acuity (0.56 ± 0.46 logMAR, 20/80) significantly improved after first treatment (0.33 ± 0.33, 20/50, P < 0.001). At 4 years (n = 86), best-corrected visual acuity was no longer significantly better than at baseline (0.55 ± 0.57, P = 0.30) and continued to deteriorate to 0.84 ± 0.76 (20/125) at 10 years (n = 27). Of the 27 eyes (23%) who reached 10 years of follow-up, 53% developed MNV-related chorioretinal atrophy. The cumulative incidence of recurrent myopic MNV was 34% at 2 years and 59% at 5 years. Best-corrected visual acuity decrease in eyes with or without recurrent MNV was similar ( P = 0.58). Patchy chorioretinal atrophy (hazard ratio 3.0, P = 0.02) and subfoveal MNVs (hazard ratio 2.5, P = 0.048) were significantly associated with recurrent MNV. CONCLUSION: This retrospective myopic MNV study revealed that visual improvement after intravitreal bevacizumab injections was not maintained over time. Macular neovascularization recurrences occurred frequently but did not alter the already poor visual prognosis.

Myopia risk behaviour related to the COVID-19 lockdown in Europe: The generation R study.

PURPOSE: To battle the spreading of the COVID-19 virus, nationwide lockdowns were implemented during 2020 and 2021. Reports from China revealed that their strict home confinements led to an increase in myopia incidence. The Netherlands implemented a more lenient lockdown, which allowed children to go outside. We evaluated the association between COVID-19 restrictions, myopia risk behaviour and myopia progression in Dutch teenagers. METHOD: A total of 1101 participants (mean age 16.3 ± 3.65 yrs) completed questionnaires about their activities before, during and after lockdown (March-October 2020). We used a repeated-measures ANOVA to compare time use between these time periods. Ocular measurements were acquired before the COVID-19 pandemic when participants were 13 years old; only 242 participants had ocular measurements at 18 years of age at the time of this analysis. Linear regression analyses were used to evaluate the association between lifestyle factors and myopia progression. RESULTS: Children were on average 16.2 (1.03) years of age during lockdown. Total nearwork increased from 8.11 h/day to 11.79 h/day, and remained higher after lockdown at 9.46 h/day (p < 0.001). Non-educational nearwork increased by 2.22 h/day (+49%) during lockdown and was associated with faster axial length progression (B 0.002 mm/h/year; SE 0.001 p = 0.03). Before and during lockdown, the mean time spent outdoors was similar (1.78 h/day and 1.80 h/day, respectively). After lockdown, time spent outdoors decreased to 1.56 h/day (p < 0.001). CONCLUSION: The Dutch lockdown significantly increased digitised nearwork in adolescents but did not affect outdoor exposure. The changes in time spent performing nearwork remained after the lockdown measures had ended. We expect that the COVID-19 pandemic may lead to an increase in myopia prevalence and progression in European children.

A view from the clinic - Perspectives from Dutch patients and professionals on high myopia care.

PURPOSE: To understand and compare perspectives of patients and professionals on current ophthalmologic care for high myopia, and to identify challenges and future opportunities. METHODS: Self-reported data were collected through two online questionnaires. Patient perspective was obtained from highly myopic members of a patient organisation based in the Netherlands using a 17-item questionnaire consisting of open and multiple-choice questions regarding personal experience with myopia care. The ophthalmologist perspective was obtained from practising Dutch ophthalmologists with a 12-item questionnaire of multiple-choice questions on work-related demographics, myopia care in daily practice and need for improvement. The response rate for patients was 27% (n = 136/500) and for ophthalmologists, 24% (n = 169/716). RESULTS: Patients were highly concerned about personal progressive loss of vision (69%) and feared their psychological well-being (82%) in case this would happen. The quality of performance of care provided by ophthalmologists was rated as excellent or satisfactory by 64% of the patients. These ratings for multidisciplinary care and insurance reimbursement were as low as 28% and 18% respectively. The mean concern among ophthalmologists about the rise in high myopia was 6.9 (SEM 0.1) on a 10-point scale. Sixty-nine per cent of the ophthalmologists reported that asymptomatic myopic patients should not be examined regularly at outpatient clinics. Ophthalmologists urged the development of clinical guidelines (74%), but did report (95%) that they informed patients about risk factors and complications. This contrasted with the view of patients, of whom 42% were discontent with information provided by ophthalmologists. CONCLUSIONS: These questionnaires demonstrated that the current clinical care delivered to highly myopic patients is in need of improvement. The expected higher demand for myopia care in the near future requires preferred practice patterns, professionals specifically trained to manage myopic pathology, accurate and comprehensive information exchange and collaboration of in- and out-of-hospital professionals across the full eye care chain.

Myopia control in Mendelian forms of myopia.

PURPOSE: To study the effectiveness of high-dose atropine for reducing eye growth in Mendelian myopia in children and mice. METHODS: We studied the effect of high-dose atropine in children with progressive myopia with and without a monogenetic cause. Children were matched for age and axial length (AL) in their first year of treatment. We considered annual AL progression rate as the outcome and compared rates with percentile charts of an untreated general population. We treated C57BL/6J mice featuring the myopic phenotype of Donnai-Barrow syndrome by selective inactivation of Lrp2 knock out (KO) and control mice (CTRL) daily with 1% atropine in the left eye and saline in the right eye, from postnatal days 30-56. Ocular biometry was measured using spectral-domain optical coherence tomography. Retinal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured using high-performance liquid chromatography. RESULTS: Children with a Mendelian form of myopia had average baseline spherical equivalent (SE) -7.6 ± 2.5D and AL 25.8 ± 0.3 mm; children with non-Mendelian myopia had average SE -7.3 ± 2.9 D and AL 25.6 ± 0.9 mm. During atropine treatment, the annual AL progression rate was 0.37 ± 0.08 and 0.39 ± 0.05 mm in the Mendelian myopes and non-Mendelian myopes, respectively. Compared with progression rates of untreated general population (0.47 mm/year), atropine reduced AL progression with 27% in Mendelian myopes and 23% in non-Mendelian myopes. Atropine significantly reduced AL growth in both KO and CTRL mice (male, KO: -40 ± 15; CTRL: -42 ± 10; female, KO: -53 ± 15; CTRL: -62 ± 3 µm). The DA and DOPAC levels 2 and 24 h after atropine treatment were slightly, albeit non-significantly, elevated. CONCLUSIONS: High-dose atropine had the same effect on AL in high myopic children with and without a known monogenetic cause. In mice featuring a severe form of Mendelian myopia, atropine reduced AL progression. This suggests that atropine can reduce myopia progression even in the presence of a strong monogenic driver.

Early onset X-linked female limited high myopia in three multigenerational families caused by novel mutations in the ARR3 gene.

This study describes the clinical spectrum and genetic background of high myopia caused by mutations in the ARR3 gene. We performed an observational case series of three multigenerational families with high myopia (SER≤-6D), from the departments of Clinical Genetics and Ophthalmology of a tertiary Dutch hospital. Whole-exome sequencing (WES) with a vision-related gene panel was performed, followed by a full open exome sequencing. We identified three Caucasian families with high myopia caused by three different pathogenic variants in the ARR3 gene (c.214C>T, p.Arg72*; c.767+1G>A; p.?; c.848delG, p.(Gly283fs)). Myopia was characterized by a high severity (<-8D), an early onset (<6 years), progressive nature, and a moderate to bad atropine treatment response. Remarkably, a female limited inheritance pattern was present in all three families accordant with previous reports. The frequency of a pathogenic variant in the ARR3 gene in our diagnostic WES cohort was 5%. To conclude, we identified three families with early onset, therapy-resistant, high myopia with a female-limited inheritance pattern, caused by a mutation in the ARR3 gene. The singular mode of inheritance might be explained by metabolic interference due to X-inactivation. Identification of this type of high myopia will improve prompt myopia treatment, monitoring, and genetic counseling.

The Phenotypic Course of Age-Related Macular Degeneration for ARMS2/HTRA1: The EYE-RISK Consortium.

PURPOSE: Age-related maculopathy susceptibility 2 (ARMS2) is considered the most enigmatic of the genes for age-related macular degeneration (AMD). We investigated the phenotypic course and spectrum of AMD for the risk haplotype at the ARMS2 and high-temperature requirement A serine peptidase 1 (HTRA1) locus in a large European consortium. DESIGN: Pooled analysis of 4 case-control and 6 cohort studies. PARTICIPANTS: Individuals (N = 17 204) aged 55 years or older participating in the European Eye Epidemiology consortium. METHODS: Age-related macular degeneration features and macular thickness were determined on multimodal images; data on genetics and phenotype were harmonized. Risks of AMD features for rs3750486 genotypes at the ARMS2/HTRA1 locus were determined by logistic regression and were compared with a genetic risk score (GRS) of 19 variants at the complement pathway. Lifetime risks were estimated with Kaplan-Meier analyses in population-based cohorts. MAIN OUTCOME MEASURES: Age-related macular degeneration features and stage. RESULTS: Of 2068 individuals with late AMD, 64.7% carried the ARMS2/HTRA1 risk allele. For homozygous carriers, the odds ratio (OR) of geographic atrophy was 8.6 (95% confidence interval [CI], 6.5-11.4), of choroidal neovascularization (CNV) was 11.2 (95% CI, 9.4-13.3), and of mixed late AMD was 12.2 (95% CI, 7.3-20.6). Cumulative lifetime risk of late AMD ranged from 4.4% for carriers of the nonrisk genotype to 9.4% and 26.8% for heterozygous and homozygous carriers. The latter received the diagnosis of late AMD 9.6 years (95% CI, 8.0-11.2) earlier than carriers of the nonrisk genotype. The risk haplotype was not associated with hard or soft drusen < 125 µm (OR, 1.2; 95% CI, 0.9-1.7), but risks increased significantly for soft drusen ≥ 125 µm (OR, 2.1; 95% CI, 1.5-3.0), up to an OR of 7.2 (95% CI, 3.8-13.8) for reticular pseudodrusen. Compared with persons with a high GRS for complement, homozygous carriers of ARMS2/HTRA1 showed a higher risk of CNV (OR, 4.1; 95% CI, 3.2-5.4); risks of other characteristics were not different. CONCLUSIONS: Carriers of the risk haplotype at ARMS2/HTRA1 have a particularly high risk of late AMD at a relatively early age. Data suggest that risk variants at ARMS2/HTRA1 act as a strong catalyst of progression once early signs are present. The phenotypic spectrum resembles that of complement genes, only with higher risks of CNV.

X-Linked Retinoschisis: Novel Clinical Observations and Genetic Spectrum in 340 Patients.

PURPOSE: To describe the natural course, phenotype, and genotype of patients with X-linked retinoschisis (XLRS). DESIGN: Retrospective cohort study. PARTICIPANTS: Three hundred forty patients with XLRS from 178 presumably unrelated families. METHODS: This multicenter, retrospective cohort study reviewed medical records of patients with XLRS for medical history, symptoms, visual acuity (VA), ophthalmoscopy, full-field electroretinography, and retinal imaging (fundus photography, spectral-domain [SD] OCT, fundus autofluorescence). MAIN OUTCOME MEASURES: Age at onset, age at diagnosis, severity of visual impairment, annual visual decline, and electroretinography and imaging findings. RESULTS: Three hundred forty patients were included with a mean follow-up time of 13.2 years (range, 0.1-50.1 years). The median ages to reach mild visual impairment and low vision were 12 and 25 years, respectively. Severe visual impairment and blindness were observed predominantly in patients older than 40 years, with a predicted prevalence of 35% and 25%, respectively, at 60 years of age. The VA increased slightly during the first 2 decades of life and subsequently transitioned into an average annual decline of 0.44% (P < 0.001). No significant difference was found in decline of VA between variants that were predicted to be severe and mild (P = 0.239). The integrity of the ellipsoid zone (EZ) as well as the photoreceptor outer segment (PROS) length in the fovea on SD OCT correlated significantly with VA (Spearman's ρ = -0.759 [P < 0.001] and -0.592 [P = 0.012], respectively). Fifty-three different RS1 variants were found. The most common variants were the founder variant c.214G→A (p.(Glu72Lys)) (101 patients [38.7%]) and a deletion of exon 3 (38 patients [14.6%]). CONCLUSIONS: Large variabilities in phenotype and natural course of XLRS were seen in this study. In most patients, XLRS showed a slow deterioration starting in the second decade of life, suggesting an optimal window of opportunity for treatment within the first 3 decades of life. The integrity of EZ as well as the PROS length on SD OCT may be important in choosing optimal candidates for treatment and as potential structural end points in future therapeutic studies. No clear genotype-phenotype correlation was found.

Common and rare variants in patients with early onset drusen maculopathy.

Early onset drusen maculopathy (EODM) can lead to advanced macular degeneration at a young age, affecting quality of life. However, the genetic causes of EODM are not well studied. We performed whole genome sequencing in 49 EODM patients. Common genetic variants were analysed by calculating genetic risk scores based on 52 age-related macular generation (AMD)-associated variants, and we analysed rare variants in candidate genes to identify potential deleterious variants that might contribute to EODM development. We demonstrate that the 52 AMD-associated variants contributed to EODM, especially variants located in the complement pathway. Furthermore, we identified 26 rare genetic variants predicted to be pathogenic based on in silico prediction tools or based on reported pathogenicity in literature. These variants are located predominantly in the complement and lipid metabolism pathways. Last, evaluation of 18 genes causing inherited retinal dystrophies that can mimic AMD characteristics, revealed 11 potential deleterious variants in eight EODM patients. However, phenotypic characteristics did not point towards a retinal dystrophy in these patients. In conclusion, this study reports new insights into rare variants that are potentially involved in EODM development, and which are relevant for future studies unravelling the aetiology of EODM.