Electrophysiology-Guided Genetic Characterisation Maximises Molecular Diagnosis in an Irish Paediatric Inherited Retinal Degeneration Population.

Inherited retinal degenerations (IRDs) account for over one third of the underlying causes of blindness in the paediatric population. Patients with IRDs often experience long delays prior to reaching a definitive diagnosis. Children attending a tertiary care paediatric ophthalmology department with phenotypic (i.e., clinical and/or electrophysiologic) evidence suggestive of IRD were contacted for genetic testing during the SARS-CoV-2-19 pandemic using a "telegenetics" approach. Genetic testing approach was panel-based next generation sequencing (351 genes) via a commercial laboratory (Blueprint Genetics, Helsinki, Finland). Of 70 patient samples from 57 pedigrees undergoing genetic testing, a causative genetic variant(s) was detected for 60 patients (85.7%) from 47 (82.5%) pedigrees. Of the 60 genetically resolved IRD patients, 5% (n = 3) are eligible for approved therapies (RPE65) and 38.3% (n = 23) are eligible for clinical trial-based gene therapies including CEP290 (n = 2), CNGA3 (n = 3), CNGB3 (n = 6), RPGR (n = 5) and RS1 (n = 7). The early introduction of genetic testing in the diagnostic/care pathway for children with IRDs is critical for genetic counselling of these families prior to upcoming gene therapy trials. Herein, we describe the pathway used, the clinical and genetic findings, and the therapeutic implications of the first systematic coordinated round of genetic testing of a paediatric IRD cohort in Ireland.

The Risks and Benefits of Myopia Control.

PURPOSE: The prevalence of myopia is increasing around the world, stimulating interest in methods to slow its progression. The primary justification for slowing myopia progression is to reduce the risk of vision loss through sight-threatening ocular pathologic features in later life. The article analyzes whether the potential benefits of slowing myopia progression by 1 diopter (D) justify the potential risks associated with treatments. METHODS: First, the known risks associated with various methods of myopia control are summarized, with emphasis on contact lens wear. Based on available data, the risk of visual impairment and predicted years of visual impairment are estimated for a range of incidence levels. Next, the increased risk of potentially sight-threatening conditions associated with different levels of myopia are reviewed. Finally, a model of the risk of visual impairment as a function of myopia level is developed, and the years of visual impairment associated with various levels of myopia and the years of visual impairment that could be prevented with achievable levels of myopia control are estimated. RESULTS: Assuming an incidence of microbial keratitis between 1 and 25 per 10 000 patient-years and that 15% of cases result in vision loss leads to the conclusion that between 38 and 945 patients need to be exposed to 5 years of wear to produce 5 years of vision loss. Each additional 1 D of myopia is associated with a 58%, 20%, 21%, and 30% increase in the risk of myopic maculopathy, open-angle glaucoma, posterior subcapsular cataract, and retinal detachment, respectively. The predicted mean years of visual impairment ranges from 4.42 in a person with myopia of -3 D to 9.56 in a person with myopia of -8 D, and a 1-D reduction would lower these by 0.74 and 1.21 years, respectively. CONCLUSIONS: The potential benefits of myopia control outweigh the risks: the number needed to treat to prevent 5 years of visual impairment is between 4.1 and 6.8, whereas fewer than 1 in 38 will experience a loss of vision as a result of myopia control.

Novel Myopia Genes and Pathways Identified From Syndromic Forms of Myopia.

Purpose: To test the hypothesis that genes known to cause clinical syndromes featuring myopia also harbor polymorphisms contributing to nonsyndromic refractive errors. Methods: Clinical phenotypes and syndromes that have refractive errors as a recognized feature were identified using the Online Mendelian Inheritance in Man (OMIM) database. One hundred fifty-four unique causative genes were identified, of which 119 were specifically linked with myopia and 114 represented syndromic myopia (i.e., myopia and at least one other clinical feature). Myopia was the only refractive error listed for 98 genes and hyperopia and the only refractive error noted for 28 genes, with the remaining 28 genes linked to phenotypes with multiple forms of refractive error. Pathway analysis was carried out to find biological processes overrepresented within these sets of genes. Genetic variants located within 50 kb of the 119 myopia-related genes were evaluated for involvement in refractive error by analysis of summary statistics from genome-wide association studies (GWAS) conducted by the CREAM Consortium and 23andMe, using both single-marker and gene-based tests. Results: Pathway analysis identified several biological processes already implicated in refractive error development through prior GWAS analyses and animal studies, including extracellular matrix remodeling, focal adhesion, and axon guidance, supporting the research hypothesis. Novel pathways also implicated in myopia development included mannosylation, glycosylation, lens development, gliogenesis, and Schwann cell differentiation. Hyperopia was found to be linked to a different pattern of biological processes, mostly related to organogenesis. Comparison with GWAS findings further confirmed that syndromic myopia genes were enriched for genetic variants that influence refractive errors in the general population. Gene-based analyses implicated 21 novel candidate myopia genes (ADAMTS18, ADAMTS2, ADAMTSL4, AGK, ALDH18A1, ASXL1, COL4A1, COL9A2, ERBB3, FBN1, GJA1, GNPTG, IFIH1, KIF11, LTBP2, OCA2, POLR3B, POMT1, PTPN11, TFAP2A, ZNF469). Conclusions: Common genetic variants within or nearby genes that cause syndromic myopia are enriched for variants that cause nonsyndromic, common myopia. Analysis of syndromic forms of refractive errors can provide new insights into the etiology of myopia and additional potential targets for therapeutic interventions.

In vivo human choroidal thickness measurements: evidence for diurnal fluctuations.

PURPOSE: The authors applied partial coherence interferometry (PCI) to estimate the thickness of the human choroid in vivo and to learn whether it fluctuates during the day. METHODS: By applying signal processing techniques to existing PCI tracings of human ocular axial length measurements, a signal modeling algorithm was developed and validated to determine the position and variability of a postretinal peak that, by analogy to animal studies, likely corresponds to the choroidal/scleral interface. The algorithm then was applied to diurnal axial eye length datasets. RESULTS: The postretinal peak was identified in 28% of subjects in the development and validation datasets, with mean subfoveal choroidal thicknesses of 307 and 293 microm, respectively. Twenty-eight of 40 diurnal PCI datasets had at least two time points with identifiable postretinal peaks, yielding a mean choroidal thickness of 426 microm and a mean high-low difference in choroidal thickness of 59.5 +/- 24.2 microm (range, 25.9-103 microm). The diurnal choroidal thickness fluctuation was larger than twice the SE of measurement (24.5 microm) in 16 of these 28 datasets. Axial length and choroidal thickness tended to fluctuate in antiphase. CONCLUSIONS: Signal processing techniques provide choroidal thickness estimates in many, but not all, PCI datasets of axial eye measurements. Based on eyes with identifiable postretinal peaks at more than one time in a day, choroidal thickness varied over the day. Because of the established role of the choroid in retinal function and its possible role in regulating eye growth, further development and refinement of clinical methods to measure its thickness are warranted.

Diurnal axial length fluctuations in human eyes.

PURPOSE: This study sought diurnal variations of eye length in human subjects, analogous to those reported in laboratory animals. METHODS: Seventeen subjects, ages 7 to 53 (median 16) years and mean spherical equivalent refractive error -0.68 D (range, -3.00 to +1.00 D), underwent axial length measurements at multiple times during the day between 7 AM and 1 AM the following day, using partial coherence interferometry (PCI), a highly precise, noncontact method. Diurnal axial length measurements were obtained on two or more days in 10 of these subjects. RESULTS: During at least 1 day, 15 subjects showed a statistically significant (ANOVA, P < 0.05) diurnal fluctuation of axial length, with a magnitude generally between 15 and 40 microm. From the diurnal tracings that fit a sine curve using statistical criteria, the mean period of fluctuation was 21.6 +/- 4.33 hours (SD), the mean amplitude was 27.1 +/- 11.9 microm (SD; range, 12.8-41.4 microm), and the maximum axial length tended to occur at midday. Each of the subjects with multiple daily measurements showed axial length fluctuations on at least 1 day, but there were day-to-day differences in the diurnal variations: most notably, four subjects showed axial length fluctuations on each day; in others, the fluctuations were not observed on each testing day. CONCLUSIONS: The human eye undergoes diurnal fluctuations in axial length, with a pattern suggesting maximum axial length at midday. Based on repeated measurements, these daily fluctuations may not appear regularly in all subjects, suggesting the possibility of physiologic influences that must be defined.

Highly precise eye length measurements in children aged 3 through 12 years.

OBJECTIVE: To determine the feasibility, reliability, and validity of using partial coherence interferometry, a noncontact method that detects interference patterns from various layers of the eye, to measure axial length in young children. METHODS: The right eye of 64 subjects (mean age, 8.4 y; age range, 3.4-12.9 y; best-corrected visual acuity >or=20/30) was measured. Subjects fixated monocularly on the collimated light pattern from a laser diode (the alignment beam) and the operator used a video monitor to align the corneal reflection in the optical path. Axial length was measured during an 0.8-second scan using interference patterns from a collimated short coherence superluminescence diode aligned coaxially with the laser diode. Five series of 16 readings each were obtained. The average axial length for each of the 5 series of readings was calculated. Main Outcome Measure Axial length. RESULTS: Within-subject precision of axial length measurements was high, with an overall SE of measurement of 8 micro m for individual subjects across the 5 sessions (95% confidence interval, +/-16 micro m). Subgroup analysis showed that sex, age, spherical equivalent, and refractive error exerted statistically significant effects on precision, but all of the differences among subgroups were 3 micro m or less and likely to be insignificant clinically. Axial length measured by partial coherence interferometry varied systematically, with factors known to influence eye length (ie, age and refractive error), further validating the measurement method. CONCLUSION: The partial coherence interferometry technique provides reproducible, extraordinarily precise eye length measurements in young children and should enable novel approaches to study eye growth and refractive development.