Virginie J M Verhoeven | Search PubMed

PubMed2026

A Comprehensive Assessment of the Shared Genetic Architecture between Myopia and Open-Angle Glaucoma.

OBJECTIVE: Individuals with high myopia have an increased prevalence of open-angle glaucoma (OAG). We aim to clarify the possibly shared genetic architecture of myopia and OAG, in particular in high myopes with myopic macular degeneration (MMD), where OAG screening is highly challenging. DESIGN: Individual participant data meta-analysis of one-sample Mendelian randomization analyses and pleiotropic analysis under a composite null hypothesis. PARTICIPANTS: A total of 34 825 participants from 6 population-based cohort studies and 1 high myopia case-control study, including 708 OAG and 1953 high-myopia cases. METHODS: First, we calculated and validated genetic risk scores (GRSs) for OAG and myopia in each cohort. We subsequently meta-analyzed linear and logistic regression models for the association of a myopia GRS with OAG, intraocular pressure (IOP), and vertical cup-to-disc ratio (VCDR), and the association of an OAG-GRS with high myopia, axial length, and spherical equivalent. We stratified the analysis of OAG in different stages of axial elongation, and in high myopes with or without MMD. Pleiotropic analysis under a composite null hypothesis was applied to genome-wide association study summary statistics. MAIN OUTCOME MEASURES: Odds ratio (OR) of OAG and high myopia, and mean difference in IOP, VCDR, axial length, and spherical equivalent. RESULTS: One standard deviation (SD) increase in myopia GRS was associated with an OR (95% CI) of 1.18 (1.09, 1.28) for OAG, a beta (95% CI) of 0.04 (0.00, 0.08) mmHg in IOP, and of 0.005 (0.003, 0.007) in VCDR. The OAG-GRS was not significantly associated with high myopia compared to emmetropes, but a 1 SD increase was associated with a beta (95% CI) of 0.05 (0.01, 0.08) mm in axial length and of -0.05 (-0.10, -0.00) diopters in spherical equivalent. One SD increase in OAG-GRS had a substantially larger effect on OAG in high myopes with MMD, with an OR (95% CI) of 3.83 (1.89, 7.78) compared to 1.55 (1.24, 1.94) in emmetropes. Finally, we identified 95 independent pleiotropic single-nucleotide polymorphisms (SNPs). CONCLUSIONS: There is strong evidence for pleiotropy between myopia and OAG. Further research into the biological mechanisms of the identified pleiotropic SNPs is needed. An OAG-GRS might help to clinically estimate OAG risk, in particular in individuals with MMD. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Axial length↗

PubMed2026

EGFLAM Pathogenic Variants and Congenital Stationary Night Blindness.

IMPORTANCE: Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous inherited retinal disorder (IRD), and in many complete CSNB (cCSNB) cases, the underlying genetic cause remains unknown. Uncovering the genetic defects of IRDs helps to refine diagnostic methods and supports the development of specific therapeutic approaches. OBJECTIVE: To describe the phenotype and the underlying gene defect in patients with cCSNB from 2 unrelated families. DESIGN, SETTING AND PARTICIPANTS: This retrospective case series was conducted from January 2023 to July 2025. Data for 3 patients from cohorts of genetically unsolved IRD cases in France (n = 140 for CSNB) and the Netherlands (n = 2730 for IRD) were analyzed clinically and genetically. EXPOSURES: Complete ocular examination, including multimodal retinal imaging and full-field electroretinography (ffERG) incorporating the International Society for Clinical Electrophysiology of Vision standards and multimodal retinal imaging, were performed. Gene defects were identified by genome sequencing (GS) and exome sequencing (ES). MAIN OUTCOMES AND MEASURES: The main outcome was a gene defect, EGFLAM, underlying cCSNB. Measures included phenotyping, GS, ES, Sanger sequencing, and cosegregation analysis. RESULTS: The series included 3 patients from 2 unrelated families of Moroccan ancestry showing high myopia, reduced visual acuity, and night blindness. Retinal imaging depicted myopic changes. ffERG revealed electronegative Schubert-Bornschein configuration in keeping with cCSNB with ON-bipolar cell dysfunction. Patients were lacking pathogenic variants in known genes implicated in IRDs, including CSNB. Two different homozygous pathogenic variants, c.1563_1566del, p.(Val522Glufs*18) and c.1795C>T, p.(Arg599*) in EGFLAM were identified by ES and GS. The corresponding protein is localized in the outer plexiform layer and important for ON-bipolar cell signaling in the retina. CONCLUSION AND RELEVANCE: This case series reports on a gene defect in EGFLAM implicated in human cCSNB. Clinicians should be aware about this association and consider including EGFLAM in diagnostic gene panels for IRDs. This discovery may lead to faster and more accurate diagnosis of cCSNB and genetic counseling, as well as a pathway for developing therapies.

Adolescent↗