In a retrospective cohort study published in JAMA Ophthalmology, researchers analyzed genomic and clinical data from patients enrolled in the Australian & New Zealand Registry of Advanced Glaucoma and the Massachusetts Eye and Ear cohort from 2008 to 2025. Patients underwent exome sequencing, whole-genome sequencing, or copy-number variant analysis to identify duplications encompassing FOXC1.
The study included 20 patients from 10 families with FOXC1 duplications. All genetically tested patients with the duplications had glaucoma, although incomplete family testing limited conclusions about inheritance patterns and penetrance.
Seventeen patients were referred with juvenile open-angle glaucoma, one with primary open-angle glaucoma, one with primary congenital glaucoma, and one with anterior segment dysgenesis. Four patients from one Massachusetts Eye and Ear family who were initially referred with juvenile open-angle glaucoma were reclassified as having anterior segment dysgenesis after gonioscopy review identified ectropion uveae and iris nodules and membranes.
In the Australian and New Zealand cohort, FOXC1 duplications accounted for 13.5% of genetically solved juvenile open-angle glaucoma cases, second only to MYOC variants in that cohort and ahead of biallelic CYP1B1 variants. In the Massachusetts Eye and Ear cohort, FOXC1 duplications accounted for 9.5% of genetically solved juvenile open-angle glaucoma cases. Across both cohorts, FOXC1 duplications represented 12.3% of genetically diagnosed juvenile open-angle glaucoma cases and 1.5% of all referred juvenile open-angle glaucoma probands.
Most juvenile open-angle glaucoma diagnoses occurred between ages 8 and 40 years. One patient had primary congenital glaucoma, and three first presented after age 40 with advanced disease likely reflecting missed earlier detection. Intraocular pressure at diagnosis ranged from 22 to 53 mmHg. Twelve patients had advanced disease at most recent examination, and some required selective laser trabeculoplasty or glaucoma surgery for pressure control.
The ocular phenotype varied across and within families. More than half of patients lacked overt anterior segment dysgenesis features, such as corectopia or pseudopolycoria. When present, anterior segment findings included peripheral anterior synechiae, iris stromal hypoplasia, iris nodules, membranes, and ectropion uveae.
About half of patients with recorded central corneal thickness measurements had thick corneas, and the researchers noted that elevated central corneal thickness can lead to overestimation of intraocular pressure during applanation tonometry.
Reported systemic findings included neurodevelopmental conditions, psychiatric diagnoses, and dental anomalies. One patient also had Kallmann syndrome, but the researchers could not determine whether the FOXC1 duplication contributed to that diagnosis. Medical histories were self-reported, and the researchers noted that systemic findings may have been underrecognized.
FOXC1 single-nucleotide variants and deletions are well-established causes of Axenfeld-Rieger syndrome, typically presenting with anterior segment dysgenesis and systemic features. FOXC1 duplications in this study were associated with a less syndromic and more variable phenotype, which the authors suggested could explain why such cases may be missed without copy-number variant analysis.
The study was limited by its retrospective design, small sample size, wide confidence intervals, incomplete family testing, and lack of standardized phenotyping across cohorts. The cohorts also differed in clinical assessment, including gonioscopy availability, and the Australian and New Zealand cohort included normal-tension juvenile open-angle glaucoma whereas the Massachusetts Eye and Ear cohort did not.
The findings "underline the potential importance of considering CNV in genetic testing strategies for early-onset glaucoma," wrote lead study author Giorgina E. Maxwell, MGC, of Flinders University, and colleagues.
In an invited commentary, John H. Fingert, MD, of the University of Iowa, wrote that the findings add FOXC1 to a growing group of juvenile open-angle glaucoma genes demonstrating allelic heterogeneity, including MYOC, EFEMP1, and CYP1B1. He noted that identifying disease-specific molecular mechanisms could eventually support targeted therapeutic approaches, as has begun to occur in MYOC-associated juvenile open-angle glaucoma.
Disclosures: The study was supported by the National Institutes of Health, the Australian National Health and Medical Research Council, and the Snow Medical Research Foundation. Maxwell reported support from the Australian Government Research Training Program Scholarship. Siggs, Wiggs, Craig, and Souzeau reported grant support, with Wiggs and Craig receiving NIH funding tied to this work. Siggs also reported being a cofounder and stockholder of Seonix Bio outside the submitted work. Fingert reported no conflicts of interest.
Source: JAMA Ophthalmology