FOXC1 Duplications and Juvenile Open-Angle Glaucoma: Why This Genetic Finding Matters
Juvenile open-angle glaucoma (JOAG) is a serious eye disease that causes progressive optic nerve damage and vision loss at a relatively young age. It often resembles adult open-angle glaucoma in the structure of the eye, but it begins earlier and can be more aggressive. Because JOAG can run in families and may be caused by specific genetic changes, identifying the underlying variant can help confirm the diagnosis, guide family testing, and improve long-term care.
A recent multicenter study focused on duplications involving FOXC1, a gene already known to be important in eye development. While FOXC1 single-nucleotide variants and deletions have long been linked to Axenfeld-Rieger syndrome and related anterior segment disorders, FOXC1 duplications have been reported much less often. This study helps clarify how often these duplications appear in glaucoma registries and what clinical features they are associated with.
What FOXC1 Does in the Eye
FOXC1 encodes a transcription factor, a type of protein that helps control the activity of other genes during development. In the eye, FOXC1 plays an important role in forming the anterior segment, which includes the iris, drainage angle, cornea, and related structures that regulate the flow of aqueous humor. When FOXC1 is altered, the angle structures may develop abnormally, which can interfere with fluid drainage and increase intraocular pressure.
This pressure-related damage can contribute to glaucoma. In some people, FOXC1-related disease is obvious because of features such as iris abnormalities, a malpositioned pupil, or corneal changes. In others, the signs are subtle, and glaucoma may be the main presenting feature. That is one reason why FOXC1 duplications can be overlooked unless genetic testing is performed.
How the Study Was Done
This retrospective observational genetic cohort study included participants from two large glaucoma registries: the Australian and New Zealand Registry of Advanced Glaucoma and the Massachusetts Eye and Ear cohort. Participants were recruited over a long interval, from 2008 through 2025, and data analyses were conducted from 2022 through 2025.
Patients with glaucoma, along with available relatives, underwent genomic testing to identify duplications encompassing FOXC1. The Australian and New Zealand cohort used exome sequencing and genotyping arrays, while the Massachusetts Eye and Ear cohort used whole-genome sequencing. These approaches can detect copy-number variants, which are genetic changes where sections of DNA are duplicated or deleted.
The main outcomes were the prevalence of FOXC1 duplications, age at glaucoma onset, and the associated phenotype, including eye findings and any systemic features.
Who Was Identified
The investigators found 20 individuals from 10 families with FOXC1 duplications. Half were female and half male. Most individuals self-described as broadly European, including Australian, British, English/German, English/Polish, European, or Scottish ancestry. A smaller proportion identified as Asian, including Chinese or Filipino ancestry, and one person identified as Latin American, specifically Salvadoran.
Importantly, every genetically tested individual with a FOXC1 duplication had glaucoma, suggesting a high level of penetrance. Penetrance refers to how often a genetic change actually leads to disease. In this study, the duplication was strongly associated with glaucoma, although the clinical presentation varied from person to person.
Most participants were referred with juvenile open-angle glaucoma. Specifically, 17 individuals had JOAG, 1 had primary open-angle glaucoma, 1 had primary congenital glaucoma, and 1 had anterior segment dysgenesis. In one family, four individuals were initially labeled as having ectropion uveae, but the diagnosis was revised to anterior segment dysgenesis after review. This highlights how genetic testing can refine or correct the clinical diagnosis.
What the Eye Findings Suggest
The study shows that FOXC1 duplications are not limited to classic Axenfeld-Rieger syndrome. Instead, they can present along a spectrum that includes subtle anterior segment abnormalities, early-onset glaucoma, and in some cases what appears to be isolated JOAG.
This is clinically important because JOAG can sometimes be mistaken for other forms of open-angle glaucoma unless the eye examination is thorough. Findings such as gonioscopic angle abnormalities, iris changes, elevated intraocular pressure at a young age, or a family history of early glaucoma should raise suspicion for a genetic cause. In FOXC1-related disease, the phenotype may be variable even within the same family, so one relative may have obvious anterior segment dysgenesis while another has only glaucoma.
Systemic Features Were Present but Often Subtle
Although FOXC1 is primarily associated with eye development, some individuals also had extraocular findings. In this study, systemic features were reported in 2 participants, or about 10.5%. These included subtle dental abnormalities and mild facial differences.
That pattern fits with the broader FOXC1-related disorder spectrum. People with FOXC1 alterations may have craniofacial or dental findings that are easy to miss unless they are specifically sought. The fact that systemic signs were uncommon and mild in this cohort also explains why some patients may present first to an eye specialist rather than to a medical geneticist.
How Common Were FOXC1 Duplications in Genetic JOAG?
Among probands with a genetic diagnosis in the Australian and New Zealand registry, FOXC1 duplications accounted for 13.5% of JOAG cases, with a 95% confidence interval of 6.7% to 25.3%. This placed FOXC1 second only to MYOC, which explained 53.8% of genetically diagnosed JOAG in that group.
In the Massachusetts Eye and Ear cohort, FOXC1 duplications accounted for 9.5% of genetically diagnosed JOAG probands, with a 95% confidence interval of 2.7% to 28.9%.
These are notable proportions for a single genetic mechanism in a rare disease. They suggest that FOXC1 copy-number changes are an important and underrecognized contributor to inherited early-onset glaucoma. At the same time, the confidence intervals were wide because the absolute number of cases was small, which is expected in rare disease research.
What This Means for Patients and Families
The practical message from this study is that FOXC1 duplications should be considered in patients with JOAG, especially when there is a family history, early onset, or signs of anterior segment dysgenesis. Because the duplication may be inherited, relatives could also be at risk, even if they have not yet developed glaucoma symptoms.
Genetic counseling is therefore an important part of care. Counseling can help explain the inheritance pattern, discuss the possibility of variable expression within a family, and guide testing of relatives. Cascade testing, meaning targeted testing of family members once a causative variant is identified, can be especially useful for early detection.
For clinicians, the study supports adding copy-number variant analysis to the genetic workup of selected JOAG patients. Standard sequencing may miss duplications if the assay is not designed to detect them. Methods such as chromosomal microarray, exome-based copy-number analysis, or whole-genome sequencing may be needed depending on the laboratory platform.
How Glaucoma Is Managed When FOXC1 Is Involved
The presence of a FOXC1 duplication does not change the basic principles of glaucoma treatment, but it can sharpen the clinical approach. Management still focuses on lowering intraocular pressure and preventing further optic nerve damage. Depending on the severity and response to treatment, this may include pressure-lowering eye drops, laser procedures, or surgery.
Because JOAG can progress silently, regular monitoring is essential. Typical follow-up includes measurement of intraocular pressure, optic nerve evaluation, visual field testing, and imaging such as optical coherence tomography when appropriate. In children, adolescents, and young adults, adherence to treatment and long-term follow-up are especially important because the disease may be active for many decades.
If anterior segment anomalies are present, surgical planning may require extra care. Eye anatomy can be atypical, and the response to therapy may differ from that seen in routine adult open-angle glaucoma. A glaucoma specialist familiar with developmental or genetic eye disease is often best positioned to manage these patients.
Study Strengths and Limitations
A major strength of this work is that it draws from two large registries and uses modern genomic methods to identify structural variants. That makes the findings highly relevant to real-world glaucoma genetics.
The main limitation is sample size. Even though 20 individuals were identified, FOXC1 duplications remain uncommon overall, and the number of genetically diagnosed JOAG probands was still relatively small. As a result, the prevalence estimates come with wide confidence intervals. The study also focused on people already enrolled in specialized registries, which may not reflect the full spectrum of disease in the general population.
Still, the consistent pattern across families and cohorts strengthens the conclusion that FOXC1 duplication is a true and important cause of JOAG.
Bottom Line
This study shows that FOXC1 duplications are a high-penetrance but variably expressive genetic cause of juvenile open-angle glaucoma. Some individuals have clear anterior segment abnormalities or mild systemic features, while others present mainly with glaucoma. Because the condition can be subtle and may be missed without advanced genetic testing, routine consideration of copy-number variant analysis may improve diagnosis and family screening in JOAG.
For patients and clinicians, the key takeaway is simple: early-onset glaucoma should not be treated as genetically uniform. FOXC1 duplications add to the growing evidence that JOAG is genetically diverse, and identifying the cause can make a meaningful difference for surveillance, counseling, and care planning.
