Objective:

To analyze the association of FOXC1 duplications with early-onset glaucoma in patients from two cohorts: the Australian & New Zealand Registry of Advanced Glaucoma and the Massachusetts Eye and Ear cohort.

Key Findings:

• All genetically tested patients with FOXC1 duplications had glaucoma.
• FOXC1 duplications accounted for 13.5% of genetically solved juvenile open-angle glaucoma cases in the Australian and New Zealand cohort.
• 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.
• More than half of patients lacked overt anterior segment dysgenesis features.
• Reported systemic findings included neurodevelopmental conditions, psychiatric diagnoses, and dental anomalies, which may have been underrecognized.

Interpretation:

FOXC1 duplications are associated with a variable ocular phenotype, which may lead to underdiagnosis without copy-number variant analysis, highlighting the need for comprehensive genetic testing.

Limitations:

• Retrospective design and small sample size limit the generalizability of the findings.
• Incomplete family testing and lack of standardized phenotyping across cohorts may affect the accuracy of inheritance patterns.
• Differences in clinical assessment between cohorts could introduce variability in results.

Conclusion:

The findings highlight the potential importance of considering copy-number variants in genetic testing strategies for early-onset glaucoma, emphasizing the need for further research.