Clinical and Genetic Features in Knobloch Syndrome: A Case Series Reporting Two Previously Unreported COL18A1 Variants

Purpose: Knobloch syndrome (KS) is a rare autosomal recessive disorder caused by biallelic variants in COL18A1 and characterized by high myopia, vitreoretinal degeneration, and occipital defects. This study examines genotype–phenotype correlations in patients with KS and reports two previously unreported COL18A1 variants. Methods: Retrospective case series from January 2010 to December 2025. From a cohort of 627 patients with inherited retinal diseases (IRDs) seen at the West Virginia University Eye Institute (WVU), all patients with clinical features of KS and pathogenic, likely pathogenic, or candidate COL18A1 variants were identified. Clinical records, multimodal retinal imaging, and electrodiagnostic testing results were reviewed and compared. Results: Four patients with clinical features of KS and genetic variants classified as pathogenic, likely pathogenic, or variants of uncertain significance in COL18A1 were identified, representing 0.64% of this single-center IRD cohort at WVU. All patients demonstrated the core ophthalmic features of KS: nystagmus, high myopia, macular atrophy, and vitreous degeneration. Systemic manifestations included seizure disorder, aplasia cutis congenita, renal anomalies, occipital encephalocele, and global developmental delay. Four distinct COL18A1 variants were identified, including two previously unreported variants: c.2673dupC p.Gly892Argfs*9 and c.3827C > T p.Ser1276Leu (variant of uncertain significance). Conclusions: We describe two previously unreported COL18A1 variants in patients with clinical features of Knobloch syndrome. This series reinforces the consistent ophthalmic phenotype of KS and highlights phenotypic variability in systemic features. Genetic testing is essential for definitive diagnosis, and KS should be considered in any child presenting with early onset nystagmus, high myopia, macular atrophy, and profoundly abnormal electroretinography.