First Chinese Cohort with Heterozygous COL9A3 Vitreoretinopathy: Beyond the Skeleton

Purpose: To delineate the ocular and systemic phenotype of the first Chinese cohort with heterozygous COL9A3 -related vitreoretinopathy, thereby expanding the genotypic and phenotypic spectrum of COL9A3 disorders beyond the established skeletal manifestations. Methods: Two Chinese families segregating an autosomal dominant vitreoretinopathy underwent comprehensive ophthalmic and rheumatologic assessment. Causative variants were identified via whole-exome sequencing and validated by Sanger sequencing. Pathogenicity was assessed through in silico analysis, ACMG guidelines, evolutionary conservation, and protein structural modeling via AlphaFold2. A systematic literature review contextualized the findings. Results: Two novel heterozygous COL9A3 missense variants (c.413G>A, p.Arg138His; c.1007C>T, p.Pro336Leu) fully co-segregated with the disease phenotype. All affected individuals presented with membranous vitreous anomalies and/or peripheral retinal degeneration. Systemic evaluation revealed joint hypermobility as a consistent feature, while notably absent were sensorineural hearing loss, facial dysmorphism, and cleft palate. Both variants were absent or extremely rare in population databases (gnomAD MAF ≤0.0006) and were unanimously predicted as damaging by computational tools, leading to their classification as likely pathogenic according to ACMG criteria. Conclusion: Heterozygous COL9A3 variants should be considered in patients with unexplained vitreoretinal degeneration even without skeletal or auditory features. Early diagnosis enables prophylactic retinal surveillance and genetic counselling in Chinese and other Asian cohorts.