A novel CAPN5 missense variant associated with autosomal dominant neovascular inflammatory vitreoretinopathy.

INTRODUCTION: Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is a rare inherited retinal disorder that often has delayed diagnosis due to overlapping features of intraocular inflammation, retinal degeneration, and retinal neovascularization.

CASE PRESENTATION: We report a case of a 53-year-old male who presented with progressive panuveitis, peripheral visual field loss, and nyctalopia. Multimodal imaging demonstrated peripheral retinal nonperfusion, vascular leakage, cystoid macular edema, and progressive tractional vitreoretinal changes. Family history was notable for presumed age-related macular degeneration in the patient's father, later found on postmortem evaluation to have features suggestive of ADNIV. To determine the etiology of the clinical presentation, the patient underwent genetic testing using a targeted long-read sequencing inherited retinal disease panel, which identified a heterozygous missense variant in CAPN5, c.728G>A (p.Arg243His).

DISCUSSION: The overlapping features of intraocular inflammation, retinal degeneration, and vasoproliferative disease frequently lead to delayed or incorrect diagnosis of ADNIV. The potentially causative variant identified has not been reported to cause disease before, but at that amino acid residue, a different missense variant has been identified as the causative variant in ADNIV patients as it localizes to a calcium-sensitive regulatory region adjacent to the catalytic domain, supporting a gain-of-function mechanism. Although currently classified as a variant of uncertain significance, its genomic context, rarity, and biologic plausibility support pathogenicity.

CONCLUSIONS: This case expands the mutational spectrum of CAPN5-associated ADNIV and highlights the importance of integrating detailed clinical phenotyping with biologically informed genetic interpretation in complex inherited retinal disorders.