Association of autosomal dominant Snowflake Vitreoretinal Degeneration with Retinoschisis

Abstract Objective To define and characterize the clinical association of autosomal dominant snowflake vitreoretinal degeneration (SVD) with retinochisis arising from a heterozygous KCNJ13 variant in unrelated multigenerational families and to investigate its genetic, molecular, and functional consequences. Design Affected individuals from four unrelated families underwent detailed ophthalmic examinations, multimodal retinal imaging, and electroretinography. Genetic testing using targeted next-generation sequencing panels and Sanger sequencing identified a heterozygous KCNJ13 c.341T>C variant (p.(L114P)). In silico analyses and functional assays were performed to assess the pathogenicity of the variant. Subjects Patients with inherited retinal degeneration are identified through genetic testing. Methods Standard clinical diagnosis and imaging. In silico prediction of gene association and protein structure. Heterologous expression of protein through plasmid transfection followed by protein expression and electrophysiological analysis of function. Main Outcome Measures Associations between clinical findings, in silico predictions, and molecular mechanism studies. Results The KCNJ13 c.341T>C (p.L114P) variant is observed in multiple affected family members and appears to be consistent with autosomal dominant inheritance. Clinically, individuals present with retinoschisis and other classical SVD features, including snowflake-like retinal deposits, peripheral pigmentary changes, and visual field loss. Functional analyses in heterologous expression systems demonstrated that the L114P substitution impaired Kir7.1 channel function, localPS3 suggesting a dominant-negative effect. Conclusions This study identifies KCNJ13 c.341T>C, p.(L114P) as a pathogenic variant that causes autosomal-dominant SVD in additional cases associated with retinoschisis, supported by molecular and functional findings. These findings expand the mutational spectrum of KCNJ13-associated retinopathies, suggest a dominant-negative pathogenic mechanism for KCNJ13 mutations in SVD, and underscore the importance of distinguishing between dominant and recessive KCNJ13 variants for clinical diagnosis and genetic counseling. Our results support the broader implementation of genetic testing for inherited retinal disorders to guide diagnosis and potential future therapeutic interventions.