KCNV2-associated Retinopathy: Genetics, Electrophysiology and Clinical Course – KCNV2 Study Group Report 1,

Abstract Purpose To investigate genetics, electrophysiology and clinical course of KCNV2-associated retinopathy in a cohort of children and adults. Study design Multicenter international clinical cohort study. Methods Review of clinical notes and molecular genetic testing. Full-field electroretinography (ERG) incorporating the international standards were reviewed and quantified and compared with age and recordings from control subjects. Results In total 230 disease-associated alleles were identified from 117 patients, corresponding to 75 different KCNV2 variants, with 28 being novel. The mean age of onset was 3.9 years old. All patients were symptomatic before the age of 12 years (age range: 0-11 years). Decreased visual acuity was present in all patients, and four other symptoms were common: reduced color vision (78.6%), photophobia (53.5%), nyctalopia (43.6%), and nystagmus (38.6%). After a mean follow of 8.4 years, the mean best corrected visual acuity (BCVA, ±SD) decreased from 0.81 LogMAR (0.27 LogMAR) to 0.90 LogMAR (0.31 LogMAR). Full-field ERGs showed pathognomonic waveform features. Quantitative assessment revealed a wide range of ERG amplitudes and peak times, with a mean rate of age-associated reduction indistinguishable from the control group. Mean amplitude reductions for the DA 0.01 ERG, DA 10 ERG a-wave, LA30Hz and LA3 ERG b-wave were 55%, 21%, 48% and 74% respectively. Peak times showed stability across 6 decades. Conclusion In KCNV2-retinopathy full-field ERGs are diagnostic, and consistent with largely stable peripheral retinal dysfunction. Report No.1 highlights the severity of the clinical phenotype and established a large cohort of patients, emphasizing the unmet need for trials of novel therapeutics.