IQCB1 (NPHP5)-retinopathy: Clinical and Genetic Characterization and Natural History

Purpose : To describe the clinical and genetic features, and explore the natural history of retinopathy associated with IQCB1 variants in children and adults with retinopathy. Design : Retrospective cohort study at a single tertiary care referral center. Methods : The study recruited 19 patients with retinopathy, harboring likely disease-causing variants in IQCB1. Demographic data and clinical presentation, best corrected visual acuity (BCVA), fundus appearance, optical coherence tomography (OCT) and autofluorescence features, electroretinography (ERG) and molecular genetics are reported. Results : Ten patients had BCVA better than 1.0 LogMAR, and BCVA remained stable till the last review. Seven patients had a vision of hand movements or worse in at least one eye at presentation. There was no correlation found between age of onset and severity of vision loss. Nine patients (47.4%) had a diagnosis of end-stage renal failure at presentation. The other 10 patients (52.6%) had a diagnosis of non-syndromic IQCB1-retinopathy and maintained normal renal function until the last follow-up. The mean age at diagnosis of renal failure was 26.3 ±19.8 years. OCT showed ellipsoid zone (EZ) disruption with foveal sparing in 8/13 patients. All patients had stable OCT findings. Full-field ERGs in four adults revealed a severe cone-rod dystrophy and three children had extinguished ERGs. We identified 17 IQCB1 variants, all predicted to cause loss of function. Conclusion : IQCB1-retinopathy is a severe early-onset cone-rod dystrophy. The dissociation between severely decreased retinal function and relative preservation of retinal structure over a wide age window makes the disease a candidate for gene therapy.