Background/aims To investigate genotype-phenotype associations in patients with KCNV2 retinopathy.Methods Review of clinical notes, best-corrected visual acuity (BCVA), molecular variants,... Show moreBackground/aims To investigate genotype-phenotype associations in patients with KCNV2 retinopathy.Methods Review of clinical notes, best-corrected visual acuity (BCVA), molecular variants, electroretinography (ERG) and retinal imaging. Subjects were grouped according to the combination of KCNV2 variants-two loss-of-function (TLOF), two missense (TM) or one of each (MLOF)-and parameters were compared.Results Ninety-two patients were included. The mean age of onset (mean +/- SD) in TLOF (n=55), TM (n=23) and MLOF (n=14) groups was 3.51 +/- 0.58, 4.07 +/- 2.76 and 5.54 +/- 3.38 years, respectively. The mean LogMAR BCVA ( +/- SD) at baseline in TLOF, TM and MLOF groups was 0.89 +/- 0.25, 0.67 +/- 0.38 and 0.81 +/- 0.35 for right, and 0.88 +/- 0.26, 0.69 +/- 0.33 and 0.78 +/- 0.33 for left eyes, respectively. The difference in BCVA between groups at baseline was significant in right (p=0.03) and left eyes (p=0.035). Mean outer nuclear layer thickness ( +/- SD) at baseline in TLOF, MLOF and TM groups was 37.07 +/- 15.20 mu m, 40.67 +/- 12.53 and 40.38 +/- 18.67, respectively, which was not significantly different (p=0.85). The mean ellipsoid zone width (EZW) loss ( +/- SD) was 2051 mu m ( +/- 1318) for patients in the TLOF, and 1314 mu m ( +/- 965) for MLOF. Only one patient in the TM group had EZW loss at presentation. There was considerable overlap in ERG findings, although the largest DA 10 ERG b-waves were associated with TLOF and the smallest with TM variants.Conclusions Patients with missense alterations had better BCVA and greater structural integrity. This is important for patient prognostication and counselling, as well as stratification for future gene therapy trials. Show less
Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated... Show moreGenome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.Large-scale sequence-based analyses identify novel risk variants and susceptibility genes for Crohn's disease, and implicate mesenchymal cell-mediated intestinal homeostasis in disease etiology. Show less
PURPOSE: To describe the detailed retinal phenotype of KCNV2-associated retinopathy.STUDY DESIGN: Multicenter international retrospective case series.METHODS: Review of retinal imaging including... Show morePURPOSE: To describe the detailed retinal phenotype of KCNV2-associated retinopathy.STUDY DESIGN: Multicenter international retrospective case series.METHODS: Review of retinal imaging including fundus autofluorescence (FAF) and optical coherence tomography (OCT), including qualitative and quantitative analyses.RESULTS: Three distinct macular FAF features were identified: (1) centrally increased signal (n = 35, 41.7%), (2) decreased autofluorescence (n = 27, 31.1%), and (3) ring of increased signal (n = 37, 44.0%). Five distinct FAF groups were identified based on combinations of those features, with 23.5% of patients changing the FAF group over a mean (range) follow-up of 5.9 years (1.9-13.1 years). Qualitative assessment was performed by grading OCT into 5 grades: (1) continuous ellipsoid zone (EZ) (20.5%); (2) EZ disruption (26.1%); (3) EZ absence, without optical gap and with preserved retinal pigment epithelium complex (21.6%); (4) loss of EZ and a hyporeflective zone at the foveola (6.8%); and (5) outer retina and retinal pigment epithelium complex loss (25.0%). Eighty-six patients had scans available from both eyes, with 83 (96.5%) having the same grade in both eyes, and 36.1% changed OCT grade over a mean follow-up of 5.5 years. The annual rate of outer nuclear layer thickness change was similar for right and left eyes.CONCLUSIONS: KCNV2-associated retinopathy is a slowly progressive disease with early retinal changes, which are predominantly symmetric between eyes. The identification of a single OCT or FAF measurement as an endpoint to determine progression that applies to all patients may be challenging, although outer nuclear layer thickness is a potential biomarker. Findings suggest a potential window for intervention until 40 years of age. (C) 2021 The Authors. Published by Elsevier Inc. Show less
Georgiou, M.; Robson, A.G.; Fujinami, K.; Leo, S.M.; Vincent, A.; Nasser, F.; ... ; Michaelides, M. 2021
center dot PURPOSE: To investigate genetics, electrophysiology, and clinical course of KCNV2-associated retinopathy in a cohort of children and adults. center dot STUDY DESIGN: This was a... Show morecenter dot PURPOSE: To investigate genetics, electrophysiology, and clinical course of KCNV2-associated retinopathy in a cohort of children and adults. center dot STUDY DESIGN: This was a multicenter international clinical cohort study. center dot METHODS: Review of clinical notes and molecular genetic testing. Full-field electroretinography (ERG) recordings, incorporating the international standards, were reviewed and quantified and compared with age and recordings from control subjects. center dot 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 12 years of age (range, 0-11 years). Decreased visual acuity was present in all patients, and 4 other symptoms were common: reduced color vision (78.6%), photophobia (53.5%), nyctalopia (43.6%), and nystagmus (38.6%). After a mean follow-up of 8.4 years, the mean best-corrected visual acuity (BCVA +/- SD) decreased from 0.81 +/- 0.27 to 0.90 +/- 0.31 logarithm of minimal angle of resolution. 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 dark-adapted 0.01 ERG, dark-adapted 10 ERG a-wave, and LA 3.0 30 Hz and LA3 ERG b-waves were 55%, 21%, 48%, and 74%, respectively compared with control values. Peak times showed stability across 6 decades. center dot CONCLUSION: In KCNV2-associated retinopathy, full field ERGs are diagnostic and consistent with largely stable peripheral retinal dysfunction. Report 1 highlights the severity of the clinical phenotype and established a large cohort of patients, emphasizing the unmet need for trials of novel therapeutics. (Am J Ophthalmol 2021;225: 95-107. (c) 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).) Show less
