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Abstract #99166 Published in IGR 22-4
Genetic and Clinical Features of Blau Syndrome among Chinese Patients with Uveitis
Zhong Z; Ding J; Su G; Liao W; Gao Y; Zhu Y; Deng Y; Li F; Du L; Yang POphthalmology 2022; 129: 821-828
PURPOSE: American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) call for cautious interpretation of variants as causative of a monogenic disorder by stringent standards. We aimed to reclassify the pathogenicity of NOD2 variants according to the ACMG guidelines and to characterize clinical features in patients whose ocular disease might actually be explained by Blau syndrome. DESIGN: Genetic analysis and descriptive study. PARTICIPANTS: A total of 1003 unrelated healthy individuals and 3921 sporadic patients who presented with uveitis. METHODS: Whole-exome sequencing was performed on all healthy participants and 551 uveitis patients, and targeted NOD2 resequencing was performed on the remaining 3370 uveitis patients. Pathogenicity for Blau syndrome was classified for NOD2 variants identified by sequencing in study participants according to the ACMG guidelines. Clinical manifestations were compared among NOD2 variants of different levels of classification. MAIN OUTCOME MEASURES: Pathogenicity of variants. RESULTS: Eight NOD2 gain-of-function mutations, p.R334W, p.R334Q, p.E383K, p.G481D, p.W490S, p.M513T, p.R587C and p.N670K, were classified as pathogenic, and 66 (1.7%) uveitis patients were diagnosed with Blau syndrome due to these mutations. Of 66 Blau syndrome, anterior uveitis accounted for 39.4%, posterior uveitis for 9.1%, and panuveitis for 51.5%. A proportion of 21.2% of Blau syndrome presented as multifocal choroiditis, 48.5% had papillitis, and 74.2% showed retinal microvasculitis detected by fundus fluorescein angiography. Six NOD2 variants, p.P268S, p.R311W, p.R471C, p.A612T, p.R702W and p.V955I, were considered non-pathogenic for Blau syndrome and were identified in 96 uveitis patients. The incidence of bilateral uveitis (86.4%), secondary glaucoma (47.0%), epiretinal membrane (7.6%), choroidal neovascularization (4.6%), retinal atrophy (10.6%), arthritis (69.7%), joint deformity (51.5%) and skin rash (40.9%) was higher in Blau syndrome than in uveitis patients carrying non-Blau syndrome-causing NOD2 variants. Patients with Blau syndrome permanently experienced overall poorer best corrected visual acuity. Several rare NOD2 mutations, p.I722L (2 cases), p.T476P (1 case), p.T476del (1 case) and p.R439H (1 case), were newly identified. CONCLUSIONS: Pathogenic NOD2 variants for Blau syndrome were limited to those gain-of-function mutations and were associated with a high risk for arthritis, skin rash, permanent visual loss and ocular complications in patients with uveitis.
The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, and Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, China.
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