Genetic and Clinical Features of Blau Syndrome among Chinese Patients with Uveitis

作者全名："Zhong, Zhenyu; Ding, Jiadong; Su, Guannan; Liao, Weiting; Gao, Yu; Zhu, Yunyun; Deng, Yang; Li, Fuzhen; Du, Liping; Gao, Yuan; Yang, Peizeng"

作者地址："[Zhong, Zhenyu; Su, Guannan; Liao, Weiting; Gao, Yu; Zhu, Yunyun; Deng, Yang; Yang, Peizeng] Chongqing Med Univ, Affiliated Hosp 1,Chongqing Eye Inst, Chongqing Branch Natl Clin Res Ctr Ocular Dis, Chongqing Key Lab Ophthalmol, Chongqing, Peoples R China; [Ding, Jiadong; Li, Fuzhen; Du, Liping] Zhengzhou Univ, Affiliated Hosp 1,Henan Prov Eye Hosp, Henan Int Joint Res Lab Ocular Immunol & Retinal I, Zhengzhou, Peoples R China; [Gao, Yuan] Army Med Univ, Mil Med Univ 3, Southwest Hosp, Southwest Eye Hosp, Chongqing, Peoples R China; [Yang, Peizeng] Chongqing Med Univ, Affiliated Hosp 1, Youyi Rd 1, Chongqing 400016, Peoples R China"

通信作者："Yang, PZ (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Youyi Rd 1, Chongqing 400016, Peoples R China."

来源：OPHTHALMOLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000885754600016

JCR分区：Q1

影响因子：13.7

年份：2022

卷号：129

期号：7

开始页：821

结束页：828

文献类型：Article

关键词：Blau syndrome; Genetic Variant; NOD2; Uveitis

摘要："Purpose: The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology call for cautious interpretation of variants as causative of a monogenic disorder by stringent standards. We aimed to reclassify the pathogenicity of nucleotide binding oligomerization domain containing 2 (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 patients with uveitis, and targeted NOD2 resequencing was performed on the remaining 3370 patients with uveitis. 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 patients (1.7%) with uveitis were diagnosed with Blau syndrome due to these mutations. Of 66 with 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 nonpathogenic for Blau syndrome and were identified in 96 patients with uveitis. 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 patients with uveitis carrying noneBlau-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. Ophthalmology 2022;129:821-828 (c) 2022 by the American Academy of Ophthalmology"

基金机构：National Natural Science Foundation of China [81720108009]; National Natural Science Foundation Key Program [81930023]; Chongqing Key Project [CSTC2021jscx-gksb-N0010]; Chongqing Outstanding Scientists Project [cstc2014pt-sy10002]; Chongqing Chief Medical Scientist Project [2008CA5003]; Chongqing Science & Technology Platform and Base Construction Program; Chongqing Key Laboratory of Ophthalmology (CSTC)

基金资助正文："The work was supported by National Natural Science Foundation of China Major International (Regional) Joint Research Project (81720108009),National Natural Science Foundation Key Program (81930023), Chongqing Key Project (CSTC2021jscx-gksb-N0010), Chongqing Outstanding Scientists Project (2019), Chongqing Chief Medical Scientist Project (2018),Chongqing Science & Technology Platform and Base Construction Program (cstc2014pt-sy10002), and Chongqing Key Laboratory of Ophthalmology (CSTC, 2008CA5003)."