粕D2基因双位点突变导致Blau综合征的家系分析

A familial case of Blau syndrome caused by dual NOD2 genetic mutations

目的通过对一疑似Blau综合征（Bs）的中国家系进行NOD2基因分析，研究中国患者的基因突变类型和临床特点。方法研究对象为疑似Bs患儿及其家属，共9例。其中男4例，女5例。患儿及其父母进行Sanger测序和医学外显子测序，其余人员仅进行Sanger测序；对于新发现错义突变，在线预测其致病性；结合基因型与Bs患者的临床资料，为Bs的诊断提供临床依据。结果1．序列分析结果显示，先证者NOD2基因4号外显子的2处位点同时发生错义突变，一处为已知突变：c．2006A〉G，P．I-1669R，另一处为新发突变：c．1981G〉C，P．A661P。2．经家系验证分析，先证者之父和祖母在这2个位点具有同样的杂合变异，先证者之母和祖父该位点无变异。3．先证者具有皮疹、虹膜睫状体炎和关节炎三联征症状，无发热，c反应蛋白（CRP）正常。结论家系中NOD2基因A661P和H669R双突变引起BS，突变由祖母经父亲传递给先证者；A661P是个新发现的突变位点；先证者无反复发热，CRP不升高，该临床表现有可能作为本病区分于其他白发炎症性疾病的鉴别标准。

Objective To provide the diagnostic proof for a suspected Chinese family with BS,and NOD2 gene mutation types and clinical features were analyzed in this study. Methods Nine members （4 males and 5 females） of this family were enrolled. To clarify the genotype, the whole exome sequencing by next - generation sequencing from the proband and his parents was performed, and all members were subjected to Sanger sequencing. For the newly discovered NOD2 missense mutation, its pathological predictions were conducted online by adopting polyphen software. Clinical da-ta of affected cases diagnosed by NOD2 analysis were collected to analyze illustrate the clinical features. Results （ 1 ） The proband of the family was a 5 - year - old Chinese Han boy, who had the clinical triad of dermatitis, polyarthritis and uveitis. The body temperature and C -reactive protein （CRP） was normal. Besides the proband, 2 members were diagnosed as BS by means of NOD2 analysis. The coexistence of 2 missense mutations was detected. One novel mutation was c. 1981 G 〉 C, p. A661 P, and another previously reported one was c. 2006A 〉 G, p. H669A. （ 2 ） Mutations identified in the male proband were inherited from his father. Tracing the other pedigree members, it was disclosed that his grand- mother had the heterozygous dual NOD2 mutations. The proband displayed a phenotype featuring the symptom triad of granulomatous dermatitis, symmetric arthritis, and recurrent uveitis, with normal temperature and CRP level. Conclusions The coexistence of A661P and H669A mutations in NOD2 caused BS in a Chinese pedigree, which derived from the proband＇s grandmother. This is the first report of A661P mutation in NOD2 in a Chinese pedigree of this disease. The proband has multi hydatoncus surrounding multi-joints, but no persistent fever and no elevated CRP, which may help to differentiate BS from other inherited autoinflammatory diseases in clinical settings.