BACKGROUND NLRP3-associated autoinflammatory diseases (NLRP3-AIDs) include conditions of various severities, due to germline or somatic mosaic NLRP3 mutations. OBJECTIVE To identify mosaic- versus germline-specific NLRP3 mutations' characteristics, we reinterpreted all the mutations reported in NLRP3-AIDs and performed an in-depth study of 3 novel patients. METHODS The pathogenicity of all reported mosaic/germline mutations was reassessed according to international recommendations and their location on the NLRP3 3-dimensional structure. Deep-targeted sequencing and NLRP3-inflammasome-activation assays were used to identify the disease-causing mutation in 3 patients. RESULTS We identified, in 3 patients, mosaic mutations affecting the same NLRP3 amino acid (Glu569). This residue belongs to 1 of the 2 mosaic mutational hot spots that face each other in the core of the NLRP3 ATPase domain. The review of the 90 NLRP3 mutations identified in 277 patients revealed that those hot spots account for 68.5% of patients (37 of 54) with mosaic mutations. Glu569 is affected in 22% of the patients (12 of 54) with mosaic mutations and in 0.4% of patients (1 of 223) with germline mutations. Only 8 of 90 mutations were found in mosaic and germinal states. All of the germline mutations were associated with a severe phenotype. These data suggest that mutations found only in mosaic state could be incompatible with life if present in germinal state. None of the 5 most frequent germline mutations was identified in mosaic state. Mutations found only in germinal state could, therefore, be asymptomatic in mosaic state. CONCLUSIONS The phenotypic spectrum of NLRP3-AIDs appears to be related to the germinal/mosaic status and localization of the underlying mutations.

中文翻译：

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NLRP3相关的自发性疾病：种系与体细胞突变的表型和分子特征。

背景技术由于种系或体细胞镶嵌NLRP3突变，与NLRP3相关的自身炎性疾病（NLRP3-AID）包括各种严重程度的疾病。目的为了鉴定镶嵌特异性与种系特异性的NLRP3突变的特征，我们重新解释了NLRP3-AID中报道的所有突变，并对3名新患者进行了深入研究。方法根据国际建议及其在NLRP3 3维结构上的位置，重新评估了所有报告的花叶/种系突变的致病性。深度靶向测序和NLRP3炎性体激活分析用于鉴定3例患者的致病突变。结果我们在3例患者中确定了影响相同NLRP3氨基酸（Glu569）的镶嵌突变。此残基属于NLRP3 ATPase结构域核心中彼此面对的2个镶嵌突变热点中的1个。对277例患者中鉴定出的90个NLRP3突变的审查显示，这些热点占镶嵌突变患者的68.5％（54人中的37人）。Glu569在22％的具有镶嵌突变的患者（54例中的12例）和0.4％的生殖系突变的患者（223例中的1例）中受到影响。在镶嵌和生发状态下仅发现90个突变中的8个。所有的种系突变都与严重的表型有关。这些数据表明，仅在镶嵌状态下发现的突变如果以生发状态存在，可能与生命不相容。5个最常见的种系突变均未在镶嵌状态下鉴定。因此，仅在生发状态下发现的突变在镶嵌状态下可能是无症状的。