Blau syndrome (BS) is a rare, chronic autoinflammatory disease with onset before age 4 and mainly characterised by granulomatous arthritis, recurrent uveitis, and skin rash. Sporadic (also known as early-onset sarcoidosis) or familial BS is caused by gain-of-function mutations in the NOD2 gene, which encodes for a multi-task protein that plays a crucial role in the innate immune defense. We report on three Mexican patients clinically diagnosed with BS who exhibited a likely pathogenic variant in NOD2 as revealed by whole-exome sequencing (WES) and Sanger sequencing: two variants (c.1000 C > T/p.Arg334Trp and c.1538 T > C/p.Met513Thr) lie in the ATP/Mg2+ binding site, whereas the other (c.3019dupC/p.Leu1007ProfsTer2) introduces a premature stop codon disrupting the last LRR domain (LRR9) formation; all three variants are consistent with gain-of-function changes. Interestingly, all these patients presented concomitant likely pathogenic variants in other inflammatory disease-related genes, i.e. TLR10, PRR12, MEFV and/or SLC22A5. Although the clinical presentation in these patients included the BS diagnostic triad, overall it was rather heterogeneous. It is plausible that this clinical variability depends partly on the patients’ genetic background as suggested by our WES results. After this molecular diagnosis and given the absence of NOD2 mutations (demonstrated in two trios) and related symptoms in the respective parents (confirmed in all trios), patients 1 and 2 were considered to have sporadic BS, while patient 3, a sporadic BS-recurrent polyserositis compound phenotype. Altogether, our observations and findings underscore the overlapping among inflammatory diseases and the importance of determining the underlying genetic cause by high-throughput methods. Likewise, this study further reinforces a pathogenic link between the here found NOD2 variants and BS and envisages potential additive effects from other loci in these, and probably other patients.

布劳综合征（BS）是一种罕见的慢性自发性疾病，发病于4岁之前，主要特征是肉芽肿性关节炎，复发性葡萄膜炎和皮疹。散发性（也称为早发型结节病）或家族性BS是由NOD2基因的功能获得性突变引起的，NOD2基因编码的多任务蛋白在先天免疫防御中起着至关重要的作用。我们报告了三名临床诊断为BS的墨西哥患者，他们在NOD2中表现出可能的致病性变异如全外显子组测序（WES）和Sanger测序所示：两个变体（c.1000 C> T / p.Arg334Trp和c.1538 T> C / p.Met513Thr）位于ATP / Mg2 +结合位点，而其他（c.3019dupC / p.Leu1007ProfsTer2）引入了过早的终止密码子，破坏了最后一个LRR结构域（LRR9）的形成；所有这三个变体都与功能增益变化保持一致。有趣的是，所有这些患者在其他炎症性疾病相关基因（即TLR10，PRR12，MEFV和/或SLC22A5）中均出现了可能的致病变异。。尽管这些患者的临床表现包括BS诊断三联征，但总体而言它是异质的。我们的WES结果表明，这种临床变异性可能部分取决于患者的遗传背景。经过分子诊断并考虑到没有NOD2突变（在两个三联症中证实）和相关父母的相关症状（在所有三联症中均得到证实），患者1和2被认为是散发性BS，而患者3被认为是散发性BS复发性多发性浆膜炎复合表型。总之，我们的观察和发现强调了炎症性疾病之间的重叠以及通过高通量方法确定潜在遗传原因的重要性。同样，这项研究进一步加强了此处发现的NOD2变体与BS之间的致病联系，并设想了这些患者以及其他患者中其他基因座的潜在加性作用。