Abstract：
Tumor necrosis factor type 1A receptor-associated periodic syndrome (TRAPS) and cryopyrin-associated autoinflammatory syndrome (CAPS) are rare monogenic autoinflammatory diseases (AIDs) mainly caused by pathogenic variations in the TNFRSF1A and NLRP3 genes, respectively. Here, we describe a unique patient presenting with symptoms overlapping both TRAPS and CAPS, without known pathogenic variants in the respective genes. The patient harbored the p.Val200Met variation in NLRP3 and the p.Ser226Cys variation in TNFRSF1A, prompting us to delve deeper into the functional analysis due to conflicting or inconclusive pathogenicity interpretations of the variants across various databases. Molecular dynamics analysis of the p.Val200Met variation in NLRP3 revealed a rigid conformation in the helical domain 2 subdomain of the NACHT domain. This increased rigidity suggests a potential mechanism by which this variation supports the assembly of the NLRP3 inflammasome. Notably, the patient\'s peripheral mononuclear blood cells demonstrated an elevated IL-1β response upon lipopolysaccharides (LPS) induction. Subsequent initiation of anti-IL-1β therapy resulted in a significant alleviation of the patient\'s symptoms, further supporting our hypothesis. We interpret these findings as suggestive of a potential pathophysiological role for the NLPR3 p.Val200Met variation in shaping the patient\'s clinical phenotype, which was also supported by clinical and genetic analysis of the family. This case underscores the complexity of the genetic landscape in AIDs and highlights the value of combining family genetic and functional data to refine the understanding and management of such challenging cases.
摘要：
肿瘤坏死因子1A型受体相关周期性综合征（TRAPS）和冷冻比林相关自身炎症综合征（CAPS）是罕见的单基因自身炎症性疾病（AIDs），主要由TNFRSF1A和NLRP3基因的致病变异引起。分别。这里,我们描述了一个独特的患者，其症状与TRAPS和CAPS重叠，在各自的基因中没有已知的致病变异。患者在NLRP3中具有p.Val200Met变异，在TNFRSF1A中具有p.Ser226Cys变异，由于各种数据库中对变异体的致病性解释相互矛盾或不确定，因此促使我们更深入地研究功能分析。NLRP3中p.Val200Met变异的分子动力学分析揭示了NACHT结构域的螺旋结构域2亚结构域中的刚性构象。这种增加的刚性表明了一种潜在的机制，这种变化支持NLRP3炎性体的组装。值得注意的是,患者的外周单核细胞在脂多糖（LPS）诱导后表现出升高的IL-1β反应。随后开始抗IL-1β治疗导致患者症状显著缓解，进一步支持我们的假设。我们将这些发现解释为NLPR3p.Val200Met变异在塑造患者临床表型方面的潜在病理生理作用，这也得到了该家族的临床和遗传分析的支持。这一案例强调了艾滋病遗传格局的复杂性，并强调了将家族遗传和功能数据结合起来以完善对此类具有挑战性病例的理解和管理的价值。
