Periodic fever syndromes (PFSs) are a family of clinical disorders, which are characterized by recurrent episodes of fever in the absence of microbial, autoimmune or malign conditions. Most common types of PFSs are associated with four genes: MEFV, MVK, TNFRSF1A and NLRP3. This paper aims to add new data to the genotype–phenotype association of MVK-, TNFRSF-1A- and NLRP3‐associated PFSs. A total number of 211 patients were evaluated. Two different approaches were used for the molecular genetic evaluation of MVK-, TNFRSF-1A- and NLRP3‐associated PFSs. For the first 147 patients, Sanger sequence analysis of selected exons of MVK, TNFRSF1A and NLRP3 genes was done. For subsequent 64 patients, targeted NGS panel analysis, covering all exons of MVK, TNFRSF1A and NLRP3 genes, was used. A total number of 48 variants were detected. The “variant detection rate in index patients” was higher in the NGS group than Sanger sequencing group (19% vs. 15,1%). For the variant positive patients, a detailed genotype–phenotype table was built. In PFSs, lack of correlation exists between genotype and phenotype in the general population and even within the families. In some cases, mutations behave differently and yield unexpected phenotypes. In this study, we discussed the clinical effects of eight different variants we have detected in the MVK, TNFRSF1A and NLRP3 genes. Four of them were previously identified in patients with PFS. The remaining four were not reported in patients with PFS. Thus, we had to interpret their clinical effects by analysing their frequencies and in silico analysis predictions. We suggest that new studies are needed to evaluate the effects of these variants more clearly. To be able to demonstrate a clearer genotype–phenotype relationship, all PFS‐related genes should be analysed together and the possibility of polygenic inheritance should be considered.

中文翻译：

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NLRP 3、MVK 和 TNFRSF 1A 相关周期性发热综合征的分子遗传学评估

周期性发热综合征 (PFS) 是一组临床疾病，其特征是在没有微生物、自身免疫或恶性肿瘤的情况下反复发热。最常见的 PFS 类型与四种基因相关：MEFV、MVK、TNFRSF1A 和 NLRP3。本文旨在为 MVK-、TNFRSF-1A- 和 NLRP3 相关 PFS 的基因型-表型关联添加新数据。共评估了 211 名患者。两种不同的方法用于对 MVK、TNFRSF-1A 和 NLRP3 相关的 PFS 进行分子遗传评估。对于前 147 名患者，对 MVK、TNFRSF1A 和 NLRP3 基因的选定外显子进行了 Sanger 序列分析。对于随后的 64 名患者，使用了靶向 NGS 面板分析，涵盖了 MVK、TNFRSF1A 和 NLRP3 基因的所有外显子。共检测到 48 个变体。NGS 组的“指标患者变异检出率”高于 Sanger 测序组（19% 对 15.1%）。对于变异阳性患者，建立了详细的基因型-表型表。在 PFS 中，一般人群甚至家庭内部的基因型和表型之间缺乏相关性。在某些情况下，突变表现不同并产生意想不到的表型。在这项研究中，我们讨论了我们在 MVK、TNFRSF1A 和 NLRP3 基因中检测到的八种不同变体的临床效果。其中四个先前在 PFS 患者中被发现。其余四种在 PFS 患者中未报告。因此，我们必须通过分析它们的频率和计算机分析预测来解释它们的临床效果。我们建议需要新的研究来更清楚地评估这些变体的影响。为了能够证明更清晰的基因型-表型关系，所有 PFS 相关基因应一起分析，并应考虑多基因遗传的可能性。