Abstract：
Familial cold autoinflammatory syndrome (FCAS) is the mildest subtype of cryopyrin-associated periodic syndrome (CAPS) and is a rare inherited systemic autoinflammatory disease (SAID). CAPS is the consequence of a rare group of genetic disorders that are mostly reported in European and American populations, but scarcely reported in Chinese populations. NLRP3, NLRP12, PLCG2, and NLRC4 are known pathogenic genes associated with FCAS, and the aim of this study was to identify pathogenic mutations in two intact pedigrees of Chinese FCAS. We performed Sanger sequencing of genomic DNA samples from 25 affected and 32 unaffected members of the two intact pedigrees and analyzed the pathogenic mutations for their conservativeness using multiple sequence alignment tools. In addition, we reviewed previously reported pathogenic genes of FCAS and their pathogenicity classification and summarized the characteristics of different genotypes and phenotypes of FCAS. This study reported two intact FCAS pedigrees with different genotypes and phenotypes, the heterozygous mutation (p.V72M) in NLRP3 in pedigree 1 and the heterozygous mutation (p.R754H) in NLRP12 in pedigree 2. There are no reports targeting p.V72M in NLRP3 in FCAS1, and there are relatively few relevant phenotypic data on the clinical manifestations identified in previous pedigrees. Multiple sequence comparisons of NLRP3 indicate that the p.V72M mutation is highly conserved during evolution. Our study has enriched the understanding of the pathogenesis of FCAS, a rare disease especially in Asian populations. KEY POINTS: •The NLRP3 (p.V72M) variant was first discovered in the Chinese pedigree of FCAS1 •NLRP12 (p.R754H) variants are not conserved in multiple sequence alignments, but they are still co-segregated and expressed in the big Chinese diseased pedigree.
摘要：
家族性冷自身炎症综合征（FCAS）是低温比林相关周期性综合征（CAPS）的最温和亚型，是一种罕见的遗传性系统性自身炎症疾病（SAID）。CAPS是一组罕见的遗传性疾病的结果，这些疾病主要在欧洲和美国人群中报道，但在中国人口中几乎没有报道。NLRP3，NLRP12，PLCG2和NLRC4是已知的与FCAS相关的致病基因，这项研究的目的是在两个完整的中国FCAS家系中鉴定致病性突变。我们对来自两个完整家系的25个受影响成员和32个未受影响成员的基因组DNA样品进行了Sanger测序，并使用多种序列比对工具分析了致病性突变的保守性。此外,我们回顾了以前报道的FCAS的致病基因及其致病性分类，并总结了FCAS的不同基因型和表型的特征。这项研究报告了两个完整的FCAS家系，具有不同的基因型和表型，杂合突变（p。V72M）在家系1中的NLRP3和杂合突变（p。R754H)在NLRP12家系中2。在FCAS1的NLRP3中没有针对p.V72M的报道，并且在以前的家谱中确定的临床表现的相关表型数据相对较少。NLRP3的多个序列比较表明p.V72M突变在进化过程中是高度保守的。我们的研究丰富了对FCAS发病机制的认识,一种罕见的疾病，特别是在亚洲人群中。关键点：•NLRP3（p。V72M）变体首次在FCAS1•NLRP12的中国家系中发现（p。R754H）变体在多序列比对中不保守，但它们仍然是共同分离的，并在中国大病谱系中表达。
