PDF(Pubmed)
Abstract：
Cryopyrin-associated periodic syndrome or NLRP3-associated autoinflammatory disease (NLRP3-AID) and NLRP12-AID are both Mendelian disorders with autosomal dominant inheritance. Both diseases are rare, primarily reported in the pediatric population, and are thought to be phenotypically indistinguishable. We provide the largest cohort of adult-onset patients and compared these diseases and the gene variant frequency to population controls.
A cohort of adult patients with AIDs were retrospectively studied. All underwent molecular testing for periodic fever syndrome gene panels after extensive and negative workups for systemic autoimmune and other related diseases. Patients were divided into Group 1- NLRP3-AID patients with NLRP3 variants (N=15), Group 2- NLRP12-AID with NLRP12 variants (N=14) and Group 3- both NLRP3 and NLRP12 (N=9) variants. Exome sequence data of two large control populations including the ARIC study were used to compare gene variant distribution and frequency.
All 38 patients were Caucasian with women accounting for 82%. Median age at diagnosis was 41 ± 23 years and the disease duration at diagnosis was 14 ± 13 years. We identified statistically significant differences between the groups, notably that gastrointestinal symptoms as well as evaluations for same were significantly more frequent in patients with NLRP12 variants, and headaches/dizziness were less common among the NLRP12 patients. Livedo reticularis was noted in four patients, exclusively among NLRP12 carriers. Over 50% of patients in Groups 1 and 2 carry low-frequency disease-associated variants, while the remaining carry rare variants. We unprecedently identified digenic variants, i.e., the coexistence of NLRP3 and NLRP12, which were either both low frequency or low frequency/rare. Allele frequencies of all variants identified in our cohort were either absent or significantly lower in the control populations, further strengthening the evidence of susceptibility of these variants to SAID phenotypes.
Our comparative study shows that both NLRP3-AID and NLRP12-AID share similar clinical phenotypes, yet there are significant differences between them with regard to gastrointestinal and neurological symptoms. A spectrum of high to low genetic variations in both genes can contribute to SAID individually or in combination.
A cohort of adult patients with AIDs were retrospectively studied. All underwent molecular testing for periodic fever syndrome gene panels after extensive and negative workups for systemic autoimmune and other related diseases. Patients were divided into Group 1- NLRP3-AID patients with NLRP3 variants (N=15), Group 2- NLRP12-AID with NLRP12 variants (N=14) and Group 3- both NLRP3 and NLRP12 (N=9) variants. Exome sequence data of two large control populations including the ARIC study were used to compare gene variant distribution and frequency.
All 38 patients were Caucasian with women accounting for 82%. Median age at diagnosis was 41 ± 23 years and the disease duration at diagnosis was 14 ± 13 years. We identified statistically significant differences between the groups, notably that gastrointestinal symptoms as well as evaluations for same were significantly more frequent in patients with NLRP12 variants, and headaches/dizziness were less common among the NLRP12 patients. Livedo reticularis was noted in four patients, exclusively among NLRP12 carriers. Over 50% of patients in Groups 1 and 2 carry low-frequency disease-associated variants, while the remaining carry rare variants. We unprecedently identified digenic variants, i.e., the coexistence of NLRP3 and NLRP12, which were either both low frequency or low frequency/rare. Allele frequencies of all variants identified in our cohort were either absent or significantly lower in the control populations, further strengthening the evidence of susceptibility of these variants to SAID phenotypes.
Our comparative study shows that both NLRP3-AID and NLRP12-AID share similar clinical phenotypes, yet there are significant differences between them with regard to gastrointestinal and neurological symptoms. A spectrum of high to low genetic variations in both genes can contribute to SAID individually or in combination.
摘要：
■Cryopyrin相关周期性综合征或NLRP3相关自身炎症性疾病(NLRP3-AID)和NLRP12-AID都是常染色体显性遗传的孟德尔疾病。这两种疾病都很罕见,主要在儿科人群中报道，并且被认为在表型上无法区分。我们提供了最大的成年发病患者队列，并将这些疾病和基因变异频率与人群对照进行了比较。
■对一组AIDs成年患者进行了回顾性研究。在对全身性自身免疫性疾病和其他相关疾病进行广泛和阴性检查后，所有患者均接受了周期性发热综合征基因面板的分子检测。患者分为1组NLRP3-AID患者NLRP3变异（N=15），具有NLRP12变体(N=14)的组2-NLRP12-AID和组3-NLRP3和NLRP12变体(N=9)。包括ARIC研究在内的两个大型对照群体的外显子组序列数据用于比较基因变异分布和频率。
■38例患者均为白种人，女性占82%。诊断时的中位年龄为41±23岁，诊断时的病程为14±13岁。我们确定了两组之间的统计学差异，值得注意的是，在患有NLRP12变异的患者中，胃肠道症状及其评估明显更频繁，头痛/头晕在NLRP12患者中不太常见。在四名患者中发现了网状Livedo，仅在NLRP12运营商中。在第1组和第2组中，超过50%的患者携带低频疾病相关变异，而其余的携带罕见的变体。我们发现了前所未有的双基因变异，即，NLRP3和NLRP12共存，两者均为低频或低频/罕见。在我们的队列中鉴定的所有变体的等位基因频率在对照群体中不存在或显著较低,进一步加强了这些变体对SAID表型的易感性的证据。
■我们的比较研究表明，NLRP3-AID和NLRP12-AID具有相似的临床表型，然而，在胃肠道和神经系统症状方面，它们之间存在显着差异。两种基因中的高至低遗传变异谱可单独或组合地促成SAID。
■对一组AIDs成年患者进行了回顾性研究。在对全身性自身免疫性疾病和其他相关疾病进行广泛和阴性检查后，所有患者均接受了周期性发热综合征基因面板的分子检测。患者分为1组NLRP3-AID患者NLRP3变异（N=15），具有NLRP12变体(N=14)的组2-NLRP12-AID和组3-NLRP3和NLRP12变体(N=9)。包括ARIC研究在内的两个大型对照群体的外显子组序列数据用于比较基因变异分布和频率。
■38例患者均为白种人，女性占82%。诊断时的中位年龄为41±23岁，诊断时的病程为14±13岁。我们确定了两组之间的统计学差异，值得注意的是，在患有NLRP12变异的患者中，胃肠道症状及其评估明显更频繁，头痛/头晕在NLRP12患者中不太常见。在四名患者中发现了网状Livedo，仅在NLRP12运营商中。在第1组和第2组中，超过50%的患者携带低频疾病相关变异，而其余的携带罕见的变体。我们发现了前所未有的双基因变异，即，NLRP3和NLRP12共存，两者均为低频或低频/罕见。在我们的队列中鉴定的所有变体的等位基因频率在对照群体中不存在或显著较低,进一步加强了这些变体对SAID表型的易感性的证据。
■我们的比较研究表明，NLRP3-AID和NLRP12-AID具有相似的临床表型，然而，在胃肠道和神经系统症状方面，它们之间存在显着差异。两种基因中的高至低遗传变异谱可单独或组合地促成SAID。
