Clinical and genetic heterogeneity among Spanish patients with recurrent autoinflammatory syndromes associated with the CIAS1/PYPAF1/NALP3 gene
Clinical and genetic heterogeneity among Spanish patients with recurrent autoinflammatory syndromes associated with the CIAS1/PYPAF1/NALP3 gene
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DOI：
10.1002/art.20633
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发表时间：
2004-12-01
影响因子：
--
通讯作者：
Yagüe, J
中科院分区：
文献类型：
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作者：
Aróstegui, JI;Aldea, A;Yagüe, J
客观的。旨在调查 7 个不相关的西班牙家系中 CIAS1/PYPAF1/NALP3 基因的参与情况，这些家系患有复发性自身炎症性疾病，其特征为早发、反复发热和慢性荨麻疹皮疹，其中怀疑临床诊断为冷吡蛋白相关周期性综合征 (CAPS)。 方法。 7个家庭成员的临床症状、实验室分析结果和既往治疗数据均记录在针对遗传性自身炎症性疾病的问卷中。通过聚合酶链反应扩增 CLAS1/PYPAF1/NALP3 基因的所有编码区和内含子侧翼边界并测序。结果。在 7 个受影响家族中的 5 个家族中，在 CIAS1/PYPAF1/NALP3 基因的外显子 3 中发现了 5 个不同的错义突变，包括 2 个从头突变和 1 个先前未报告的突变 (R488K)。对健康个体的扩展遗传分析发现，两个家庭存在不完全外显率。 3 名慢性婴儿神经、皮肤、关节 (CINCA) 综合征/新生儿多系统炎症性疾病 (NOMID) 患者中，有 2 名未发现突变。结论。临床数据提示 3 个家庭诊断为家族性寒冷诱发的自身炎症综合征，另外 3 个家庭诊断为 CINCA/NOMID 综合征，可能诊断为 Muckle-Wells 综合征，而突变分析显示 5 个家庭存在不同的 CLaS1/PYPAF1/NALP3 错义突变。这些数据与这些疾病的共同分子基础一致，并强调了 CIAS1/PYPAF1/NALP3 基因相关综合征之间的表型异质性。在两个家族中发现的先前未报告的突变和不完全外显率扩大了这些自身炎症综合征的遗传基础。这些发现应该提醒临床医生，即使在没有家族史的情况下，这些疾病可能存在遗传基础，以试图建立准确的诊断和最佳的治疗方法。
Objective. To investigate the involvement of the CIAS1/PYPAF1/NALP3 gene in 7 unrelated Spanish families with recurrent autoinflammatory diseases characterized by early onset, recurrent fever, and a chronic urticarial rash, in whom a clinical diagnosis of cryopyrin-associated periodic syndromes (CAPS) is suspected.Methods. Clinical symptoms, results of laboratory analyses, and data on previous treatments in members of the 7 families were recorded on a questionnaire specific for hereditary autoinflammatory diseases. All coding regions and intronic flanking boundaries of the CLAS1/PYPAF1/NALP3 gene were amplified by polymerase chain reaction and sequenced.Results. Five different missense mutations, including 2 de novo and 1 previously unreported mutation (R488K), were identified in exon 3 of the CIAS1/ PYPAF1/NALP3 gene in 5 of the 7 affected families. Expanded genetic analysis among the healthy individuals identified incomplete penetrance in 2 families. No mutations were found in 2 of the 3 patients with chronic infantile neurologic, cutaneous, articular (CINCA) syndrome/neonatal-onset multisystern inflammatory disease (NOMID).Conclusion. The clinical data suggested a diagnosis of familial cold-induced autoinflammatory syndrome in 3 families, CINCA/NOMID syndrome in 3 others, and a possible Muckle-Wells syndrome, whereas mutational analysis showed different CLaS1/PYPAF1/NALP3 missense mutations in 5 families. These data are consistent with a common molecular basis of these diseases and highlights the phenotypic heterogeneity among CIAS1/ PYPAF1/NALP3 gene-associated syndromes. The previously unreported mutation and the incomplete penetrance found in 2 families expand the genetic basis underlying these autoinflammatory syndromes. These findings should alert clinicians to the possible genetic basis of these conditions, even in the absence of a family history, in their attempts to establish an accurate diagnosis and the optimal therapeutic approach.