Autoinflammatory diseases comprise a wide range of syndromes caused by dysregulation of the innate immune response. They are difficult to diagnose due to their phenotypic heterogeneity and variable expressivity. Thus, the genetic origin of the disease remains undetermined for an important proportion of patients. We aim to identify causal genetic variants in patients with suspected autoinflammatory disease and to test the advantages and limitations of the clinical exome gene panels for molecular diagnosis. Twenty-two unrelated patients with clinical features of autoinflammatory diseases were analyzed using clinical exome sequencing (~4800 genes), followed by bioinformatic analyses to detect likely pathogenic variants. By integrating genetic and clinical information, we found a likely causative heterozygous genetic variant in NFKBIA (p.D31N) in a North-African patient with a clinical picture resembling the deficiency of interleukin-1 receptor antagonist, and a heterozygous variant in DNASE2 (p.G322D) in a Spanish patient with a suspected lupus-like monogenic disorder. We also found variants likely to increase the susceptibility to autoinflammatory diseases in three additional Spanish patients: one with an initial diagnosis of juvenile idiopathic arthritis who carries two heterozygous UNC13D variants (p.R727Q and p.A59T), and two with early-onset inflammatory bowel disease harbouring NOD2 variants (p.L221R and p.A728V respectively). Our results show a similar proportion of molecular diagnosis to other studies using whole exome or targeted resequencing in primary immunodeficiencies. Thus, despite its main limitation of not including all candidate genes, clinical exome targeted sequencing can be an appropriate approach to detect likely causative variants in autoinflammatory diseases.

自身炎症性疾病包括由先天免疫反应失调引起的多种综合症。由于它们的表型异质性和可变表达性，因此难以诊断。因此，对于大部分患者来说，该疾病的遗传起源仍未确定。我们旨在鉴定可疑的自身炎症性疾病患者的因果遗传变异，并测试用于分子诊断的临床外显子组的优势和局限性。使用临床外显子组测序（〜4800个基因）对22例具有自身炎症性疾病临床特征的不相关患者进行了分析，随后进行了生物信息学分析以检测可能的致病变异。通过整合遗传和临床信息，我们发现了可能的致病性杂合遗传变异北部非洲患者的NFKBIA（p.D31N），其临床表现类似于白细胞介素1受体拮抗剂的缺乏，而西班牙患者患有疑似狼疮样单基因疾病，其DNASE2杂合子变体（p.G322D）。我们还发现另外三名西班牙患者中的变体可能会增加对自身炎性疾病的易感性：一名初诊断为幼年特发性关节炎的人携带两个杂合的UNC13D变体（p.R727Q和p.A59T），以及两个患有早发性炎症携带NOD2的肠道疾病变体（分别为p.L221R和p.A728V）。我们的结果显示，与在原发性免疫缺陷中使用全外显子组或靶向重测序的其他研究相比，分子诊断的比例与其他研究相似。因此，尽管其主要局限性在于不包括所有候选基因，但临床外显子组靶向测序仍是检测自身炎性疾病中可能的致病变异的合适方法。