OBJECTIVE Autoinflammatory diseases (AIDs) are characterized by recurrent sterile systemic inflammation attacks. More than half of the patients remain genetically undiagnosed with next-generation sequencing panels for common AIDs. In this study, we aimed to define phenotype-genotype correlations in a cohort of unclassified AID patients via whole exome sequencing (WES). METHODS Patients with features of AIDs were included in this study followed in the Department of Pediatric Rheumatology at Hacettepe University. They were first screened for MEFV with Sanger sequencing and then WES performed for the patients with clinically insignificant results. Pre-analysis of WES data was done by considering the 13 most common AID-related genes. Further bioinformatic analysis was performed if the patient remained genetically undiagnosed. RESULTS The median age at disease onset was 1.2 years (range 0.2-16) and at the time of study recruitment was 14 years (range 3.5-17). In our cohort, WES provided a definite or probable disease-causing variant in 4 of 11 patients (36%). Heterozygous mutations for two of these genes were previously associated with neurological defects (ADAM17, TBK1), also homozygous ADAM17 mutations were observed in one family with neonatal inflammatory skin and bowel disease. Besides, two genes (LIG4, RAG1) were associated with immunodeficiency although the patients had presented with inflammatory features. Finally, for one patient, we associated a strong candidate gene (NLRC3) with autoinflammatory features. CONCLUSION WES strategy is cost-effective and provides substantial results for a selected group of undefined AID patients. Our results will contribute to the spectrum of unclassified AIDs.

中文翻译：

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未分类自身炎症性疾病中的全外显子组测序：更多单基因疾病正在研发中？

目的 自身炎症性疾病 (AID) 的特征是复发性无菌全身性炎症发作。超过一半的患者仍未通过下一代常见 AID 测序面板进行基因诊断。在这项研究中，我们旨在通过全外显子组测序 (WES) 在一组未分类的 AID 患者中定义表型 - 基因型相关性。方法 本研究包括具有 AID 特征的患者，随后在 Hacettepe 大学小儿风湿病学系进行随访。他们首先用 Sanger 测序筛查 MEFV，然后对临床上无显着结果的患者进行 WES。WES 数据的预分析是通过考虑 13 个最常见的 AID 相关基因来完成的。如果患者仍未被基因诊断，则进行进一步的生物信息学分析。结果 发病时的中位年龄为 1.2 岁（范围 0.2-16），研究招募时的中位年龄为 14 岁（范围 3.5-17）。在我们的队列中，WES 在 11 名患者中的 4 名 (36%) 中提供了明确或可能的致病变异。其中两个基因的杂合突变以前与神经缺陷（ADAM17、TBK1）有关，在一个患有新生儿炎症性皮肤和肠道疾病的家庭中也观察到了纯合 ADAM17 突变。此外，尽管患者具有炎症特征，但有两个基因（LIG4、RAG1）与免疫缺陷有关。最后，对于一名患者，我们将一个强候选基因 (NLRC3) 与自身炎症特征相关联。结论 WES 策略具有成本效益，并为选定的一组未定义的 AID 患者提供了实质性的结果。