Department of Bioinformatics, Institute of Health Sciences, Ankara, Turkey.
Faculty of Medicine, Department of Medical Genetics, Ankara, Turkey.
Rheumatology (Oxford). 2021 Feb 1;60(2):607-616. doi: 10.1093/rheumatology/keaa165.
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).
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.
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.
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.
自身炎症性疾病（AIDs）的特征是反复发作的无菌性全身炎症发作。超过一半的患者在进行常见 AIDs 的下一代测序（NGS）面板检测后仍未发现遗传诊断。在这项研究中，我们旨在通过全外显子组测序（WES）定义未分类 AID 患者队列中的表型-基因型相关性。
本研究纳入了具有 AIDs 特征的患者，他们在哈塞特佩大学儿科风湿病科就诊。他们首先进行 Sanger 测序以筛查 MEFV，然后对临床意义不大的患者进行 WES。在进行 WES 数据分析之前，先考虑了 13 个最常见的与 AID 相关的基因。如果患者仍然无法进行基因诊断，则进行进一步的生物信息学分析。
疾病发病的中位年龄为 1.2 岁（范围 0.2-16 岁），研究招募时的中位年龄为 14 岁（范围 3.5-17 岁）。在我们的队列中，WES 在 11 名患者中的 4 名（36%）提供了明确或可能的致病变异。其中两个基因（ADAM17、TBK1）的杂合突变先前与神经缺陷有关，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，两个基因（LIG4、RAG1）与免疫缺陷有关，尽管这些患者表现出炎症特征。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。
WES 策略对于选定的未分类 AID 患者群体是具有成本效益的，并提供了大量的结果。我们的研究结果将有助于未分类 AIDs 的研究。
