PDF(Pubmed)
Abstract：
Monogenic autoinflammatory diseases (AID) encompass a growing group of inborn errors of the innate immune system causing unprovoked or exaggerated systemic inflammation. Diagnosis of monogenic AID requires an accurate description of the patients\' phenotype, and the identification of highly penetrant genetic variants in single genes is pivotal. We performed whole exome sequencing (WES) of 125 pediatric patients with suspected monogenic AID in a routine genetic diagnostic setting. Datasets were analyzed in a step-wise approach to identify the most feasible diagnostic strategy. First, we analyzed a virtual gene panel including 13 genes associated with known AID and, if no genetic diagnosis was established, we then analyzed a virtual panel including 542 genes published by the International Union of Immunological Societies associated including all known inborn error of immunity (IEI). Subsequently, WES data was analyzed without pre-filtering for known AID/IEI genes. Analyzing 13 genes yielded a definite diagnosis in 16.0% (n = 20). The diagnostic yield was increased by analyzing 542 genes to 20.8% (n = 26). Importantly, expanding the analysis to WES data did not increase the diagnostic yield in our cohort, neither in single WES analysis, nor in trio-WES analysis. The study highlights that the cost- and time-saving analysis of virtual gene panels is sufficient to rapidly confirm the differential diagnosis in pediatric patients with AID. WES data or trio-WES data analysis as a first-tier diagnostic analysis in patients with suspected monogenic AID is of limited benefit.
摘要：
单基因自身炎性疾病（AID）包括越来越多的先天免疫系统的先天性错误，导致无端或过度的全身性炎症。单基因AID的诊断需要准确描述患者的表型，在单个基因中鉴定高度渗透的遗传变异是关键的。我们在常规遗传诊断环境中对125例疑似单基因AID的儿科患者进行了全外显子组测序（WES）。以逐步方法分析数据集以确定最可行的诊断策略。首先,我们分析了一个虚拟基因组，包括与已知AID相关的13个基因，如果没有基因诊断，然后,我们分析了一个虚拟小组,该小组包括由国际免疫学会联合会发表的542个相关基因,包括所有已知的先天性免疫错误(IEI).随后，分析WES数据而不对已知AID/IEI基因进行预过滤。分析13个基因在16.0％（n=20）中获得了明确的诊断。通过分析542个基因,诊断产量增加到20.8%(n=26)。重要的是,将分析扩展到WES数据并没有增加我们队列的诊断率，在单一的WES分析中都没有，在三重WES分析中也是如此。该研究强调，虚拟基因面板的成本和时间节省分析足以快速确认AID儿科患者的鉴别诊断。WES数据或三联WES数据分析作为疑似单基因AID患者的一级诊断分析的益处有限。
