Laboratory of FMF, Amyloidosis and Rare Autoinflammatory Diseases, Heller Institute, Sheba Medical Center, Tel Hashomer, Israel.
UOC Medical Genetics, IRCCS Istituto Giannina Gaslini, Genova, Italy.
Clin Chem. 2020 Apr 1;66(4):525-536. doi: 10.1093/clinchem/hvaa024.
Monogenic autoinflammatory diseases are caused by pathogenic variants in genes that regulate innate immune responses, and are characterized by sterile systemic inflammatory episodes. Since symptoms can overlap within this rapidly expanding disease category, accurate genetic diagnosis is of the utmost importance to initiate early inflammation-targeted treatment and prevent clinically significant or life-threatening complications. Initial recommendations for the genetic diagnosis of autoinflammatory diseases were limited to a gene-by-gene diagnosis strategy based on the Sanger method, and restricted to the 4 prototypic recurrent fevers (MEFV, MVK, TNFRSF1A, and NLRP3 genes). The development of best practices guidelines integrating critical recent discoveries has become essential.
The preparatory steps included 2 online surveys and pathogenicity annotation of newly recommended genes. The current guidelines were drafted by European Molecular Genetics Quality Network members, then discussed by a panel of experts of the International Society for Systemic Autoinflammatory Diseases during a consensus meeting.
In these guidelines, we combine the diagnostic strength of next-generation sequencing and recommendations to 4 more recently identified genes (ADA2, NOD2, PSTPIP1, and TNFAIP3), nonclassical pathogenic genetic alterations, and atypical phenotypes. We present a referral-based decision tree for test scope and method (Sanger versus next-generation sequencing) and recommend on complementary explorations for mosaicism, copy-number variants, and gene dose. A genotype table based on the 5-category variant pathogenicity classification provides the clinical significance of prototypic genotypes per gene and disease.
These guidelines will orient and assist geneticists and health practitioners in providing up-to-date and appropriate diagnosis to their patients.
单基因自身炎症性疾病是由调节固有免疫反应的基因中的致病性变异引起的，其特征为无菌性全身炎症发作。由于此类疾病的症状可能存在重叠，因此准确的基因诊断对于启动早期炎症靶向治疗和预防具有临床意义的或危及生命的并发症至关重要。最初，自身炎症性疾病的遗传诊断仅限于基于 Sanger 方法的逐个基因诊断策略，且仅限于 4 种典型复发性发热（MEFV、MVK、TNFRSF1A 和 NLRP3 基因）。整合关键最新发现的最佳实践指南的制定已变得至关重要。
准备步骤包括 2 项在线调查和新推荐基因的致病性注释。当前指南由欧洲分子遗传学质量网络成员起草，然后在国际系统性自身炎症性疾病学会的专家小组的共识会议上进行讨论。
在这些指南中，我们结合了下一代测序和对 4 个最近发现的基因（ADA2、NOD2、PSTPIP1 和 TNFAIP3）的诊断优势，非典型致病性遗传改变和非典型表型。我们提出了一种基于转诊的测试范围和方法（Sanger 与下一代测序）决策树，并建议对嵌合体、拷贝数变异和基因剂量进行补充探索。基于 5 类变异致病性分类的基因型表提供了每个基因和疾病的典型基因型的临床意义。
这些指南将为遗传学家和医疗保健从业者提供指导和帮助，以便为其患者提供最新和适当的诊断。
