Clinical Chemistry 2020;66 (4):525-536
Monogenic autoinflammatory diseases are caused by pathogenic variants in genes that regulate innate immune responses. These conditions are characterised by sterile systemic inflammatory episodes. Because symptoms often overlap within this rapidly expanding disease category, accurate genetic diagnosis is essential to initiate early inflammation-targeted treatment and prevent serious or life-threatening complications.
Initial recommendations for diagnosing autoinflammatory diseases relied on a gene-by-gene strategy using the Sanger method, limited to four prototypic recurrent fever genes: MEFV, MVK, TNFRSF1A, and NLRP3. With recent discoveries, the development of updated best practice guidelines has become critical.
Methods: Preparatory steps included two online surveys and pathogenicity annotation of newly recommended genes. The current guidelines were drafted by members of the European Molecular Genetics Quality Network, and discussed during a consensus meeting with experts from the International Society for Systemic Autoinflammatory Diseases.
These guidelines integrate the diagnostic power of next-generation sequencing and expand recommendations to four additional genes: ADA2, NOD2, PSTPIP1, and TNFAIP3. They also address nonclassical pathogenic alterations and atypical phenotypes. A referral-based decision tree guides test scope and method (Sanger vs. next-generation sequencing), with recommendations for exploring mosaicism, copy-number variants, and gene dosage.
A genotype table based on a five-category variant pathogenicity classification outlines the clinical significance of prototypic genotypes per gene and disease. These guidelines aim to support geneticists and healthcare practitioners in delivering accurate, up-to-date diagnoses for patients with autoinflammatory diseases.
