Best Practices for Diagnosing Systemic Autoinflammatory Diseases

Updated guidelines reflect broad use of next-generation sequencing, newly identified causative genes, and evolved understanding of inheritance patterns for rare diseases with overlapping symptoms.
Widespread implementation of next-generation sequencing (NGS) methods, along with identification of new genes associated with and a new understanding of inheritance patterns for systemic autoinflammatory diseases (SAIDs), led the International Society of Systemic Auto-Inflammatory Diseases (ISSAID) and The European Molecular Genetics Quality Network to update guidelines on diagnosing SAIDs.
The best practice guidelines, which appear in the April issue of Clinical Chemistry, also offer information for healthcare practitioners and geneticists to appropriately diagnose and administer inflammation-targeted treatments. In addition, the guidelines help to draw proper conclusions about DNA variants for SAIDs—such as whether or not to consider a certain genotype confirmatory for disease, Marielle van Gjin, PhD, of the University of Groningen’s Department of Genetics in the Netherlands, and the corresponding author of the guidelines. “Approximately 1,300 DNA variants in the eight genes have been classified by experts, and a consensus interpretation has been made publicly available, helping nonexpert laboratories with the interpretation of genetic test results.”
SAIDs include familial Mediterranean fever, deficiency of ADA2, haploinsufficiency of A20, mevalonate kinase deficiency, cryopyrin-associated periodic syndromes, pyogenic arthritis, pyoderma gangrenosum and acne, PSTPIP1-associated myeloid-related proteinemia inflammatory, and TNF receptor-associated periodic syndrome. SAIDs are associated with a variety of symptoms, including fever, serositis, skin lesions, arthralgia/arthritis, acute abdominal pain, and at times, central nervous system lesions. Symptoms can overlap among SAIDs, however, underscoring the importance of using genetic testing to accurately diagnose a patient’s condition, initiate early treatment, and prevent serious complications.
Four hereditary recurrent fevers (HRFs) associated with the genes MEFV, MVK, TNFRSF1A, and NLRP3 were the first group identified among monogenic SAIDs. They have “provided an insight into SAIDs physiopathology. A common defect is dysregulation and/or overactivation of intracellular pathways of innate immune cells,” wrote the guideline authors.
Previous guidelines from 2012 were based on the four most classic genes causing HRFs, identified through Sanger sequencing, said van Gjin. The rise in NGS, however, has shown an association between HRFs and unexpected phenotypes, nonclassical modes of inheritance, and postzygotic variants.
“Nowadays, most laboratories use the NGS sequencing technique for the simultaneous screening of multiple genes,” van Gjin explained. “This, next to diagnosing more patients, also results in more patients being identified with variants of unknown significance and/or common variants in multiple genes.” In addition to new genes and DNA variants, novel modes of inheritance and increased genetic and allelic heterogeneity has made genetic testing for SAIDs complex, which could lead to ambiguous or misleading conclusions, she added. This called for a reassessment of the genetic diagnostic protocol.
The new guidelines developed by European Molecular Genetics Quality Network members were presented before a panel of experts of the ISSAID during a consensus meeting. Based on the experience of many experts and the type of disease-causing mutations detected in the different genes, the panelists “proposed a decision tree to help labs decide which strategy to choose for an efficient genetic test and to avoid unnecessary detection of DNA variants of unknown clinical significance,” van Gjin said.
The new guidelines reflect the use of NGS technology and recommendations about four newly identified genes of importance in SAIDs: ADA2, NOD2, PSTPIP1, and TNFAIP3. The authors also contemplate nonclassical pathogenic genetic alterations and atypical phenotypes.
Several important discoveries accompany these new guidelines. Copy-number variations, for example, have been known to contribute to MVK, ADA2, and TNFAIP3. For this reason, “they should be considered for those disorders when no or only one mutation can be detected,” van Gjin said.