Current and future advances in genetic testing in systemic autoinflammatory diseases

Abstract

Systemic autoinflammatory diseases (SAIDs) are a group of inflammatory disorders caused by dysregulation in the innate immune system that leads to enhanced immune responses. The clinical diagnosis of SAIDs can be difficult since individually these are rare diseases with considerable phenotypic overlap. Most SAIDs have a strong genetic background, but environmental and epigenetic influences can modulate the clinical phenotype. Molecular diagnosis has become essential for confirmation of clinical diagnosis. To date there are over 30 genes and a variety of modes of inheritance that have been associated with monogenic SAIDs. Mutations in the same gene can lead to very distinct phenotypes and can have different inheritance patterns. In addition, somatic mutations have been reported in several of these conditions. New genetic testing methods and databases are being developed to facilitate the molecular diagnosis of SAIDs, which is of major importance for treatment, prognosis and genetic counselling. The aim of this review is to summarize the latest advances in genetic testing for SAIDs and discuss potential obstacles that might arise during the molecular diagnosis of SAIDs.

A comprehensive interaction study provides a potential domain interaction network of human death domain superfamily proteins

“…Mutations of NLRP3 that lead to constitutive activation of the inflammasome cause an autoinflammatory disease called cryopyrin-associated periodic syndrome [ 8 , 9 ]. Many autoinflammatory diseases are regarded as rare diseases, with few patients, and their pathogenesis has not been fully elucidated [ 10 , 11 ].…”

Anakinra and canakinumab for patients with R92Q-associated autoinflammatory syndrome: a multicenter observational study from the AIDA Network

“…A recent concept hypothesizes a synergic pro-inflammatory function of R92Q in a context of oligogenic transmission, intermediate in the continuum from monogenic to multifactorial polygenic inheritance: the affected individual would inherit multiple low-frequency allele variants that act synergistically in determining the clinical picture. 53 …”

Management of Monogenic IL-1 Mediated Autoinflammatory Diseases in Childhood

“…The reported diagnostic yield of comprehensive gene testing panels seems to range between 21 and 32% ( 51 , 52 ). Whole exome sequencing (WES) should be considered in patients with negative panel testing to improve the diagnostic yield preferably using a family-based trio approach ( 53 ). In addition, WES enables the discovery of novel variants in known AID genes and in those not yet associated with diseases.…”

“…In addition, WES enables the discovery of novel variants in known AID genes and in those not yet associated with diseases. Whole genome sequencing (WGS) can identify deep intronic variants and mutations in non-coding regulatory regions and therefore increases the diagnostic yield ( 53 ). Additionally, it allows a much more reliable identification of copy number variations compared with WES ( 53 ).…”