The classification, genetic diagnosis and modelling of monogenic autoinflammatory disorders

Abstract

Monogenic autoinflammatory disorders are an increasingly heterogeneous group of conditions characterised by innate immune dysregulation. Improved genetic sequencing in recent years has led not only to the discovery of a plethora of conditions considered to be ‘autoinflammatory’, but also the broadening of the clinical and immunological phenotypic spectra seen in these disorders. This review outlines the classification strategies that have been employed for monogenic autoinflammatory disorders to date, including the primary innate immune pathway or the dominant cytokine implicated in disease pathogenesis, and highlights some of the advantages of these models. Furthermore, the use of the term ‘autoinflammatory’ is discussed in relation to disorders that cross the innate and adaptive immune divide. The utilisation of next-generation sequencing (NGS) in this population is examined, as are potential in vivo and in vitro methods of modelling to determine pathogenicity of novel genetic findings. Finally, areas where our understanding can be improved are highlighted, such as phenotypic variability and genotype–phenotype correlations, with the aim of identifying areas of future research.

Positive Impact of Expert Reference Center Validation on Performance of Next-Generation Sequencing for Genetic Diagnosis of Autoinflammatory Diseases

“…All coding exons and intronic borders of 55 genes (Table S1) were screened. All the known AIDs genes at the time of the design of the panel were selected [1,17]. Some candidates’ genes presented at our biennial international congress of AIDs were also added (Table S1).…”

“…Monogenic autoinflammatory diseases (AIDs) are characterized by variants in genes coding proteins involved in innate immunity [1]. Inflammatory episodes are either systemic, generally associated with an increase in acute phase reactants, and/or organ-specific.…”

“…Since the discovery in 1997 of the first gene MEFV (Mediterranean fever (MIM 608107)), responsible for familial Mediterranean fever (FMF), more than 40 new known genetically defined AIDs have been identified, notably by high-throughput sequencing approaches (Table S1) [1,3,4,5]. The significant expansion of clinical features and genes involved in AIDs has challenged the utility of these approaches in routine diagnosis and supplanted the ‘gold standard’ Sanger sequencing.…”

“…Because of the somewhat phenotypic similarity between the different AIDs (recurrent fever, arthralgia, abdominal pain, skin rash, etc. ), formulating an initial diagnostic hypothesis is sometimes difficult, especially for physicians unfamiliar with this group of rare diseases [1]. Hence, preliminary advice from expert clinicians might help improve the performance of targeted NGS for a diagnosis of AIDs.…”

β-Glucan–induced reprogramming of human macrophages inhibits NLRP3 inflammasome activation in cryopyrinopathies

“…26). Interestingly, the first described monogenic autoinflammatory diseases, now classified as inflammasomopathies, are linked to mutations in inflammasome components (29,30). Inflammasomes are molecular platforms that form to mediate the activation of caspase-1, a cysteine protease responsible for the processing and release of the proinflammatory cytokines IL-1β and IL-18 (31,32).…”