Monogenic autoinflammatory disorders: streamlining the identification and validation of novel variants and exploring the phenotypic variability of disease.

Monogenic autoinflammatory disorders (AIDs) are a group of rare conditions caused by inappropriate activation or lack of regulation of the innate immune system. There has been an increase in the number of AIDs described in the past decade, providing insight into different innate immune pathways in both health and disease. These diagnoses have been made with the use of next generation sequencing, namely whole exome and now whole genome sequencing. The techniques have introduced or highlighted a number of deficiencies in our current approach to these conditions. The first is our ability to appropriately model variants that may be contributing to disease- that is, how we confirm that a variant is pathogenic and causing disease. Secondly, the broadening of phenotype of the patients described suggests that the trope that autoinflammatory conditions affect the innate immune system alone does not acknowledge the intimate link between the innate and adaptive immune system, and that both may be perturbed in AIDs. This study aims to develop techniques to model novel variants in relevant human cells using CRISPR/Cas9 gene editing techniques and iPSCs. Furthermore, it aims to investigate the phenotypic spectrum seen in patients with AIDs using in vitro modelling as well as patient clinical, biochemical, immunological and genetic data.
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