Background/Purpose

The role of IL-1 in the pathogenesis of many of the monogenic autoinflammatory diseases is clinically validated by the response to IL-1 blocking therapies. However, patients who are unresponsive to IL-1 blocking therapy have more recently been identified.  We have identified mutations in proteasome components as the cause of CANDLE syndrome and a mutation affecting IFN beta secretion as the cause for a severe vasculopathy and lung disease, SAVI. CANDLE and SAVI patients do not respond to IL-1 inhibition and consistently demonstrate marked up-regulation of IFN-inducible genes. These data suggest that autoinflammatory phenotypes can also be caused by IFN signaling dysregulation. 

Methods

Total RNA was extracted from total blood collected in PaxGene tubes and RNA sequencing was performed using HiSeq 2000 Illumina® platform (Illumina). Blood DNA was extracted and whole exome sequencing was performed using human exome capture by Agilent V4 (51Mbp) exome enrichment kit, followed by next generation sequencing using Illumina HiSeq2000. 

Results

Using RNA sequencing we have identified a group of 11 patients with markedly differentially expression of IFN inducible genes. WES was performed in 8 patients and parents (trios) and in 3 individual patients in order to identify genetic defects affecting the IFN signaling pathway. Seven probands were female and 4 were male; 4 probands were Hispanic, 2 were Asian and 1 proband was Caucasian, Israeli, Azerbaijani, Iranian and Norwegian, respectively. All patients presented with immunodysregulatory phenotypes with clinical similarities to the previously described interferonopathies, including skin vasculitis/vasculopathy, panniculitis, myositis and basal ganglion calcifications, but did not have a genetic diagnosis identified prior to evaluation at the NIH. The bioinformatics variant annotation, analysis and filtering workflow has allowed us to successfully identify de novo mutations in IFN-regulating genes in 2 of the 8 trios. In one patient, we found a disease causing de novo and somatic mutation in TREX1. This patient also presented with an in-frame deletion in DHX9 inherited from her mother and a missense mutation in MAVS inherited from her father. In one patient, we identified a de novo mutation in DHX9 and this patient was also a compound heterozygous for mutations in IFIH1/MDA5. In a third patient, we found a missense mutation in TREX1 inherited from the mother and a heterozygous variant in MB21D1 (gene encoding cGAS) was detected in one patient. For this last patient, parental samples are not available yet for evaluation of inheritance. All mutations described were confirmed by Sanger sequencing.

Conclusion

RNA sequencing and genetic analysis can be an important tool for the identification of patients with an IFN signature and guide the search for disease causing variants in IFN-regulating genes by WES. These preliminary findings need to be validated in larger groups of patients. The validation of the pathogenic role for interferon dysregulation in patients with autoinflammatory phenotypes may lead to the identification of a clinical subset with poor IL-1 responses that may respond to targeted therapies that block the IFN signaling pathways.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-autoinflammatory-interferonopathies-a-new-class-of-autoinflammatory-conditions/