BACKGROUND: Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused 
by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, 
and ADAR). The disease is severe and effective treatments are urgently needed. 
We investigated the status of interferon-related biomarkers in patients with AGS 
with a view to future use in diagnosis and clinical trials.
METHODS: In this case-control study, samples were collected prospectively from 
patients with mutation-proven AGS. The expression of six interferon-stimulated 
genes (ISGs) was measured by quantitative PCR, and the median fold change, when 
compared with the median of healthy controls, was used to create an interferon 
score for each patient. Scores higher than the mean of controls plus two SD 
(>2·466) were designated as positive. Additionally, we collated historical data 
for interferon activity, measured with a viral cytopathic assay, in CSF and 
serum from mutation-positive patients with AGS. We also undertook neutralisation 
assays of interferon activity in serum, and looked for the presence of 
autoantibodies against a panel of interferon proteins.
FINDINGS: 74 (90%) of 82 patients had a positive interferon score (median 12·90, 
IQR 6·14-20·41) compared with two (7%) of 29 controls (median 0·93, IQR 
0·57-1·30). Of the eight patients with a negative interferon score, seven had 
mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this 
gene). Repeat sampling in 16 patients was consistent for the presence or absence 
of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 
147 patients) was negatively correlated with age (CSF, r=-0·604; serum, 
r=-0·289), and was higher in CSF than in serum in 104 of 136 paired samples. 
Neutralisation assays suggested that measurable antiviral activity was related 
to interferon α production. We did not record significantly increased 
concentrations of autoantibodies to interferon subtypes in patients with AGS, or 
an association between the presence of autoantibodies and interferon score or 
serum interferon activity.
INTERPRETATION: AGS is consistently associated with an interferon signature, 
which is apparently sustained over time and can thus be used to differentiate 
patients with AGS from controls. If future studies show that interferon status 
is a reactive biomarker, the measurement of an interferon score might prove 
useful in the assessment of treatment efficacy in clinical trials.
FUNDING: European Union's Seventh Framework Programme; European Research 
Council.