We explore a novel interferon (IFN) gene expression score in a cohort of subjects with genetically determined Aicardi-Goutières Syndrome (AGS).

AGS is a rare interferonopathy characterized by neurologic disability and multi-organ autoinflammation. It is caused by mutations in genes involved in the recognition of intracellular nucleic acids (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1 and IFIH1).

NanoString nCounter™ Digital Analyzer measured expression of 25 IFN-stimulated genes in blood. Z score calculation of gene expression normalized to a standard aliquot allows for semi-quantitative analysis compared to a normative sample (elevated is > 1.96). Specimens were obtained at three distinct time points in 54 subjects. IFN scores were assessed using Anova with Tukey’s multiple comparisons for variables: gene, gender, duration since onset and motor impairment defined by Gross Motor Functional Classification Score (GMFCS). 

IFN scores were increased across 47/54 subjects (0.14 years to 21.45 years). Means ranged from 3.5 to 54.4 (SEM 0.5-12.2, proportional to the elevation). IFN scores were measured over a median of 0.14 years, with at least 2-week intervals over 4-6 weeks. There was no correlation of IFN scores with gender or GMFCS. IFN scores did not decrease with greater disease duration, and indeed there was a trend to higher scores in patients with longer disease length (p=0.01). Genotype as a variable, excluding RNASEH2A and RNASEH2C for low sample size, showed a statistically significant decrease in RNASEH2B (p<0.01) and a trend to higher levels in IFIH1 (p=0.052) relative to the remainder of the cohort. 

IFN scores were elevated across genotypes of AGS, although RNASEH2B were lower than other genotypes. No significant association between motor function and IFN score was identified, and IFN scores continued to be elevated beyond 20 years since disease onset. IFN score is a robust marker associated with AGS disease regardless of disease length or severity.