Aicardi-Goutières Syndrome Panel

Aicardi-Goutiéres syndrome (AGS) is a rare, early-onset progressive encephalopathy typically characterized by basal ganglia calcification, white matter abnormalities, and cerebral atrophy (Crow and Livingston 2008; Crow and Manel 2015). Affected individuals can present with progressive microcephaly, hypotonia, dystonia, seizures, spastic quadriplegia, and severe developmental delay (Crow 2014). Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, and systemic lupus erythematosus are also associated with the AGS spectrum of disease (Crow et al. 2015). Cerebrospinal fluid analyses show lymphocytosis and increased type I interferon activity. AGS individuals are often misdiagnosed with congenital infections due to similar presentation. Onset can occur in utero (~25%), while the majority of patients present within the first year of life (~70%) (Crow et al. 2015). Recently, six interferon-stimulated genes were measured and found to be useful biomarkers in most AGS patients (Rice et al. 2013).

AGS is an inflammatory disease that occurs due to pathogenic variants in the ADAR, IFIH1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and TREX1 genes (Crow et al. 2015). Each of these seven genes encode proteins that are involved in nucleotide metabolism/signaling. The innate immune response is likely triggered by endogenously-derived nucleic acids that are not processed correctly and are immunostimulatory (Rice et al. 2013; Crow and Manel 2015). TREX1 encodes a DNA 3' repair exonuclease I. RNASEH2A, RNASEH2B, and RNASEH2C encode three components of the RNase H2 endonuclease complex. SAMHD1 encodes a SAM and HD domain containing protein that functions as a deoxynucleoside triphosphate triphosphohydrolase. ADAR1 encodes an enzyme that catalyzes the hydrolytic deamination of adenosine to inosine in double-stranded RNA. IFIH1 encodes an RNA receptor that activates type I interferon signaling (Crow and Manel 2015).

The majority of AGS cases are inherited in an autosomal recessive manner. Pathogenic variants in the RNASEH2A, RNASEH2B, RNASEH2C, and SAMHD1 are inherited in an autosomal recessive manner, while variants in the ADAR and TREX1 genes can exhibit both autosomal recessive and dominant inheritance (Crow et al. 2015). Dominant disease causing variants in TREX1 include Asp18Asn and Asp200Asn and in ADAR, Gly1007Arg (Crow et al. 2015). IFIH1 pathogenic variants are inherited in an autosomal dominant manner and many times occur de novo (Rice et al. 2014; Oda et al. 2014).

ADAR pathogenic variants for AGS include missense and small deletions. ADAR variants can also be causative for dyschromatosis symmetrica hereditaria and include missense, nonsense, splicing, and small deletions and insertions. Missense, nonsense, splicing, and small insertions or deletions are found in the other genes in this panel (Human Gene Mutation Database). The RNASEH2B and SAMHD1 genes also have a small number of reported gross deletions that are not detectable by sequencing.

In a recent comprehensive study of 374 patients (299 families) with a molecular diagnosis of AGS, pathogenic variants were found in the following percentages: 23% TREX1, 5% RNASEH2A, 36% RNASEH2B, 12% RNASEH2C, 13% SAMHD1, 7% ADAR, and 3% IFIH1 (Crow et al. 2015). Clinical sensitivity was found to be around 90% before the identification of the additional causative gene IFIH1 (Crow 2014). Therefore, clinical sensitivity for patients with clinical and radiologic findings consistent with AGS will be greater than 90%. Analytical sensitivity should be high, since only a few large deletions/duplications in the relevant genes have been reported.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).