Aicardi-Goutières Syndrome 7 and Singleton-Merton Syndrome 1 via the IFIH1 Gene

Aicardi-Goutières Syndrome 7 is a phenotypically heterogeneous inflammatory disorder linked to inappropriate upregulation of Type I interferon. The symptoms can appear similar to those of neonatal Aicardi-Goutières Syndrome 1, which include irritability, hepatomegaly with elevated liver enzymes, and thrombocytopenia. In one alternate form of the disease, developmental progress is normal until 13-15 months of age, at which point rapid neurological regression occurs. A third type of the condition involves only spastic paraparesis, with adult patients displaying normal neuroimaging (Rice et al. 2014). A heightened state of inflammation affecting blood vessels, teeth and bones is present in Singleton-Merton syndrome 1 (SMS1). This rare autosomal dominant disorder can cause severe childhood aortic and valvular calcification, dental anomalies and skeletal abnormalities such as osteoporosis and osteolysis. Less commonly, affected individuals may have generalized muscle weakness, psoriasis, early onset glaucoma, and particular facial features. (Feigenbaum et al. 2013).

An atypical form of Aicardi-Goutieres Syndrome (Aicardi-Goutieres 7) and SMS1 are both caused by autosomal dominant pathogenic variants in IFIH1. This gene encodes a cytoplasmic protein that senses double-stranded viral RNAs and mediates an immune activation. Heterozygous IFIH1 missense variants have been detected in 15 individuals from 13 families with atypical Aicardi-Goutieres syndrome (Crow et al. 2015; Rice at al. 2009; Oda et al. 2014). Most IFIH1 variants are located within the Hel1 and Hel2 helicase domains of the IFIH1 protein. Functional studies indicate that the variants are gain of function variants because they confer an induction of interferon activity that is consistently higher than in mutation-negative family members. Testing of parental samples demonstrated that the pathogenic variants arose de novo in the majority of patients. In one family, a mutation positive father with an affected son was not clinically affected, a finding that indicates that IFIH1 pathogenic variants may not be fully penetrant.

Whole exome sequencing identified a unique IFIH1 missense variant in a patient with SMS1. This variant was also located in the Hel2 helicase domain, displayed an autosomal dominant mode of transmission, and was linked to upregulation of interferon. Sanger sequencing identified the presence of this variant in additional family members of the proband and in two other SMS1 families. In one family, the IFIH1 pathogenic variant appeared to have arisen de novo. In two other SMS1 families, no unaffected member was found to possess the pathogenic variant, and the pathogenic variant segregated with the disorder, though disease symptoms and severity differed among affected family members. (Rutch et al 2015). The clinical variability in Aicardi-Goutières Syndrome 7 and SMS1 families suggests that external factors such as differential pathogen exposure or other genetic or epigenetic influences may modify the penetrance of IFIH1 pathogenic variants. A separate clinical disorder, Singleton-Merton syndrome 2, shares many clinical features with SMS1 but is linked to pathogenic variants in DDX58. The protein product of DDX58 also functions as an double-stranded RNA sensor that up regulates type 1 interferon through the same pathway as IFIH1 (Jang et al. 2015).

The observation of the inflammatory nature of IFIH1 gain of function pathogenic variants suggests that the pathology of the associated disorders is progressive. Early treatment may therefore result in disease attenuation. Antibodies targeted against interferon alpha subtypes and the type I interferon receptor are in clinical trials for a related immune disorder (Crow et al. 2013).

Approximately 3% of Aicardi-Goutières Syndrome is due to heterozygous missense variants in the IFIH1 gene (Crow et al. 2015). It is difficult to estimate the clinical sensitivity of sequencing for Singleton-Merton Syndrome 1. It is a rare disorder with only three index cases reported in the literature. For these cases, the causative variants were all detectable by sequencing. Due to the heterogeneity of clinical features, the prevalence of IFIH1 pathogenic variants in the population is currently unknown.

This test provides full coverage of all coding exons of the IFIH1 gene 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 full 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).