Submission Details

Autosomal dominant

03/04/2020

The IFIH1 gene is located on chromosome 2 at 2q24.2 and encodes the interferon induced with helicase C domain 1 protein which is associated with innate immunity. This protein identifies and attaches to double stranded RNA from certain viruses, forming a filament which stimulates the induction of interferon and proinflammatory cytokines. The IFIH1 gene was first reported in relation to autosomal dominant Aicardi-Goutieres syndrome in 2014 (24686847: Rice et al. 2014). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least five unique missense variants in this gene have been reported in at least three publications (24686847: Rice et al. 2014; 24995871: Oda et al. 2014; 30219631: Adang et al. 2018). Most variants were confirmed to be de novo; however, in one case the variant was inherited from a clinically asymptomatic father (24686847: Rice et al. 2014). The maximum score for genetic evidence has been reached. This gene-disease relationship is supported by functional alteration in non-patient and patient cells demonstrating disease-associated IFIH1 variants result in excessive interferon signalling, suggesting gain-of-function as the disease mechanism (24686847: Rice et al. 2014). Homozygous knockout mice show impaired interferon signalling in response to picornavirus infection (16625202: Kato et al. 2006). In summary, IFIH1 is definitively associated with Aicardi-Goutieres syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

24686847 24995871 30219631 16625202