Submission Details

IFNAR1 was first reported in relation to autosomal recessive immunodeficiency 106, susceptibility to viral infections in 2019 (Hernandez N, et al., 2019, PMID: 31270247). IFNAR1 encodes one of the 2 chains of the receptor of type I interferons. The predicted effect of IFNAR1 deficiency is to prevent signaling and downstream functional responses to type I interferons but leave intact responses to type II and III. IFNAR1 deficiency predisposes to disease following live attenuated viral vaccine, but also to Herpes Simplex Encephalitis and severe COVID-19. Genetic evidence was included in this curation from 8 probands in 6 publications (PMIDs: 31270247, 32960813, 33252644, 32972995, 35091979, 35442418). The proposed mechanism of disease is loss of function and the nine reported variants include missense, splice site, nonsense, and full exon deletions. There is no in vivo evidence of susceptibility to viral infections in healthy carriers. Experimentally, this gene-disease relationship is supported by its function as a receptor of type I interferons (PMID: 2153461). Functional alteration in patient cells resulted in major defects in type I IFN signaling (PMIDs: 31270247, 32960813, 33252644, 32972995) and inability to surpress viral replication, which could be rescued with WT IFNAR1 (PMIDs: 31270247, 33252644, 32972995). Additionally, a null mouse model recapitulates diesase with increased susceptibility to viral infection (PMID: 7479980). In summary, there is Definitive evidence to support this gene-disease relationship. This has been repeatedly demonstrated in both research and the clinical diagnostic setting and has been upheld over time.