IFIH1 was first reported in relation to autosomal dominant type 1 interferonopathy in 2014 (Rice et al., PMID 24686847). Variants in IFIH1 have been reported with the following disease entities: Aicardi-Goutieres syndrome and Singleton-Merten syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern or phenotypic variability between the two disease entities. Therefore, Aicardi-Goutieres syndrome and Singleton-Merten syndrome have been lumped into one disease entity, “IFIH1-related type 1 interferonopathy” (MONDO:0700262). Type 1 interferonopathies are defined as conditions in which increased type 1 interferon signaling leads to autoimmune and neurological disorders. These disorders are caused by variants in genes involved in nucleic acid metabolism, sensing, and the innate immune response. Individuals with variants in IFIH1 can present with a range of symptoms of variable severity and age of onset, within the context of an autoimmune disease. At least 44 pathogenic or likely pathogenic variants have been reported in humans. These variants have mostly been missense, although some nonsense and frameshift variants have also been reported. Evidence supporting this gene-disease relationship includes case level, segregation, and experimental data.
Summary of Case Level Data: 12 POINTS. Variants in this gene have been reported in at least 17 probands in 5 publications (PMIDs 24686847, 24995871, 25620204, 30219631, 31898846). Variants in this gene segregated with disease in 9 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. The mechanism for disease is gain of function. This gene-disease relationship is supported by expression studies in vitro and in zebrafish (PMIDs 25620204, 38077314). In summary, there is definitive evidence to support the relationship between IFIH1 and autosomal dominant type 1 interferonopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy Gene Curation Expert Panel on the meeting date 07/22/2024 (SOP Version #10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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