ADAR was first suspected to be associated with autosomal dominant type 1 interferonopathy in 2003 when Zhang et al. (PMID: 12713580) identified the location of the gene via genome wide scanning and two point linkage analysis in two families with dyschromatosis symmetrica hereditaria. In 2009, Hartner et al. (PMID: 19060901) proposed the role of ADAR in type I interferon-inducible transcripts. In 2012 Rice et al. (PMID: 23001123) described the role of ADAR in the suppression of type I interferon (IFN) signaling in autosomal dominant presentations of Aicardi–Goutières syndrome and the phenotype was expanded.
The described autosomal dominant ADAR phenotypes are considered forms of type 1 interferonopathy, which is defined as a condition in which increased type 1 interferon signaling leads to autoimmune and neurological disorders (MONDO:0700261). Therefore, the following disease entities have been lumped into one disease entity: Aicardi–Goutières syndrome, dyschromatosis symmetrica hereditaria (OMIM: 127400), and bilateral striatal necrosis (not listed on OMIM). The split curation for autosomal recessive ADAR and ADAR-related type 1 interferonopathy has been curated separately by the Brain Malformations GCEP.
Seven variants reported in ten probands across six publications (PMIDs: 28561207, 25982145, 24262145, 37770123, 32911246, 18705826), including one publication of case-level segregation data (PMID: 12916015), are included in this curation. The mechanism of pathogenicity appears to be loss of function, however, some suggest that a specific ADAR variant, c.3019G>A (p.G1007R), confers a dominant negative effect (PMIDs: 19713932, 23001123, 28561207). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by experimental evidence including biochemical function, non-human model organism(s), and functional alteration in non-patient cells (PMIDs: 19060901, 38190734).
In summary, there is definitive evidence supporting the relationship between ADAR and autosomal dominant ADAR-related 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 and Leukoencephalopathy GCEP on the meeting date April 29th, 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).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.