ADAR was first reported in relation to type 1 interferonopathy in 2012 when it was found to be associated with Aicardi-Goutieres syndrome (AGS) (Rice et al., PMID: 23001123), a form of type 1 interferonopathy. Type 1 interferonopathies are defined as conditions in which increased type 1 interferon signaling leads to autoimmune and neurological disorders (MONDO:0700261). ADAR-related type 1 interferonopathies are seen in both the autosomal recessive and autosomal dominant forms. The autosomal dominant forms of ADAR-related type 1 interferonopathy have been curated separately.
There are 7 missense, 3 frameshift, and 1 nonsense variants that have been reported in 10 probands in 3 publications (PMIDs: 23001123, 24262145, 29221912) included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by rescue studies, protein-protein interactions, and animal models (PMIDs: 26275108, 29022589, 34772697).
In summary, there is definitive evidence supporting the relationship between ADAR and ADAR-related type 1 interferonopathy, including autosomal recessive Aicardi Goutieres syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
The original curation of the association of ADAR with autosomal recessive Aicardi-Goutieres syndrome (AGS) was approved by the ClinGen Brain Malformations GCEP on the meeting date December 12th, 2023 (SOP Version 9). This gene-disease validity curation was transferred to the Leukodystrophy and Leukoencephalopathy GCEP on October 23, 2024, at which time the disease entity was changed from “autosomal recessive Aicardi Goutieres syndrome” to the more broad disease entity of “autosomal recessive ADAR-related type 1 interferonopathy,” consistent with other genes that are involved in causing type 1 interferonopathies.
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.