ADAR

Inheritance Pattern: AR

Disease ID:MONDO:0014007

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014007

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0010080

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between ADAR and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of April 20, 2020. The ADAR gene encodes RNA-specific adenosine deaminase, an RNA editing enzyme that catalyzes the deamination of adenosine to inosine in double-stranded RNA. Defects in this process result in an upregulation of interferon response. As such, pathogenic variants in ADAR were initially reported to cause an interferonopathy, Aicardi-Goutieres syndrome type 6. Pathogenic variants in ADAR have been associated with Leigh syndrome spectrum (detailed below), however the diagnosis is often made based on imaging findings alone therefore metabolic laboratory testing required as part of the Leigh syndrome spectrum definition is often not performed, so many reported cases could not be curated for Leigh syndrome spectrum. The ADAR gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2019 (PMID: 31772029). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four unique variants identified in two cases from two publications (PMIDs: 31772029, 30692772). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function, expression, and model systems (PMIDs: 27977873, 25613900, 11099415, 26275108). In summary, there is limited evidence to support this gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on April 20, 2020 (SOP Version 7).

Inheritance Pattern: AD

Disease ID:MONDO:0007483

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0014007

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0700261

Submitter: ClinGen

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.

Inheritance Pattern: AD

Disease ID:MONDO:0007483

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0007483

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0014007

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0007483

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0014007

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0007483

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0018866

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0700261

Submitter: ClinGen

*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).