{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T16:33:22Z","timestamp":1775320402475,"version":"3.50.1"},"reference-count":20,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T00:00:00Z","timestamp":1752796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Heterozygous pathogenic variants in <jats:italic>ADAR<\/jats:italic> have been associated with dyschromatosis symmetrica hereditaria, while biallelic pathogenic variants have been associated with Aicardi-Gouti\u00e8res syndrome 6 (AGS6). However, the heterozygous variant c.3019G&amp;gt;A, (p.Gly1007Arg) has been described to cause neurological manifestations, which resemble AGS6 and are associated with an upregulation of interferon-stimulated genes. We report a four-generation family with two symptomatic family members and five unaffected carriers of the heterozygous pathogenic <jats:italic>ADAR<\/jats:italic> variant c.3019G&amp;gt;A. The index (patient 1) manifested a gait disorder at three years of age (weakness in his legs, a tendency to fall and hyperreflexia), dyslalia, and mild cognitive developmental delay. A paternal half-brother (patient 4) to patient\u00b4s father (patient 2) presented with irritability and regression of previous skills at the age of 6 months after a fever reaction, following the second routine hexavalent vaccination at the age of 4 months. At 20 years of age, the patient was wheelchair-bound, had spasticity and severe global development delay. A blood test in both patients showed increased interferon signature with activation of type 1-interferon. Five asymptomatic carriers were identified in this family (age range 2\u201381 years of age) nearly all of them (except the 81-year old patient) showed a strong activation of type 1 interferon response in peripheral blood. Affected individuals had higher interferon signature than asymptomatic, underlining the possible role of interferon activation in disease mechanism. To our knowledge, this is the biggest family reported to date, encompassing a wide age-range of carriers, including an asymptotic carrier of advanced age (81 years of age).<\/jats:p>","DOI":"10.3389\/fimmu.2025.1453496","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T06:19:55Z","timestamp":1752819595000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Case Report: Heterozygous ADAR c.3019G&gt;A pathogenic variant associated with variable neurological symptoms and incomplete penetrance in a four-generational family"],"prefix":"10.3389","volume":"16","author":[{"given":"Ann-Kathrin","family":"Bauer","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iris","family":"Marquardt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benedikt","family":"Sundermann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Wolf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrin","family":"Raupach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathrin","family":"Grundmann-Hauser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Gieldon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maximilian","family":"Otterbach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Maurer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tobias","family":"Haack","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min Ae","family":"Lee-Kirsch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georg-Christoph","family":"Korenke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc-Phillip","family":"Hitz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1038\/nri.2016.78","article-title":"Discriminating self from non-self in nucleic acid sensing","volume":"16","author":"Schlee","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/wrna.1322","article-title":"ADAR1, inosine and the immune sensing system: distinguishing self from non-self. Wiley interdisciplinary reviews","volume":"7","author":"Liddicoat","year":"2016","journal-title":"RNA"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2527","DOI":"10.1084\/jem.20161596","article-title":"Type I interferon\u2013mediated monogenic autoinflammation: The type I interferonopathies, a conceptual overview","volume":"213","author":"Rodero","year":"2016","journal-title":"J Exp Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2414","article-title":"Mutations in ADAR1 cause Aicardi-Gouti\u00e8res syndrome associated with a type I interferon signature","volume":"44","author":"Rice","year":"2012","journal-title":"Nat Genet"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1346-8138.2012.01661.x","article-title":"Dyschromatosis symmetrica hereditaria","volume":"40","author":"Hayashi","year":"2013","journal-title":"J Dermatol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1136\/jmedgenet-2013-102038","article-title":"A type I interferon signature identifies bilateral striatal necrosis due to mutations inADAR1","volume":"51","author":"Livingston","year":"2013","journal-title":"J Med Genet"},{"key":"B7","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1136\/jmedgenet-2019-106457","article-title":"Cardiac valve involvement in ADAR-related type I interferonopathy","volume":"57","author":"Crow","year":"2019","journal-title":"J Med Genet"},{"key":"B8","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1055\/s-0037-1601449","article-title":"Genetic, phenotypic, and interferon biomarker status in ADAR1-related neurological disease","volume":"48","author":"Rice","year":"2017","journal-title":"Neuropediatrics"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.braindev.2021.10.001","article-title":"Autosomal dominant ADAR c.3019G>A (p.(G1007R)) variant is an important mimic of hereditary spastic paraplegia and cerebral palsy","volume":"44","author":"Jones","year":"2022","journal-title":"Brain Dev (Tokyo 1979)"},{"key":"B10","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1212\/WNL.0000000000002228","article-title":"Neuroradiologic patterns and novel imaging findings in Aicardi-Gouti\u00e8res syndrome","volume":"86","author":"La Piana","year":"2016","journal-title":"Neurology"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3174\/ajnr.A1694","article-title":"Aicardi-goutieres syndrome: neuroradiologic findings and follow-up","volume":"30","author":"Uggetti","year":"2009","journal-title":"Am J Neuroradiol: AJNR"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1111\/j.1346-8138.2008.00540.x","article-title":"Dyschromatosis symmetrica hereditaria associated with neurological disorders","volume":"35","author":"Kondo","year":"2008","journal-title":"J Dermatol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/mds.21011","article-title":"Dystonia, mental deterioration, and dyschromatosis symmetrica hereditaria in a family withADAR1 mutation","volume":"21","author":"Tojo","year":"2006","journal-title":"Movement Disord"},{"key":"B14","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.ymgme.2020.03.008","article-title":"Development of a neurologic severity scale for Aicardi Gouti\u00e8res Syndrome","volume":"130","author":"Adang","year":"2020","journal-title":"Mol Genet Metab"},{"key":"B15","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1111\/dmcn.14268","article-title":"Treatments in aicardi\u2013gouti\u00e8res syndrome","volume":"62","author":"Crow","year":"2019","journal-title":"Dev Med Child Neuro"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-023-01500-z","article-title":"JAK inhibition in aicardi-gouti\u00e8res syndrome: a monocentric multidisciplinary real-world approach study","volume":"43","author":"Fr\u00e9mond","year":"2023","journal-title":"J Clin Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/j.0022-202X.2005.23732.x","article-title":"Mutation analysis of the ADAR1 gene in dyschromatosis symmetrica hereditaria and genetic differentiation from both dyschromatosis universalis hereditaria and acropigmentatio reticularis","volume":"124","author":"Suzuki","year":"2005","journal-title":"J Invest Dermatol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1002\/ajmg.a.36887","article-title":"Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1","volume":"167","author":"Crow","year":"2015","journal-title":"Am J Med Genet Part A"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2020.08.039","article-title":"Movement disorders in ADAR1 disease: Insights from a comprehensive cohort","volume":"79","author":"Di Lazzaro","year":"2020","journal-title":"Parkinsonism Relat Disord"},{"key":"B20","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1007\/s10875-023-01438-2","article-title":"Clinical non-penetrance associated with biallelic mutations in the RNase H2 complex","volume":"43","author":"Crow","year":"2023","journal-title":"J Clin Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1453496\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T06:19:57Z","timestamp":1752819597000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1453496\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,18]]},"references-count":20,"alternative-id":["10.3389\/fimmu.2025.1453496"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1453496","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,18]]},"article-number":"1453496"}}