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Many patients exhibit immunotherapy-responsiveness, indicative of immune dysregulation as a potential underlying etiology. While hypotheses are emerging regarding the role of interferon signaling in DSRD and other autoimmune conditions associated with DS, it is unclear why a small subset of individuals with DS develop DSRD. The aim of this study was to investigate genes of immune regulation in persons with DSRD.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>This study included individuals with DSRD aged 10\u201330\u00a0years with trio exome sequencing performed during the diagnostic work up. Descriptive statistics and univariate analysis (Chi-square and Fisher\u2019s exact test) were used to describe and compare the characteristics of individuals with and without variants.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Forty-one individuals with DSRD had trio exome sequencing results. Eight (20%) had heterozygous de novo variants of immune regulatory genes, with four variants being pathogenic or likely pathogenic (<jats:italic>UNC13D, XIAP, RNASEH2A, and DNASE1L3<\/jats:italic>). All genes harboring pathogenic variants were associated with interferon type-1 inflammatory response. Individuals harboring variants were more likely to have a preceding trigger (<jats:italic>p<\/jats:italic>\u2009=\u20090.03, 95% CI 1.21\u201397.06), rapid clinical decline in less than 1\u00a0month (<jats:italic>p<\/jats:italic>\u2009=\u20090.01, 95% CI 1.67\u201352.06), and MRI abnormalities (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001, 95% CI 4.89\u2013527.71).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Discussion<\/jats:title>\n                <jats:p>A distinct subset of individuals with DSRD exhibited pathogenic variants in immune regulation genes associated with interferon-mediated inflammatory response, coinciding with previously established links between these genes and interferonopathies such as Aicardi-Goutieres syndrome. Our observations suggest that these variants might potentially contribute to the development of DSRD in individuals with DS.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00415-024-12521-y","type":"journal-article","created":{"date-parts":[[2024,6,22]],"date-time":"2024-06-22T16:01:34Z","timestamp":1719072094000},"page":"5567-5576","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["De novo variants in immune regulatory genes in Down syndrome regression disorder"],"prefix":"10.1007","volume":"271","author":[{"given":"Saba","family":"Jafarpour","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhik K.","family":"Banerjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mellad M.","family":"Khoshnood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin N.","family":"Vogel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie K.","family":"Boyd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Partridge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie L.","family":"Santoro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace Y.","family":"Gombolay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen S.","family":"Fisher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego Real","family":"de Asua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Carmen","family":"del Ortega","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathy","family":"Franklin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Rafii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8350-8234","authenticated-orcid":false,"given":"Jonathan D.","family":"Santoro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,22]]},"reference":[{"key":"12521_CR1","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/gim.2016.15","volume":"18","author":"G de Graaf","year":"2016","unstructured":"de Graaf G, Buckley F, Skotko BG (2016) Live births, natural losses, and elective terminations with Down syndrome in Massachusetts. 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