{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T03:34:39Z","timestamp":1784691279281,"version":"3.55.0"},"reference-count":20,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,8,20]],"date-time":"2022-08-20T00:00:00Z","timestamp":1660953600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["VENI grant number 016.196.107"],"award-info":[{"award-number":["VENI grant number 016.196.107"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004752","name":"State Government of Victoria","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004752","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007747","name":"University of Utah","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007747","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015079","name":"ARUP Laboratories","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015079","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001794","name":"University of Queensland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001794","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:p>NOTCH1 belongs to the NOTCH family of proteins that regulate cell fate and inflammatory responses. Somatic and germline <jats:italic>NOTCH1<\/jats:italic> variants have been implicated in cancer, Adams\u2010Oliver syndrome, and cardiovascular defects. We describe 7 unrelated patients grouped by the presence of leukoencephalopathy with calcifications and heterozygous de novo gain\u2010of\u2010function variants in <jats:italic>NOTCH1<\/jats:italic>. Immunologic profiling showed upregulated CSF IP\u201010, a cytokine secreted downstream of NOTCH1 signaling. Autopsy revealed extensive leukoencephalopathy and microangiopathy with vascular calcifications. This evidence implicates that heterozygous gain\u2010of\u2010function variants in <jats:italic>NOTCH1<\/jats:italic> lead to a chronic central nervous system (CNS) inflammatory response resulting in a calcifying microangiopathy with leukoencephalopathy<jats:italic>.<\/jats:italic> ANN NEUROL 2022;92:895\u2013901<\/jats:p>","DOI":"10.1002\/ana.26477","type":"journal-article","created":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T14:46:14Z","timestamp":1660142774000},"page":"895-901","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Heterozygous <scp><i>NOTCH1<\/i><\/scp> Variants Cause <scp>CNS<\/scp> Immune Activation and Microangiopathy"],"prefix":"10.1002","volume":"92","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4784-7423","authenticated-orcid":false,"given":"Guy","family":"Helman","sequence":"first","affiliation":[{"name":"Murdoch Children's Research Institute, The Royal Children's Hospital  Victoria Australia"},{"name":"Institute for Molecular Bioscience, The University of Queensland  Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parand","family":"Zarekiani","sequence":"additional","affiliation":[{"name":"Department of Pathology Amsterdam University Medical Centers, VU University Amsterdam and Amsterdam Neuroscience  Amsterdam HV The Netherlands"},{"name":"Amsterdam Leukodystrophy Center Emma Children's Hospital, Amsterdam University Medical Centers  Amsterdam DD The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha A.M.","family":"Tromp","sequence":"additional","affiliation":[{"name":"Department of Pediatric Immunology, Rheumatology and Infectious Disease Emma Children's Hospital, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam  Amsterdam DD The Netherlands"},{"name":"Department of Experimental Immunology Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, University of Amsterdam  Amsterdam DD The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Andrews","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics University of Utah  Salt Lake City UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo D.","family":"Botto","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics University of Utah  Salt Lake City UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8775-147X","authenticated-orcid":false,"given":"Joshua L.","family":"Bonkowsky","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology, Department of Pediatrics University of Utah  Salt Lake City UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Chassevent","sequence":"additional","affiliation":[{"name":"Division of Neurogenetics Kennedy Krieger Institute  Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Giorgio","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia Italy"},{"name":"Medical Genetics Unit IRCCS Mondino Foundation  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Pippucci","sequence":"additional","affiliation":[{"name":"U.O. 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