{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T05:11:53Z","timestamp":1778130713855,"version":"3.51.4"},"reference-count":34,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:00:00Z","timestamp":1778025600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:00:00Z","timestamp":1778025600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004690","name":"Minist\u00e8re de la Sant\u00e9","doi-asserted-by":"publisher","award":["PHRC AOR 02\u2010001"],"award-info":[{"award-number":["PHRC AOR 02\u2010001"]}],"id":[{"id":"10.13039\/501100004690","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR\u201019\u2010P3IA\u20100001"],"award-info":[{"award-number":["ANR\u201019\u2010P3IA\u20100001"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Despite its monogenic origin, Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy exhibits marked variability in clinical expression and severity. Variants in the NOTCH3 gene, within epidermal growth factor\u2010like repeat domains 1\u20136 or 7\u201334, are known to influence disease onset, but their impact on long\u2010term progression remains unclear. This study assesses mutation location effects on post\u2010first stroke clinical trajectories.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Clinical data from a large cohort were analyzed (Patients EGFR 1\u20136 mutation group\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009210 and 7\u201334 mutation group\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009116) with target emulated trial framework. To study the impact of mutation location on stroke recurrence, disability (modified Rankin score \u2265\u20093) and mortality, following a first stroke event. Propensity score matching was used to balance covariates between mutation location groups and principal stratification to consider truncation by death. Events occurrence differences were compared using Restricted Mean Survival Time at 2, 5, 10 and 15\u2009years.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      At first stroke, patients with mutation in domains 1\u20136 were younger than those in the 7\u201334 mutation group (49.51\u2009\u00b1\u20097.4 vs. 55.00\u2009\u00b1\u20097.4\u2009years). Ten years after first stroke event, mortality occurred slightly later in the 7\u201334 group (9.63 [9.33\u20139.92] vs. 9.11 [8.71\u20139.52] years,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.04), also at 15\u2009years (14.0 [13.42\u201314.63] vs. 12.4 [11.62\u201313.24] years;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.002). Second stroke occurrence did not differ between groups. Time beyond modified Rankin of 3 slightly differed between groups at 5 and 10\u2009years, with a difference of 0.22 [0.01\u20130.044] and 0.72 [0.14\u20131.30] year respectively (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.044 and 0.017).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Although NOTCH3 variants location influences the delay to the first stroke, it has no or little impact on the recurrence of stroke, risk of disability and death after the first stroke manifestation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.70424","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T04:24:33Z","timestamp":1778127873000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical Impact of\n                    <scp>NOTCH3<\/scp>\n                    Variant Location After First Stroke in\n                    <scp>CADASIL<\/scp>"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7835-4525","authenticated-orcid":false,"given":"L\u00e9a","family":"Aguilhon","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9, Institut du Cerveau\u2014Paris Brain Institute\u2014ICM, CNRS, Inria, Inserm, AP\u2010HP, H\u00f4pital de la Piti\u00e9 Salp\u00eatri\u00e8re  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8436-6074","authenticated-orcid":false,"given":"Hugues","family":"Chabriat","sequence":"additional","affiliation":[{"name":"GENOVASC, INSERM U1127 Paris Brain Institute (Institut du Cerveau\u2014ICM)  Paris France"},{"name":"Centre de R\u00e9f\u00e9rence National des Maladies Rares des Vaisseaux du Cerveau et de L'\u0153il (CERVCO) and Centre Neurovascular Translationnel (CNVT), FHU\u2010NeuroVasc\u20102030 Hopital Lariboisi\u00e9re APHP  Paris France"},{"name":"Universit\u00e9 Paris\u2010Cit\u00e9  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominique","family":"Herv\u00e9","sequence":"additional","affiliation":[{"name":"GENOVASC, INSERM U1127 Paris Brain Institute (Institut du Cerveau\u2014ICM)  Paris France"},{"name":"Centre de R\u00e9f\u00e9rence National des Maladies Rares des Vaisseaux du Cerveau et de L'\u0153il (CERVCO) and Centre Neurovascular Translationnel (CNVT), FHU\u2010NeuroVasc\u20102030 Hopital Lariboisi\u00e9re APHP  Paris France"},{"name":"Universit\u00e9 Paris\u2010Cit\u00e9  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"St\u00e9phanie","family":"Guey","sequence":"additional","affiliation":[{"name":"GENOVASC, INSERM U1127 Paris Brain Institute (Institut du Cerveau\u2014ICM)  Paris France"},{"name":"Centre de R\u00e9f\u00e9rence National des Maladies Rares des Vaisseaux du Cerveau et de L'\u0153il (CERVCO) and Centre Neurovascular Translationnel (CNVT), FHU\u2010NeuroVasc\u20102030 Hopital Lariboisi\u00e9re APHP  Paris France"},{"name":"Universit\u00e9 Paris\u2010Cit\u00e9  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie Tezenas","family":"Du Montcel","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Institut du Cerveau\u2014Paris Brain Institute\u2014ICM, CNRS, Inria, Inserm, AP\u2010HP, H\u00f4pital de la Piti\u00e9 Salp\u00eatri\u00e8re  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juliette","family":"Ortholand","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Institut du Cerveau\u2014Paris Brain Institute\u2014ICM, CNRS, Inria, Inserm, AP\u2010HP, H\u00f4pital de la Piti\u00e9 Salp\u00eatri\u00e8re  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,5,6]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/S1474-4422(09)70127-9","article-title":"CADASIL","volume":"8","author":"Chabriat H.","year":"2009","journal-title":"Lancet Neurology"},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1111\/ene.14293","article-title":"CADASIL: Yesterday, Today, Tomorrow","volume":"27","author":"Chabriat H.","year":"2020","journal-title":"European Journal of Neurology"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1038\/383707a0","article-title":"Notch3 Mutations in CADASIL, a Hereditary Adult\u2010Onset Condition Causing Stroke and Dementia","volume":"383","author":"Joutel 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Stroke"},{"key":"e_1_2_10_11_1","doi-asserted-by":"crossref","DOI":"10.1212\/WNL.0000000000210193","article-title":"Determining Clinical Disease Progression in Symptomatic Patients With CADASIL","volume":"104","author":"Kaisaridi S.","year":"2025","journal-title":"Neurology"},{"key":"e_1_2_10_12_1","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1002\/acn3.344","article-title":"Archetypal NOTCH3 Mutations Frequent in Public Exome: Implications for CADASIL","volume":"3","author":"Rutten J. W.","year":"2016","journal-title":"Annals of Clinical Translational Neurology"},{"key":"e_1_2_10_13_1","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/s41436-018-0088-3","article-title":"The Effect of NOTCH3 Pathogenic Variant Position on CADASIL Disease Severity: NOTCH3 EGFr 1\u20136 Pathogenic Variant Are Associated With a More Severe Phenotype and Lower Survival Compared With EGFr 7\u201334 Pathogenic Variant","volume":"21","author":"Rutten J. W.","year":"2019","journal-title":"Genetics in Medicine"},{"key":"e_1_2_10_14_1","doi-asserted-by":"crossref","first-page":"e1835","DOI":"10.1212\/WNL.0000000000010525","article-title":"Broad Phenotype of Cysteine\u2010Altering NOTCH3 Variants in UK Biobank","volume":"95","author":"Rutten J. 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