{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T10:47:13Z","timestamp":1792234033839,"version":"4.4.0"},"reference-count":23,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Cerebral small vessel disease (CSVD) is a major cause of stroke and vascular cognitive impairment, yet its mechanisms remain incompletely understood. While heterozygous point mutations in\n                      <jats:italic toggle=\"yes\">COL4A1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">COL4A2<\/jats:italic>\n                      are established monogenic cause of CSVD, the contribution of copy number gains involving these 2 genes has only recently been recognized. We aimed to define the clinical and radiological spectrum of\n                      <jats:italic toggle=\"yes\">COL4A1\/2<\/jats:italic>\n                      duplications and triplications in adults.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We report 7 adult probands carrying duplications or triplications of\n                      <jats:italic toggle=\"yes\">COL4A1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">COL4A2<\/jats:italic>\n                      , in whom no pathogenic variants were identified in other known CSVD genes. Targeted high-throughput sequencing, quantitative multiplex polymerase chain reaction of short fluorescent fragments, and SNP arrays were used to confirm and characterize genomic rearrangements spanning the 13q33q34 region.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Genomic rearrangements ranged from 328 kb to 11.8 Mb, involving complete or partial duplication\/triplication of\n                      <jats:italic toggle=\"yes\">COL4A1\/2<\/jats:italic>\n                      . Patients presented heterogeneous cerebrovascular manifestations, including ischemic and hemorrhagic events, motor impairment, and cognitive decline. Brain magnetic resonance imaging consistently showed extensive white matter hyperintensities, lacunes (particularly in the pons), microbleeds, and, in some cases, saccular aneurysms or arterial dolichoectasia. Only 2 probands had a positive family history of CSVD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      This large series confirms the pathogenicity of\n                      <jats:italic toggle=\"yes\">COL4A1\/2<\/jats:italic>\n                      duplications and triplications in adult-onset CSVD. Phenotypic variability likely reflects differences in duplication\/triplication size, gene content, and modifying factors. Our findings highlight a distinct cerebral-only phenotype linked to gene dosage\u2013related overexpression and underscore the importance of screening for copy number variations in patients with otherwise unexplained cerebral microangiopathy, even in the absence of a family history.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/strokeaha.125.053813","type":"journal-article","created":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T10:00:26Z","timestamp":1767348026000},"page":"794-801","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["<i>COL4A1<\/i>\n                    and\n                    <i>COL4A2<\/i>\n                    Gene Duplication or Triplication as a Genetic Cause of Cerebral Small Vessel Disease in Adults"],"prefix":"10.1161","volume":"57","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6197-6275","authenticated-orcid":true,"given":"Dominique","family":"Herv\u00e9","sequence":"first","affiliation":[{"name":"Centre de R\u00e9f\u00e9rence des Maladies Vasculaires Rares du Cerveau et de L\u2019oeil - Centre de Neurologie Vasculaire Translationnel (CERVCO-CNVT), Lariboisi\u00e8re Hospital (D.H., S.G., H.C.), Assistance Publique - Hopitaux de Paris (AP-HP), France."},{"name":"Universit\u00e9 Paris Cit\u00e9, France (D.H., F.B., S.G., H.C., E.T.-L., T.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1268-8995","authenticated-orcid":true,"given":"Saskia A.J.","family":"Lesnik Oberstein","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Leiden University Medical Center, the Netherlands (S.A.J.L.O., E.A.R.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Pipiras","sequence":"additional","affiliation":[{"name":"UF M\u00e9decine G\u00e9nomique et G\u00e9n\u00e9tique Clinique, H\u00f4pital Jean Verdier, et UF de G\u00e9nomique du D\u00e9veloppement et de la Reproduction, H\u00f4pital Piti\u00e9 Salp\u00eatri\u00e8re, Universit\u00e9 Sorbonne Paris Nord et Sorbonne-Paris, INSERM\/UMR (Unit\u00e9 Mixte de Recherche) 1141, France (E.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8457-8744","authenticated-orcid":true,"given":"Steven J.","family":"Kittner","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Maryland School of Medicine, Baltimore (S.J.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3511-8151","authenticated-orcid":true,"given":"Dimitri","family":"Renard","sequence":"additional","affiliation":[{"name":"Department of Neurology, Centre Hospitalier Universitaire de N\u00eemes, Universit\u00e9 Montpellier, N\u00eemes, France (D.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7663-8380","authenticated-orcid":true,"given":"H\u00e9l\u00e8ne","family":"Morel","sequence":"additional","affiliation":[{"name":"Department of Genetics, Bichat Claude-Bernard Hospital (H.M., M.C., T.C.), Assistance Publique - Hopitaux de Paris (AP-HP), France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9468-652X","authenticated-orcid":true,"given":"Fran\u00e7oise","family":"Bergametti","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, France (D.H., F.B., S.G., H.C., E.T.-L., T.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaelle","family":"Corpechot","sequence":"additional","affiliation":[{"name":"Department of Genetics, Bichat Claude-Bernard Hospital (H.M., M.C., T.C.), Assistance Publique - Hopitaux de Paris (AP-HP), France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8818-3232","authenticated-orcid":true,"given":"Esther A.R.","family":"Nibbeling","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Leiden University Medical Center, the Netherlands (S.A.J.L.O., E.A.R.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5591-1659","authenticated-orcid":true,"given":"Gwenola","family":"Boulday","sequence":"additional","affiliation":[{"name":"Paris Brain Institute\/Institut du Cerveau et de la Moelle \u00e9pini\u00e8re (ICM), INSERM UMR 1127, Sorbonne University, France (G.B., C.A., E.T.-L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6096-3595","authenticated-orcid":true,"given":"St\u00e9phanie","family":"Guey","sequence":"additional","affiliation":[{"name":"Centre de R\u00e9f\u00e9rence des Maladies Vasculaires Rares du Cerveau et de L\u2019oeil - Centre de Neurologie Vasculaire Translationnel (CERVCO-CNVT), Lariboisi\u00e8re Hospital (D.H., S.G., H.C.), Assistance Publique - Hopitaux de Paris (AP-HP), France."},{"name":"Universit\u00e9 Paris Cit\u00e9, France (D.H., F.B., S.G., H.C., E.T.-L., T.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0914-5260","authenticated-orcid":true,"given":"Chaker","family":"Aloui","sequence":"additional","affiliation":[{"name":"Paris Brain Institute\/Institut du Cerveau et de la Moelle \u00e9pini\u00e8re (ICM), INSERM UMR 1127, Sorbonne University, France (G.B., C.A., E.T.-L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8436-6074","authenticated-orcid":true,"given":"Hugues","family":"Chabriat","sequence":"additional","affiliation":[{"name":"Centre de R\u00e9f\u00e9rence des Maladies Vasculaires Rares du Cerveau et de L\u2019oeil - Centre de Neurologie Vasculaire Translationnel (CERVCO-CNVT), Lariboisi\u00e8re Hospital (D.H., S.G., H.C.), Assistance Publique - 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