{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T12:13:43Z","timestamp":1790079223819,"version":"4.0.1"},"reference-count":24,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>Background\/Objectives: Pathogenic variants in collagen type 4 \u03b15 chain (COL4A5), responsible for X-linked Alport syndrome, are classically associated with progressive kidney disease, sensorineural hearing impairment, and ocular abnormalities. Cerebrovascular involvement is not considered part of the COL4A5-related phenotype, although rare recent reports suggest it may occur. We describe a family with cerebrovascular events across three generations, segregating in a clear X-linked pattern, and evaluate whether these events could be linked to a pathogenic COL4A5 variant identified in the proband. Methods: We report the clinical, radiological, and genetic findings in a 16-year-old heterozygous female proband, interpreted in the context of her family\u2019s cerebrovascular history. Exome sequencing, chromosomal microarray, and familial segregation analysis were performed. Results: The proband presented with severe migraine, cerebellar microhemorrhage, and poor visualization of the left distal posterior cerebral artery (PCA) branches. Exome sequencing detected the heterozygous COL4A5 pathogenic variant c.1871G&gt;A; p.(Gly624Asp), inherited from her hemizygous father, who has Alport syndrome. The proband\u2019s sister, an obligate carrier of the same variant with a history of migraine, was found to have a small brain aneurysm. In the paternal line, the great-grandmother died of a cerebrovascular event in her early 40 s, the great-aunt had a stroke at around 40, and her son died of a cerebrovascular event at 35; the obligate-carrier grandmother had chronic kidney disease and migraine. Conclusions: This COL4A5 variant is usually associated with late-onset Alport syndrome and variable renal involvement, even in obligate carriers, and has not previously been linked to cerebrovascular disease. In the present family, the X-linked clustering of cerebrovascular events raises the possibility that COL4A5 may contribute to cerebrovascular fragility, with an effect that may extend beyond the kidney. These findings suggest that COL4A5 may be relevant in selected families with unexplained cerebrovascular disease, even when renal manifestations are mild or absent.<\/jats:p>","DOI":"10.3390\/jcm15197350","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:09:35Z","timestamp":1790075375000},"page":"7350","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cerebrovascular Manifestations in a Family with a Pathogenic COL4A5 Variant"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9898-3054","authenticated-orcid":false,"given":"Hagit","family":"Toledano-Alhadef","sequence":"first","affiliation":[{"name":"Gilbert\u2019s Israeli and International Neurofibromatosis Center, Tel Aviv-Yafo 6423906, Israel"},{"name":"Pediatric Neurology Institute and Child Development Center, Dana-Dwek Children\u2019s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv-Yafo 6423906, Israel"},{"name":"The Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv-Yafo 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Aviva","family":"Fattal Valevski","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Institute and Child Development Center, Dana-Dwek Children\u2019s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv-Yafo 6423906, Israel"},{"name":"The Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv-Yafo 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5315-3738","authenticated-orcid":false,"given":"Moran","family":"Hausman-Kedem","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Institute and Child Development Center, Dana-Dwek Children\u2019s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv-Yafo 6423906, Israel"},{"name":"The Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv-Yafo 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Shlomi","family":"Constantini","sequence":"additional","affiliation":[{"name":"Gilbert\u2019s Israeli and International Neurofibromatosis Center, Tel Aviv-Yafo 6423906, Israel"},{"name":"The Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv-Yafo 6997801, Israel"},{"name":"Department of Pediatric Neurosurgery, Tel Aviv Sourasky Medical Center, Tel Aviv-Yafo 6423906, Israel"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Shelly","family":"Shiran","sequence":"additional","affiliation":[{"name":"The Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv-Yafo 6997801, Israel"},{"name":"Pediatric Radiology Unit, Dana-Dwek Children\u2019s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv-Yafo 6423906, Israel"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Anat","family":"Oron","sequence":"additional","affiliation":[{"name":"The Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv-Yafo 6997801, Israel"},{"name":"Medical Division, Maccabi Healthcare Services, Tel Aviv-Yafo 6816330, Israel"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Keren","family":"Yosovich","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics, Wolfson Medical Center, Holon 5822012, Israel"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6641-6875","authenticated-orcid":false,"given":"Tally","family":"Lerman-Sagie","sequence":"additional","affiliation":[{"name":"The Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv-Yafo 6997801, Israel"},{"name":"Multidisciplinary Fetal Neurology Center, Fetal Brain Research Center, Wolfson Medical Center, Holon 5822012, Israel"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3794-0843","authenticated-orcid":false,"given":"Marina","family":"Michelson","sequence":"additional","affiliation":[{"name":"Medical Division, Maccabi Healthcare Services, Tel Aviv-Yafo 6816330, Israel"},{"name":"Institute of Medical Genetics, Wolfson Medical Center, Holon 5822012, Israel"},{"name":"Adelson School of Medicine, Ariel University, Ariel 40700, Israel"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"ref_1","first-page":"100140","article-title":"Main features of COL4A1-COL4A2 related cerebral microangiopathies","volume":"3","author":"Guey","year":"2022","journal-title":"Cereb. Circ.-Cogn. Behav."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1126\/science.1109418","article-title":"Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly","volume":"308","author":"Gould","year":"2005","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"eadi3966","DOI":"10.1126\/scisignal.adi3966","article-title":"Impaired intracellular Ca2+ signaling contributes to age related cerebral small vessel disease in Col4a1 mutant mice","volume":"16","author":"Yamasaki","year":"2023","journal-title":"Sci. Signal."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"105315","DOI":"10.1016\/j.ebiom.2024.105315","article-title":"Collagen IV deficiency causes hypertrophic remodeling and endothelium-dependent hyperpolarization in small vessel disease with intracerebral hemorrhage","volume":"107","author":"McNeilly","year":"2024","journal-title":"eBioMedicine"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e025629","DOI":"10.1161\/JAHA.121.025629","article-title":"Systematic Review of Cerebral Phenotypes Associated with Monogenic Cerebral Small-Vessel Disease","volume":"11","author":"Whittaker","year":"2022","journal-title":"J. Am. Heart Assoc."},{"key":"ref_6","first-page":"e47129","article-title":"Alport Syndrome: A Comprehensive Review","volume":"15","author":"Adone","year":"2023","journal-title":"Cureus"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1097\/MNH.0000000000000983","article-title":"Alport syndrome and Alport kidney diseases\u2014Elucidating the disease spectrum","volume":"33","author":"Puapatanakul","year":"2024","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/S0090-3019(00)00253-6","article-title":"Ruptured intracranial aneurysm in an adolescent with Alport\u2019s syndrome-a new expression of type IV collagenopathy: Case report","volume":"54","author":"Vaicys","year":"2000","journal-title":"Surg. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e11538","DOI":"10.1097\/MD.0000000000011538","article-title":"Missense mutations in COL4A5 or COL4A6 genes may cause cerebrovascular fibromuscular dysplasia: Case report and literature review","volume":"97","author":"Wang","year":"2018","journal-title":"Medicine"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e228175","DOI":"10.1136\/bcr-2018-228175","article-title":"Alport\u2019s syndrome and intracranial aneurysm: Mere coincidence or undiscovered causal relationship","volume":"12","author":"Bose","year":"2019","journal-title":"BMJ Case Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1177\/19418744231175561","article-title":"Vertebral and Basilar Artery Dissection in a Patient with Alport Syndrome","volume":"13","author":"Saleh","year":"2023","journal-title":"Neurohospitalist"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"107816","DOI":"10.1016\/j.jstrokecerebrovasdis.2024.107816","article-title":"Exploring the link between Alport syndrome and multiple intracranial artery stenoses: A case report of COL4A5 mutation","volume":"33","author":"Egashira","year":"2024","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.spen.2015.11.001","article-title":"Mosaic Neurocutaneous Disorders and Their Causes","volume":"22","author":"Ruggieri","year":"2015","journal-title":"Semin. Pediatr. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.clineuro.2018.02.040","article-title":"Segmental neurofibromatosis type 1 complicated with multiple intracranial arteriovenous fistulas: A case study","volume":"168","author":"He","year":"2018","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1055\/s-0029-1214422","article-title":"Segmental neurofibromatosis type 1 (NF1) associated with Cobb syndrome: Case report","volume":"39","year":"2008","journal-title":"Neuropediatrics"},{"key":"ref_16","first-page":"207","article-title":"X-linked, COL4A5 hypomorphic Alport mutations such as G624D and P628L may only exhibit thin basement membrane nephropathy with microhematuria and late onset kidney failure","volume":"17","author":"Pierides","year":"2013","journal-title":"Hippokratia"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1016\/j.kint.2020.10.040","article-title":"Mild X-linked Alport syndrome due to the COL4A5 G624D variant originating in the Middle Ages is predominant in Central\/East Europe and causes kidney failure in midlife","volume":"99","author":"Bielska","year":"2021","journal-title":"Kidney Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1016\/j.ekir.2025.02.031","article-title":"COL4A5-p.Gly624Asp is the Predominant Variant in Europe Associated with a Mild Alport Syndrome Phenotype","volume":"10","author":"Jens","year":"2025","journal-title":"Kidney Int. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Macheroux, E.P., Braunisch, M.C., Pucci Pegler, S., Satanovskij, R., Riedhammer, K.M., G\u00fcnthner, R., Gross, O., Nagel, M., Renders, L., and Hoefele, J. (2019). The Hypomorphic Variant p.(Gly624Asp) in COL4A5 as a Possible Cause for an Unexpected Severe Phenotype in a Family with X-Linked Alport Syndrome. Front. Pediatr., 7.","DOI":"10.3389\/fped.2019.00485"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1038\/s41586-024-07283-6","article-title":"A brain-specific angiogenic mechanism enabled by tip cell specialization","volume":"628","author":"Schevenels","year":"2024","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/gim.2014.210","article-title":"The expanding phenotype of COL4A1 and COL4A2 mutations: Clinical data on 13 newly identified families and a review of the literature","volume":"17","author":"Meuwissen","year":"2015","journal-title":"Genet. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"101514","DOI":"10.1016\/j.gim.2025.101514","article-title":"COL4A1 and COL4A2-related disorders: Clinical features, diagnostic guidelines, and management","volume":"27","author":"Tambala","year":"2025","journal-title":"Genet. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"226","DOI":"10.3390\/neurolint16010015","article-title":"Missense Variants in COL4A1\/2 Are Associated with Cerebral Aneurysms: A Case Report and Literature Review","volume":"16","author":"Uemura","year":"2024","journal-title":"Neurol. Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e73486","DOI":"10.7554\/eLife.73486","article-title":"Kidney organoids recapitulate human basement membrane assembly in health and disease","volume":"11","author":"Morais","year":"2022","journal-title":"eLife"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/19\/7350\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:38:51Z","timestamp":1790077131000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/19\/7350"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,22]]},"references-count":24,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["jcm15197350"],"URL":"https:\/\/doi.org\/10.3390\/jcm15197350","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,22]]}}}