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Altered genes play a prominent role in the aetiology of moyamoya disease, but a causative gene is not identified in the majority of cases.<\/jats:p>\n                  <jats:p>Exome sequencing data from 151 individuals from 84 unsolved families were analysed to identify further genes for moyamoya disease, then candidate genes assessed in additional cases (150 probands). Two families had the same rare variant in ANO1, which encodes a calcium-activated chloride channel, anoctamin-1. Haplotype analyses found the families were related, and ANO1 p.Met658Val segregated with moyamoya disease in the family with an LOD score of 3.3. Six additional ANO1 rare variants were identified in moyamoya disease families.<\/jats:p>\n                  <jats:p>The ANO1 rare variants were assessed using patch-clamp recordings, and the majority of variants, including ANO1 p.Met658Val, displayed increased sensitivity to intracellular Ca2+. Patients harbouring these gain-of-function ANO1 variants had classic features of moyamoya disease, but also had aneurysm, stenosis and\/or occlusion in the posterior circulation.<\/jats:p>\n                  <jats:p>Our studies support that ANO1 gain-of-function pathogenic variants predispose to moyamoya disease and are associated with unique involvement of the posterior circulation.<\/jats:p>","DOI":"10.1093\/brain\/awad172","type":"journal-article","created":{"date-parts":[[2023,5,24]],"date-time":"2023-05-24T21:35:41Z","timestamp":1684964141000},"page":"3616-3623","source":"Crossref","is-referenced-by-count":30,"title":["Rare variants in\n                    <i>ANO1<\/i>\n                    , encoding a calcium-activated chloride channel, predispose to moyamoya disease"],"prefix":"10.1093","volume":"146","author":[{"given":"Am\u00e9lie","family":"Pinard","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Medical Genetics, McGovern Medical School, University of Texas Health Science Center at Houston , Houston, TX 77030 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlei","family":"Ye","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, Department of Physiology, University of California San Francisco , San Francisco, CA 94158 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart M","family":"Fraser","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Child Neurology, McGovern Medical School, University of Texas Health Science Center at Houston , Houston, TX 77030 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5664-7987","authenticated-orcid":false,"given":"Jill A","family":"Rosenfeld","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavel","family":"Pichurin","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics, Mayo Clinic , Rochester, MN 55902 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott E","family":"Hickey","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The Ohio State University , Columbus, OH 43210 ,","place":["USA"]},{"name":"Division of Genetic and Genomic Medicine, Nationwide Children\u2019s Hospital , Columbus, OH 43205 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongchuan","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Medical Genetics, McGovern Medical School, University of Texas Health Science Center at Houston , Houston, TX 77030 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alana C","family":"Cecchi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Medical Genetics, McGovern Medical School, University of Texas Health Science Center at Houston , Houston, TX 77030 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maura L","family":"Boerio","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Medical Genetics, McGovern Medical School, University of Texas Health Science Center at Houston , Houston, TX 77030 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phanie","family":"Guey","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Inserm U1141, AP-HP Groupe hospitalier Lariboisi\u00e8re Saint Louis , 75019 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0914-5260","authenticated-orcid":false,"given":"Chaker","family":"Aloui","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Inserm U1141, AP-HP Groupe hospitalier Lariboisi\u00e8re Saint Louis , 75019 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwanghyuk","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Kraemer","sequence":"additional","affiliation":[{"name":"Department of Neurology, Alfried Krupp-Hospital , 45131 Essen ,","place":["Germany"]},{"name":"Department of Neurology, Medical Faculty, Heinrich-Heine-University , 40225 D\u00fcsseldorf ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saleh Omar","family":"Alyemni","sequence":"additional","affiliation":[{"name":"UCL School of Pharmacy, Bloomsbury , London WC1N 1AX ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"University of Washington Center for Mendelian Genomics","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J","family":"Bamshad","sequence":"additional","affiliation":[{"name":"Division of Genetics Medicine, Department of Pediatrics, University of Washington , Seattle, WA 98195 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah A","family":"Nickerson","sequence":"additional","affiliation":[{"name":"Department of Genome Sciences, University of Washington , Seattle, WA 98195 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Tournier-Lasserve","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Inserm U1141, AP-HP Groupe hospitalier Lariboisi\u00e8re Saint Louis , 75019 Paris ,","place":["France"]},{"name":"AP-HP, Service de g\u00e9n\u00e9tique mol\u00e9culaire neurovasculaire, Centre de R\u00e9f\u00e9rence des Maladies Vasculaires Rares du Cerveau et de l\u2019oeil, Groupe Hospitalier Saint-Louis Lariboisi\u00e8re , 75010 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2650-2925","authenticated-orcid":false,"given":"Shozeb","family":"Haider","sequence":"additional","affiliation":[{"name":"UCL School of Pharmacy, Bloomsbury , London WC1N 1AX ,","place":["UK"]},{"name":"UCL Centre for Advanced Research Computing, University College London , London WC1H 9RN ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5777-7262","authenticated-orcid":false,"given":"Sheng Chih","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Genetics, Washington University School of Medicine , St Louis, MO 63110 ,","place":["USA"]},{"name":"Department of Pediatrics, Washington University School of Medicine , St Louis, MO 63110 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward R","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA 02115 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristopher T","family":"Kahle","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Yale University School of Medicine , New Haven, CT 06510 ,","place":["USA"]},{"name":"Department of 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disease","volume":"13","author":"Mertens","year":"2022","journal-title":"Transl Stroke Res"},{"key":"2026041420133093400_awad172-B6","doi-asserted-by":"crossref","first-page":"e51","DOI":"10.1161\/STR.0000000000000183","article-title":"Management of stroke in neonates and children: A scientific statement from the American Heart Association\/American Stroke Association","volume":"50","author":"Ferriero","year":"2019","journal-title":"Stroke"},{"key":"2026041420133093400_awad172-B7","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1002\/humu.22858","article-title":"The matchmaker exchange: A platform for rare disease gene discovery","volume":"36","author":"Philippakis","year":"2015","journal-title":"Hum Mutat"},{"key":"2026041420133093400_awad172-B8","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1146\/annurev-physiol-022516-034031","article-title":"Anoctamins\/TMEM16 proteins: Chloride channels flirting with lipids and extracellular 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