{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T02:00:25Z","timestamp":1790301625771,"version":"4.1.0"},"reference-count":13,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100014249","name":"International Centre for Mathematical Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014249","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"abstract":"ABSTRACT<\/jats:title>\n \n Hereditary cerebral cavernous malformations (CCMs) are characterized by lesion multiplicity and the formation of\n de novo<\/jats:italic>\n lesions, in contrast to sporadic forms. We performed sequencing analyses covering the known autosomal dominant loci CCM1\/\n KRIT1<\/jats:italic>\n , CCM2\/\n CCM2<\/jats:italic>\n (\n Malcavernin<\/jats:italic>\n ), and CCM3\/\n PDCD10<\/jats:italic>\n in 11 patients from eight families with CCMs. All patients had multiple lesions, and\n de novo<\/jats:italic>\n lesions were observed in four patients (36.4%). Heterozygous loss\u2010of\u2010function variants were identified in seven families, including four variants of\n KRIT1<\/jats:italic>\n , two of\n CCM2<\/jats:italic>\n , and one of\n PDCD10<\/jats:italic>\n . Among them, c.1730\u2009+\u20094_1730\u2009+\u20097delAGTA in\n KRIT1<\/jats:italic>\n and c.609G>A (p.Lys203=) in\n CCM2<\/jats:italic>\n were putative splicing variants located outside the invariant GT\/AG dinucleotides at the splice junction because AI\u2010based prediction tools indicated that both variants may disrupt normal splicing. In\u00a0vitro splicing assays confirmed that the AI\u2010based predictions were correct, and the same aberrant splicing pattern was reproduced by reverse transcription PCR using tissue\u2010derived RNA for the c.609G>A variant in\n CCM2<\/jats:italic>\n . In one patient with numerous CCM lesions, whole\u2010genome sequencing was performed, which showed no abnormalities in the three known CCM loci, including deep intronic and structural variants. This may indicate the technological limitations of current bioinformatics analyses or the presence of a novel CCM gene.\n <\/jats:p>","DOI":"10.1111\/cge.70253","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T01:45:28Z","timestamp":1790300728000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Loss\u2010Of\u2010Function\n CCM<\/scp>\n Gene Variants in Japanese Patients With Cerebral Cavernous Malformations"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5550-6965","authenticated-orcid":false,"given":"Takahiro","family":"Hori","sequence":"first","affiliation":[{"name":"Institute for Comprehensive Medical Sciences Tokyo Women's Medical University Tokyo Japan"},{"name":"Department of Neurosurgery Tokyo Women's Medical University Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4651-3018","authenticated-orcid":false,"given":"Satoshi","family":"Tsutumi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Juntendo University Urayasu Hospital Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazutoshi","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Tokyo Women's Medical University Yachiyo Medical Center Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6660-9316","authenticated-orcid":false,"given":"Taichi","family":"Ishiguro","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Tokyo Women's Medical University Yachiyo Medical Center Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidenori","family":"Ohbuchi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Tokyo Women's Medical University Adachi Medical Center Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasunaga","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Kobayashi Neurosurgery and Neurology Hospital Nagano Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2201-3534","authenticated-orcid":false,"given":"Emi","family":"Nomura","sequence":"additional","affiliation":[{"name":"Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenko","family":"Azuma","sequence":"additional","affiliation":[{"name":"Institute for Comprehensive Medical Sciences Tokyo Women's Medical University Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6487-2065","authenticated-orcid":false,"given":"Yuichi","family":"Kubota","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Tokyo Women's Medical University Adachi Medical Center Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7791-7384","authenticated-orcid":false,"given":"Hiroyuki","family":"Akagawa","sequence":"additional","affiliation":[{"name":"Institute for Comprehensive Medical Sciences Tokyo Women's Medical University Tokyo Japan"},{"name":"Department of Neurosurgery Tokyo Women's Medical University Adachi Medical Center Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"issue":"2","key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1159\/000486292","article-title":"Cerebral Cavernous Malformations: An Update on Prevalence, Molecular Genetic Analyses, and Genetic Counselling","volume":"9","author":"Spiegler S.","year":"2018","journal-title":"Molecular Syndromology"},{"issue":"10","key":"e_1_2_9_3_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0110438","article-title":"PDCD10 Gene Mutations in Multiple Cerebral Cavernous Malformations","volume":"9","author":"Cigoli M. S.","year":"2014","journal-title":"PLoS One"},{"key":"e_1_2_9_4_1","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.wneu.2019.02.115","article-title":"Hemorrhage, Seizures, and Dynamic Changes of Familial Versus Nonfamilial Cavernous Malformation: Systematic Review and Meta\u2010Analysis","volume":"126","author":"Taslimi S.","year":"2019","journal-title":"World Neurosurgery"},{"key":"e_1_2_9_5_1","doi-asserted-by":"crossref","first-page":"16032","DOI":"10.1038\/hgv.2016.32","article-title":"KRIT1 Mutations in Three Japanese Pedigrees With Hereditary Cavernous Malformation","volume":"3","author":"Hirota K.","year":"2016","journal-title":"Human Genome Variation"},{"issue":"5","key":"e_1_2_9_6_1","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1002\/ana.20947","article-title":"Genotype\u2010Phenotype Correlations in Cerebral Cavernous Malformations Patients","volume":"60","author":"Denier C.","year":"2006","journal-title":"Annals of Neurology"},{"issue":"3","key":"e_1_2_9_7_1","first-page":"211","article-title":"Genetics of Cerebral Cavernous Malformations: Current Status and Future Prospects","volume":"59","author":"Choquet H.","year":"2015","journal-title":"Journal of Neurosurgical Sciences"},{"issue":"5","key":"e_1_2_9_8_1","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1111\/ncn3.12649","article-title":"A Japanese Case of Successful Surgical Resection of Cerebral Cavernous Malformations With a CCM2 Mutation","volume":"10","author":"Nomura E.","year":"2022","journal-title":"Neurology and Clinical Neuroscience"},{"issue":"1","key":"e_1_2_9_9_1","doi-asserted-by":"crossref","first-page":"D622","DOI":"10.1093\/nar\/gkad978","article-title":"jMorp: Japanese Multi\u2010Omics Reference Panel Update Report 2023","volume":"52","author":"Tadaka S.","year":"2024","journal-title":"Nucleic Acids Research"},{"issue":"7993","key":"e_1_2_9_10_1","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41586-023-06045-0","article-title":"A Genomic Mutational Constraint Map Using Variation in 76,156 Human Genomes","volume":"625","author":"Chen S.","year":"2024","journal-title":"Nature"},{"issue":"3","key":"e_1_2_9_11_1","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","article-title":"Predicting Splicing From Primary Sequence With Deep Learning","volume":"176","author":"Jaganathan K.","year":"2019","journal-title":"Cell"},{"issue":"1","key":"e_1_2_9_12_1","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1186\/s13059-022-02664-4","article-title":"Predicting RNA Splicing From DNA Sequence Using Pangolin","volume":"23","author":"Zeng T.","year":"2022","journal-title":"Genome Biology"},{"issue":"5","key":"e_1_2_9_13_1","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards S.","year":"2015","journal-title":"Genetics in Medicine"},{"issue":"1","key":"e_1_2_9_14_1","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1161\/CIRCRESAHA.121.318174","article-title":"Cerebral Cavernous Malformation: From Mechanism to Therapy","volume":"129","author":"Snellings D. A.","year":"2021","journal-title":"Circulation Research"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70253","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cge.70253","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70253","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T01:45:30Z","timestamp":1790300730000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.70253"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,24]]},"references-count":13,"alternative-id":["10.1111\/cge.70253"],"URL":"https:\/\/doi.org\/10.1111\/cge.70253","archive":["Portico"],"relation":{},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,24]]},"assertion":[{"value":"2026-07-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"cge.70253"}}