{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T03:45:36Z","timestamp":1790221536335,"version":"4.1.0"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"15","license":[{"start":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T00:00:00Z","timestamp":1747872000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Health and Medical Research Council Australia"},{"name":"Medical Research Future Fund Australia"},{"name":"Victorian State Government Operational Infrastructure Support and Australian Government National Health and Medical Research Council"},{"name":"Institute Infrastructure Support Scheme"},{"name":"NHMRC Investigator","award":["2017651"],"award-info":[{"award-number":["2017651"]}]},{"name":"NHMRC Investigator","award":["1172897"],"award-info":[{"award-number":["1172897"]}]},{"name":"NHMRC Investigator","award":["1195236"],"award-info":[{"award-number":["1195236"]}]},{"name":"University of Melbourne, Monash University"},{"DOI":"10.13039\/100012128","name":"Austin Medical Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012128","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015988","name":"Norman Beischer Medical Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015988","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Synergy Grant","award":["2010562"],"award-info":[{"award-number":["2010562"]}]},{"name":"MRFF Genomics Health Futures Mission Grant","award":["2007707"],"award-info":[{"award-number":["2007707"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cerebral cavernous malformations (CCMs) are intracranial vascular lesions associated with risk of haemorrhages and seizures. While the majority are sporadic and often associated with somatic variants in PIK3CA and MAP3K3, around 20% are familial with germline variants in one of three CCM genes\u2014KRIT1\/CCM1, CCM2 and PDCD10\/CCM3. We performed comprehensive phenotyping and genetic analysis of nine multiplex families and ten sporadic individuals with CCM. In the familial cases, initial standard analyses had a low yield, we therefore searched for small copy number changes and deep intronic variants. Subsequently, pathogenic germline variants in KRIT1\/CCM1 or CCM2 were identified in all 9 multiplex families. Single or multiple exon deletions or splice site variants in KRIT1\/CCM1 were found in 3\/9 families. Where cavernous malformation tissue was available, second hit somatic PIK3CA variants were identified in 4\/7 individuals. These 4 individuals were from separate families with germline KRIT1\/CCM1 variants. In 8\/10 sporadic cases, we detected recurrent pathogenic somatic PIK3CA, MAP3K3 or CCM2 variants. All familial cases had multiple CCMs, whereas the sporadic cases had a single lesion only, which was in the temporal lobe in 9\/10 individuals. Our comprehensive approach interrogating deep intronic variants combined with detection of small copy number variants warrants implementation in standard clinical genetic testing pipelines to increase diagnostic yield. We also build on the established second hit germline and somatic variant mechanism in some CCM lesions. Genetic diagnosis has clinical implications such as reproductive counselling and provides potential eligibility for precision medicine therapies to treat rapidly growing CCMs.<\/jats:p>","DOI":"10.1093\/hmg\/ddaf077","type":"journal-article","created":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T07:26:55Z","timestamp":1746689215000},"page":"1286-1293","source":"Crossref","is-referenced-by-count":3,"title":["Improving genetic diagnostic yield in familial and sporadic cerebral cavernous malformations: detection of copy number and deep Intronic variants"],"prefix":"10.1093","volume":"34","author":[{"given":"Neblina","family":"Sikta","sequence":"first","affiliation":[{"name":"Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health , 245 Burgundy St, Heidelberg, VIC 3084 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Gooley","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health , 245 Burgundy St, Heidelberg, VIC 3084 ,","place":["Australia"]},{"name":"Bladin-Berkovic Comprehensive Epilepsy Program, Department of Neurology, Austin Health , 145 Studley Rd, Heidelberg, VIC 3084 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy E","family":"Green","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health , 245 Burgundy St, Heidelberg, VIC 3084 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Hoeper","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health , 245 Burgundy St, Heidelberg, VIC 3084 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Witkowski","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health , 245 Burgundy St, Heidelberg, VIC 3084 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin","family":"Bennett","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health , 245 Burgundy St, Heidelberg, VIC 3084 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Francis","sequence":"additional","affiliation":[{"name":"Victorian Clinical Genetics Services and Murdoch Children\u2019s Research Institute, The Royal Children\u2019s Hospital , 50 Flemington Rd, Parkville, VIC 3052 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Reid","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health , 245 Burgundy St, Heidelberg, VIC 3084 ,","place":["Australia"]},{"name":"Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade, Parkville, VIC 3052 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Mao","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health , 245 Burgundy St, Heidelberg, VIC 3084 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Awad","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The Royal Melbourne hospital , 300 Grattan St, Parkville, VIC 3052 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Roberts-Thomson","sequence":"additional","affiliation":[{"name":"Anatomical Pathology, The Royal Melbourne hospital , 300 Grattan St, Parkville, VIC 3052 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian","family":"Bulluss","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Austin Health , 145 Studley Rd, Heidelberg, VIC 3084 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Clark","sequence":"additional","affiliation":[{"name":"Anatomical Pathology, Austin Health , Heidelberg, 145 Studley Rd. VIC 3084 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid E","family":"Scheffer","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health , 245 Burgundy St, Heidelberg, VIC 3084 ,","place":["Australia"]},{"name":"Bladin-Berkovic Comprehensive Epilepsy Program, Department of Neurology, Austin Health , 145 Studley Rd, Heidelberg, VIC 3084 ,","place":["Australia"]},{"name":"Department of Paediatrics, The University of Melbourne, The Royal Children's Hospital, 50 Flemington Rd, Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, and Murdoch Children's Research Institute , 50 Flemington Rd, Parkville, VIC 3052 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piero","family":"Perucca","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health , 245 Burgundy St, Heidelberg, VIC 3084 ,","place":["Australia"]},{"name":"Bladin-Berkovic Comprehensive Epilepsy Program, Department of Neurology, Austin Health , 145 Studley Rd, Heidelberg, VIC 3084 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark F","family":"Bennett","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health , 245 Burgundy St, Heidelberg, VIC 3084 ,","place":["Australia"]},{"name":"Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade, Parkville, VIC 3052 ,","place":["Australia"]},{"name":"Department of Medical Biology, University of Melbourne , Royal Parade, Parkville, VIC 3052 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5132-0774","authenticated-orcid":false,"given":"Melanie","family":"Bahlo","sequence":"additional","affiliation":[{"name":"Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade, Parkville, VIC 3052 ,","place":["Australia"]},{"name":"Department of Medical Biology, University of Melbourne , Royal Parade, Parkville, VIC 3052 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel F","family":"Berkovic","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health , 245 Burgundy St, Heidelberg, VIC 3084 ,","place":["Australia"]},{"name":"Bladin-Berkovic Comprehensive Epilepsy Program, Department of Neurology, Austin Health , 145 Studley Rd, Heidelberg, VIC 3084 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2739-0515","authenticated-orcid":false,"given":"Michael S","family":"Hildebrand","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health , 245 Burgundy St, Heidelberg, VIC 3084 ,","place":["Australia"]},{"name":"Neuroscience Group, Murdoch Children's Research Institute , 50 Flemington Rd, Parkville, VIC 3052 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,5,22]]},"reference":[{"key":"2025072110122497900_ref1","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1056\/NEJM198808113190605","article-title":"Cerebral cavernous malformations","volume":"319","author":"Rigamonti","year":"1988","journal-title":"N Engl J Med"},{"key":"2025072110122497900_ref2","first-page":"198","article-title":"Natural history and imaging prevalence of cavernous malformations in children and young adults: clinical article","volume":"9","author":"Al-Holou","year":"2012","journal-title":"J Neurosurg: Pediatr"},{"key":"2025072110122497900_ref3","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/S1474-4422(07)70053-4","article-title":"Genetics of cavernous angiomas","volume":"6","author":"Labauge","year":"2007","journal-title":"Lancet Neurol"},{"key":"2025072110122497900_ref4","doi-asserted-by":"crossref","first-page":"377","DOI":"10.3174\/ajnr.A1822","article-title":"Familial versus sporadic cavernous malformations: differences in developmental venous anomaly association and lesion phenotype","volume":"31","author":"Petersen","year":"2010","journal-title":"Am J Neuroradiol"},{"key":"2025072110122497900_ref5","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/13815","article-title":"Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas","volume":"23","author":"Couteulx","year":"1999","journal-title":"Nat Genet"},{"key":"2025072110122497900_ref6","doi-asserted-by":"crossref","first-page":"2325","DOI":"10.1093\/hmg\/8.12.2325","article-title":"Mutations in the gene encoding KRIT1, a Krev-1\/rap1a binding protein, cause cerebral cavernous malformations (CCM1)","volume":"8","author":"Sahoo","year":"1999","journal-title":"Hum Mol Genet"},{"key":"2025072110122497900_ref7","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1086\/380314","article-title":"Mutations in a gene encoding a novel protein containing a Phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations","volume":"73","author":"Liquori","year":"2003","journal-title":"Am J Hum Genet"},{"key":"2025072110122497900_ref8","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1086\/381718","article-title":"Mutations within the MGC4607 gene cause cerebral cavernous malformations","volume":"74","author":"Denier","year":"2004","journal-title":"Am J Hum Genet"},{"key":"2025072110122497900_ref9","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1086\/426952","article-title":"Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations","volume":"76","author":"Bergametti","year":"2005","journal-title":"Am J Hum Genet"},{"key":"2025072110122497900_ref10","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/j.ajhg.2021.04.005","article-title":"Somatic MAP3K3 mutation defines a subclass of cerebral cavernous malformation","volume":"108","author":"Weng","year":"2021","journal-title":"Am J Hum Genet"},{"key":"2025072110122497900_ref11","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1056\/NEJMoa2100440","article-title":"Somatic PIK3CA mutations in sporadic cerebral cavernous malformations","volume":"385","author":"Peyre","year":"2021","journal-title":"N Engl J Med"},{"key":"2025072110122497900_ref12","doi-asserted-by":"crossref","first-page":"2648","DOI":"10.1093\/brain\/awab117","article-title":"Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations","volume":"144","author":"Hong","year":"2021","journal-title":"Brain"},{"key":"2025072110122497900_ref13","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/s41586-021-03562-8","article-title":"PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism","volume":"594","author":"Ren","year":"2021","journal-title":"Nature"},{"key":"2025072110122497900_ref14","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1093\/hmg\/ddn430","article-title":"Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis","volume":"18","author":"Akers","year":"2009","journal-title":"Hum Mol Genet"},{"key":"2025072110122497900_ref15","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1161\/01.STR.0000157586.20479.fd","article-title":"Biallelic somatic and germ line CCM1 truncating mutations in a cerebral cavernous malformation lesion","volume":"36","author":"Gault","year":"2005","journal-title":"Stroke"},{"key":"2025072110122497900_ref16","article-title":"Genotype-phenotype correlations in multiple lesions of familial cerebral cavernous malformations concerning phosphatidylinositol 3-kinase catalytic subunit alpha mutations","volume":"14","author":"Wang","year":"2024","journal-title":"Clin Transl Med"},{"key":"2025072110122497900_ref17","doi-asserted-by":"crossref","first-page":"e86286","DOI":"10.1371\/journal.pone.0086286","article-title":"Mutation prevalence of cerebral cavernous malformation genes in Spanish patients","volume":"9","author":"Mond\u00e9jar","year":"2014","journal-title":"PLoS One"},{"key":"2025072110122497900_ref18","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","year":"2016","journal-title":"Hum Genome Var"},{"key":"2025072110122497900_ref19","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/nature17178","article-title":"Cerebral cavernous malformations arise from endothelial gain of MEKK3\u2013KLF2\/4 signalling","volume":"532","author":"Zhou","year":"2016","journal-title":"Nature"},{"key":"2025072110122497900_ref20","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/s10048-013-0362-0","article-title":"CCM molecular screening in a diagnosis context: novel unclassified variants leading to abnormal splicing and importance of large deletions","volume":"14","author":"Riant","year":"2013","journal-title":"Neurogenetics"},{"key":"2025072110122497900_ref21","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.devcel.2014.12.009","article-title":"The cerebral cavernous malformation pathway controls cardiac development via regulation of endocardial MEKK3 Signaling and KLF expression","volume":"32","author":"Zhou","year":"2015","journal-title":"Dev Cell"},{"key":"2025072110122497900_ref22","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1038\/s41431-022-01232-5","article-title":"Comparing saliva and blood for the detection of mosaic genomic abnormalities that cause syndromic intellectual disability","volume":"31","author":"Francis","year":"2023","journal-title":"Eur J Hum Genet"},{"key":"2025072110122497900_ref23","first-page":"609","volume-title":"Surgical treatment of the epilepsies","author":"Engel","year":"1993","edition":"2nd"},{"key":"2025072110122497900_ref24","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/s41587-020-0439-x","article-title":"The nf-core framework for community-curated bioinformatics pipelines","volume":"38","author":"Ewels","year":"2020","journal-title":"Nat Biotechnol"},{"key":"2025072110122497900_ref25","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"2025072110122497900_ref26","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1006360","article-title":"Ggsashimi: sashimi plot revised for browser- and annotation-independent splicing visualization","volume":"14","author":"Garrido-Mart\u00edn","year":"2018","journal-title":"PLoS Comput Biol"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/34\/15\/1286\/63280236\/ddaf077.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/34\/15\/1286\/63280236\/ddaf077.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T14:12:39Z","timestamp":1753107159000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/34\/15\/1286\/8140463"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,22]]},"references-count":26,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2025,5,22]]},"published-print":{"date-parts":[[2025,7,20]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddaf077","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,8,1]]},"published":{"date-parts":[[2025,5,22]]}}}