{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T14:23:14Z","timestamp":1769437394165,"version":"3.49.0"},"reference-count":12,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T00:00:00Z","timestamp":1756339200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T00:00:00Z","timestamp":1756339200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Universit\u00e4tsmedizin Greifswald"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Neurogenetics"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The detection of complex structural variants in patients with familial cerebral cavernous malformations (FCCM) remains challenging. Short-read whole genome sequencing was performed for a patient with strong clinical evidence of FCCM but negative results from previous genetic tests. The analysis revealed a large insertion of an intronic\n                    <jats:italic>KRIT1<\/jats:italic>\n                    fragment into a coding exon of\n                    <jats:italic>KRIT1<\/jats:italic>\n                    . This novel structural variant results in a frameshift and was classified as pathogenic. Predictive testing can now be offered to asymptomatic family members. This case expands the known mutation spectrum in FCCM and suggests that, after negative whole exome or gene panel sequencing, whole genome sequencing should be offered as a second-line diagnostic test.\n                  <\/jats:p>","DOI":"10.1007\/s10048-025-00847-2","type":"journal-article","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T06:32:02Z","timestamp":1756362722000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Familial cerebral cavernous malformations caused by a novel germline structural variant in the KRIT1 gene"],"prefix":"10.1007","volume":"26","author":[{"given":"Robin A.","family":"Pilz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Begemann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Surema","family":"Pfister","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paranchai","family":"Boonsawat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anita","family":"Rauch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingo","family":"Kurth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ute","family":"Felbor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Rath","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,8,28]]},"reference":[{"key":"847_CR1","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1159\/000486292","volume":"9","author":"S Spiegler","year":"2018","unstructured":"Spiegler S, Rath M, Paperlein C, Felbor U (2018) Cerebral cavernous malformations: an update on prevalence, molecular genetic analyses, and genetic counselling. Mol Syndromol 9:60\u201369. https:\/\/doi.org\/10.1159\/000486292","journal-title":"Mol Syndromol"},{"key":"847_CR2","doi-asserted-by":"publisher","first-page":"D980","DOI":"10.1093\/nar\/gkt1113","volume":"42","author":"MJ Landrum","year":"2014","unstructured":"Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, Maglott DR (2014) ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res 42:D980\u2013985. https:\/\/doi.org\/10.1093\/nar\/gkt1113","journal-title":"Nucleic Acids Res"},{"key":"847_CR3","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1007\/s10048-017-0531-7","volume":"19","author":"S Spiegler","year":"2018","unstructured":"Spiegler S, Rath M, Hoffjan S, Dammann P, Sure U, Pagenstecher A, Strom T, Felbor U (2018) First large genomic inversion in familial cerebral cavernous malformation identified by whole genome sequencing. Neurogenetics 19:55\u201359. https:\/\/doi.org\/10.1007\/s10048-017-0531-7","journal-title":"Neurogenetics"},{"key":"847_CR4","doi-asserted-by":"publisher","first-page":"6306","DOI":"10.1038\/s41598-020-63337-5","volume":"10","author":"RA Pilz","year":"2020","unstructured":"Pilz RA, Schwefel K, Weise A, Liehr T, Demmer P, Spuler A, Spiegler S, Gilberg E, H\u00fcbner CA, Felbor U, Rath M (2020) First interchromosomal insertion in a patient with cerebral and spinal cavernous malformations. Sci Rep 10:6306. https:\/\/doi.org\/10.1038\/s41598-020-63337-5","journal-title":"Sci Rep"},{"key":"847_CR5","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1038\/s41431-024-01626-7","volume":"32","author":"A Chaussenot","year":"2024","unstructured":"Chaussenot A, Ayrignac X, Chatron N, Granchon-Riolzir T, Labauge P, Tournier-Lasserve E, Riant F (2024) Loss of heterozygosity in CCM2 cDNA revealing a structural variant causing multiple cerebral cavernous malformations. Eur J Hum Genet 32:876\u2013878. https:\/\/doi.org\/10.1038\/s41431-024-01626-7","journal-title":"Eur J Hum Genet"},{"key":"847_CR6","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1111\/cge.12322","volume":"86","author":"F Riant","year":"2014","unstructured":"Riant F, Odent S, Cecillon M, Pasquier L, de Barac\u00e9 C, Carney MP, Tournier-Lasserve E (2014) Deep intronic KRIT1 mutation in a family with clinically silent multiple cerebral cavernous malformations. Clin Genet 86:585\u2013588. https:\/\/doi.org\/10.1111\/cge.12322","journal-title":"Clin Genet"},{"key":"847_CR7","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.1093\/bioinformatics\/btv710","volume":"32","author":"X Chen","year":"2016","unstructured":"Chen X, Schulz-Trieglaff O, Shaw R, Barnes B, Schlesinger F, K\u00e4llberg M, Cox AJ, Kruglyak S, Saunders CT (2016) Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics 32:1220\u20131222. https:\/\/doi.org\/10.1093\/bioinformatics\/btv710","journal-title":"Bioinformatics"},{"key":"847_CR8","doi-asserted-by":"publisher","first-page":"1517","DOI":"10.1002\/humu.23626","volume":"39","author":"AN Abou Tayoun","year":"2018","unstructured":"Abou Tayoun AN, Pesaran T, DiStefano MT, Oza A, Rehm HL, Biesecker LG, Harrison SM, ClinGen Sequence Variant Interpretation Working Group (ClinGen SVI) (2018) Recommendations for interpreting the loss of function PVS1 ACMG\/AMP variant criterion. Hum Mutat 39:1517\u20131524. https:\/\/doi.org\/10.1002\/humu.23626","journal-title":"Hum Mutat"},{"key":"847_CR9","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee (2015) 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. Genet Med 17:405\u2013424. https:\/\/doi.org\/10.1038\/gim.2015.30","journal-title":"Genet Med"},{"key":"847_CR10","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1093\/neuros\/nyx091","volume":"80","author":"A Akers","year":"2017","unstructured":"Akers A, Al-Shahi Salman R, Awad IA, Dahlem K, Flemming K, Hart B, Kim H, Jusue-Torres I, Kondziolka D, Lee C, Morrison L, Rigamonti D, Rebeiz T, Tournier-Lasserve E, Waggoner D, Whitehead K (2017) Synopsis of guidelines for the clinical management of cerebral cavernous malformations: consensus recommendations based on systematic literature review by the Angioma alliance scientific advisory board clinical experts panel. Neurosurgery 80:665\u2013680. https:\/\/doi.org\/10.1093\/neuros\/nyx091","journal-title":"Neurosurgery"},{"key":"847_CR11","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1002\/mgg3.60","volume":"2","author":"S Spiegler","year":"2014","unstructured":"Spiegler S, Najm J, Liu J, Gkalympoudis S, Schr\u00f6der W, Borck G, Brockmann K, Elbracht M, Fauth C, Ferbert A, Freudenberg L, Grasshoff U, Hellenbroich Y, Henn W, Hoffjan S, H\u00fcning I, Korenke GC, Kroisel PM, Kunstmann E, Mair M, Munk-Schulenburg S, Nikoubashman O, Pauli S, Rudnik-Sch\u00f6neborn S, Sudholt I, Sure U, Tinschert S, Wiednig M, Zoll B, Ginsberg MH, Felbor U (2014) High mutation detection rates in cerebral cavernous malformation upon stringent inclusion criteria: one-third of probands are minors. Mol Genet Genomic Med 2:176\u2013185. https:\/\/doi.org\/10.1002\/mgg3.60","journal-title":"Mol Genet Genomic Med"},{"key":"847_CR12","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1038\/s41586-020-2287-8","volume":"581","author":"RL Collins","year":"2020","unstructured":"Collins RL, Brand H, Karczewski KJ, Zhao X, Alf\u00f6ldi J, Francioli LC, Khera AV, Lowther C, Gauthier LD, Wang H, Watts NA, Solomonson M, O\u2019Donnell-Luria A, Baumann A, Munshi R, Walker M, Whelan CW, Huang Y, Brookings T, Sharpe T, Stone MR, Valkanas E, Fu J, Tiao G, Laricchia KM, Ruano-Rubio V, Stevens C, Gupta N, Cusick C, Margolin L, Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, Taylor KD, Lin HJ, Rich SS, Post WS, Chen YI, Rotter JI, Nusbaum C, Philippakis A, Lander E, Gabriel S, Neale BM, Kathiresan S, Daly MJ, Banks E, MacArthur DG, Talkowski ME (2020) A structural variation reference for medical and population genetics. Nature 581:444\u2013451. https:\/\/doi.org\/10.1038\/s41586-020-2287-8","journal-title":"Nature"}],"container-title":["Neurogenetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10048-025-00847-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10048-025-00847-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10048-025-00847-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T04:05:09Z","timestamp":1769400309000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10048-025-00847-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,28]]},"references-count":12,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["847"],"URL":"https:\/\/doi.org\/10.1007\/s10048-025-00847-2","relation":{},"ISSN":["1364-6753"],"issn-type":[{"value":"1364-6753","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,28]]},"assertion":[{"value":"11 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 August 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the local ethics committee of the University Medicine Greifswald (BB 047\/14a) and was conducted in accordance with the ethical guidelines of the Declaration of Helsinki.\u00a0","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Research involving human participants"}},{"value":"The patient provided written informed consent to participate in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}},{"value":"The patient provided written informed consent for the publication of the medical information and images.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"65"}}