High mutation detection rates in cerebral cavernous malformation upon stringent inclusion criteria: one-third of probands are minors

Stefanie Spiegler, Juliane Najm, Jian Liu, Stephanie Gkalympoudis, Winnie Schröder, Guntram Borck, Knut Brockmann, Miriam Elbracht, Christine Fauth, Andreas Ferbert, Leonie Freudenberg, Ute Grasshoff, Yorck Hellenbroich, Wolfram Henn, Sabine Hoffjan, Irina Hüning, G. Christoph Korenke, Peter M. Kroisel, Erdmute Kunstmann, Martina MairSusanne Munk-Schulenburg, Omid Nikoubashman, Silke Pauli, Sabine Rudnik-Schöneborn, Irene Sudholt, Ulrich Sure, Sigrid Tinschert, Michaela Wiednig, Barbara Zoll, Mark H. Ginsberg, Ute Felbor

Abstract

Cerebral cavernous malformations (CCM) are prevalent vascular malformations occurring in familial autosomal dominantly inherited or isolated forms. Once CCM are diagnosed by magnetic resonance imaging, the indication for genetic testing requires either a positive family history of cavernous lesions or clinical symptoms such as chronic headaches, epilepsy, neurological deficits, and hemorrhagic stroke or the occurrence of multiple lesions in an isolated case. Following these inclusion criteria, the mutation detection rates in a consecutive series of 105 probands were 87% for familial and 57% for isolated cases. Thirty-one novel mutations were identified with a slight shift towards proportionally more CCM3 mutations carriers than previously published (CCM1: 60%, CCM2: 18%, CCM3: 22%). In-frame deletions and exonic missense variants requiring functional analyses to establish their pathogenicity were rare: An in-frame deletion within the C-terminal FERM domain of CCM1 resulted in decreased protein expression and impaired binding to the transmembrane protein heart of glass (HEG1). Notably, 20% of index cases carrying a CCM mutation were below age 10 and 33% below age 18 when referred for genetic testing. Since fulminant disease courses during the first years of life were observed in CCM1 and CCM3 mutation carriers, predictive testing of minor siblings became an issue.
Original languageEnglish
JournalMolecular Genetics & Genomic Medicine
Volume2
Issue number2
Pages (from-to)176-185
Number of pages10
ISSN2324-9269
DOIs
Publication statusPublished - 03.2014

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