title: High mutation detection rates in cerebral cavernous malformation upon stringent inclusion criteria: one-third of probands are minors.
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.
authors.affiliation: Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald Greifswald, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Spiegler
authors.affiliation: Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald Greifswald, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Najm
authors.affiliation: Department of Medicine, University of California San Diego San Diego, California.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald Greifswald, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gkalympoudis
authors.affiliation: Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald Greifswald, Germany.
authors.forename: Winnie
authors.initials: W
authors.lastname: Schröder
authors.affiliation: Institute of Human Genetics, University of Ulm Ulm, Germany.
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
authors.affiliation: Department of Paediatrics and Paediatric Neurology, University of Göttingen Göttingen, Germany.
authors.forename: Knut
authors.initials: K
authors.lastname: Brockmann
authors.affiliation: Institute of Human Genetics, University of Aachen Aachen, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Elbracht
authors.affiliation: Division of Human Genetics, Medical University Innsbruck Innsbruck, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Fauth
authors.affiliation: Department of Neurology, Klinikum Kassel GmbH Kassel, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ferbert
authors.affiliation: Department of Neuropaediatrics, University Hospital Dresden Dresden, Germany.
authors.forename: Leonie
authors.initials: L
authors.lastname: Freudenberg
authors.affiliation: Institute of Medical Genetics and Applied Genomics, Rare Disease Center Tübingen, University of Tübingen Tübingen, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Grasshoff
authors.affiliation: Institute of Human Genetics, University of Lübeck Lübeck, Germany.
authors.forename: Yorck
authors.initials: Y
authors.lastname: Hellenbroich
authors.affiliation: Department of Human Genetics, Saarland University Homburg/Saar, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Henn
authors.affiliation: Department of Human Genetics, Ruhr-University Bochum, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hoffjan
authors.affiliation: Institute of Human Genetics, University of Lübeck Lübeck, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Hüning
authors.affiliation: Department of Neuropaediatrics, Children's Hospital Oldenburg, Germany.
authors.forename: G Christoph
authors.initials: GC
authors.lastname: Korenke
authors.affiliation: Institute of Human Genetics, Medical University Graz Graz, Austria.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kroisel
authors.affiliation: Institute of Human Genetics, University of Würzburg Würzburg, Germany.
authors.forename: Erdmute
authors.initials: E
authors.lastname: Kunstmann
authors.affiliation: Department of Human Genetics, Saarland University Homburg/Saar, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Mair
authors.affiliation: Institute of Human Genetics, University of Freiburg Freiburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Munk-Schulenburg
authors.affiliation: Department for Interventional and Diagnostic Neuroradiology, University Hospital Aachen Aachen, Germany.
authors.forename: Omid
authors.initials: O
authors.lastname: Nikoubashman
authors.affiliation: Institute of Human Genetics, University of Göttingen Göttingen, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Pauli
authors.affiliation: Institute of Human Genetics, University of Aachen Aachen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Rudnik-Schöneborn
authors.affiliation: Institute of Medical Genetics, University of Zürich Zürich, Switzerland.
authors.forename: Irene
authors.initials: I
authors.lastname: Sudholt
authors.affiliation: Department of Neurosurgery, University Hospital Essen Essen, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Sure
authors.affiliation: Institute of Clinical Genetics, Technical University of Dresden Dresden, Germany.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Tinschert
authors.affiliation: Department of Environmental Dermatology and Venereology, Medical University Graz Graz, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Wiednig
authors.affiliation: Institute of Human Genetics, University of Göttingen Göttingen, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Zoll
authors.affiliation: Department of Medicine, University of California San Diego San Diego, California.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ginsberg
authors.affiliation: Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald Greifswald, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Felbor
keywords: Age at disease onset; CCM1; CCM2; CCM3; HEG1; cerebral cavernous malformation; mutation detection rate; predictive testing