title: Constitutional de novo and postzygotic mutations in isolated cases of cerebral cavernous malformations.
abstract: BACKGROUND
  Cerebral cavernous malformations (CCM) are vascular lesions of the central nervous system that can be found in sporadic or autosomal dominantly inherited forms and manifest with headaches, seizures, and hemorrhagic stroke. The precise proportion of de novo mutations in theCCM1,CCM2, andCCM3genes remains unknown.
  
  
  METHODS
  We here present a series of six trios with de novo mutations that have been analyzed by amplicon deep sequencing to differentiate between constitutional and postzygotic mutations.
  
  
  RESULTS
  In one case, allelic ratios clearly indicated mosaicism for aCCM3splice site mutation found in blood and buccal mucosa of a 2-year-old boy with multiple CCMs. The remaining five de novo mutations proved to be constitutional. In addition to threeCCM3, twoCCM1, and oneCCM2de novo point mutations, a deletion of the entireCCM3gene was identified in an index case that most likely originated from an early postzygotic event. These are the first high-level mosaic mutations reported in blood samples of isolated CCM cases.
  
  
  CONCLUSIONS
  Our data demonstrate that de novo mutations inCCM1-3might be more frequent than previously thought. Furthermore, amplicon deep sequencing is useful to discriminate between patients with constitutional and postzygotic mutations, and thereby improves genetic counseling.
authors.affiliation: Department of Human Genetics University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics University of Greifswald Greifswald Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Rath
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: Institute for Bioinformatics University Medicine Greifswald Greifswald Germany.
authors.forename: Neetika
authors.initials: N
authors.lastname: Nath
authors.affiliation: Department of Human Genetics University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics University of Greifswald Greifswald Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Schwefel
authors.affiliation: Institute for Clinical Genetics Faculty of Medicine Carl Gustav Carus TU Dresden Dresden Germany.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Di Donato
authors.affiliation: Department of Neuroradiology University Hospital Carl Gustav Carus Dresden Germany.
authors.forename: Johannes
authors.identifier: 0000-0001-7465-8700
authors.initials: J
authors.lastname: Gerber
authors.affiliation: Department of Neuropaediatrics Children's Hospital Oldenburg Oldenburg Germany.
authors.forename: G Christoph
authors.initials: GC
authors.lastname: Korenke
authors.affiliation: Institute of Human Genetics University of Lübeck Lübeck Germany.
authors.forename: Yorck
authors.initials: Y
authors.lastname: Hellenbroich
authors.affiliation: Center for and Institute of Human Genetics University of Regensburg Regensburg Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Hehr
authors.affiliation: Department of Neuropediatrics Justus-Liebig-University Gießen Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gross
authors.affiliation: Department of Neurosurgery University Hospital Essen University of Duisburg-Essen Essen Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Sure
authors.affiliation: Institute of Human Genetics Georg August University Göttingen Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Zoll
authors.affiliation: Department of Human Genetics University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics University of Greifswald Greifswald Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Gilberg
authors.affiliation: Institute for Bioinformatics University Medicine Greifswald Greifswald Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Kaderali
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: CCM1; CCM2; CCM3; cerebral cavernous malformation; de novo mutation; deep sequencing; postzygotic mutation