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Mol Genet Genomic Med. 2016 Dec 20;5(1):21-27. doi: 10.1002/mgg3.256. eCollection 2017 Jan.

Constitutional de novo and postzygotic mutations in isolated cases of cerebral cavernous malformations.

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Department of Human Genetics University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics University of Greifswald Greifswald Germany.
Institute for Bioinformatics University Medicine Greifswald Greifswald Germany.
Institute for Clinical Genetics Faculty of Medicine Carl Gustav Carus TU Dresden Dresden Germany.
Department of Neuroradiology University Hospital Carl Gustav Carus Dresden Germany.
Department of Neuropaediatrics Children's Hospital Oldenburg Oldenburg Germany.
Institute of Human Genetics University of Lübeck Lübeck Germany.
Center for and Institute of Human Genetics University of Regensburg Regensburg Germany.
Department of Neuropediatrics Justus-Liebig-University Gießen Germany.
Department of Neurosurgery University Hospital Essen University of Duisburg-Essen Essen Germany.
Institute of Human Genetics Georg August University Göttingen Germany.



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 the CCM1,CCM2, and CCM3 genes remains unknown.


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.


In one case, allelic ratios clearly indicated mosaicism for a CCM3 splice 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 three CCM3, two CCM1, and one CCM2 de novo point mutations, a deletion of the entire CCM3 gene 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.


Our data demonstrate that de novo mutations in CCM1-3 might 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.


CCM1; CCM2; CCM3; cerebral cavernous malformation; de novo mutation; deep sequencing; postzygotic mutation

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