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First large genomic inversion in familial cerebral cavernous malformation identified by whole genome sequencing

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Abstract

Familial cerebral cavernous malformations (CCMs) predispose to seizures and hemorrhagic stroke. Molecular genetic analyses of CCM1, CCM2, and CCM3 result in a mutation detection rate of up to 98%. However, only whole genome sequencing (WGS) in combination with the Manta algorithm for analyses of structural variants revealed a heterozygous 24 kB inversion including exon 1 of CCM2 in a 12-year-old boy with familial CCMs. Its breakpoints were fine-mapped, and quantitative analysis on RNA confirmed reduced CCM2 expression. Our data expand the spectrum of CCM mutations and indicate that the existence of a fourth CCM disease gene is rather unlikely.

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Acknowledgements

The authors thank the patient and his family for their cooperation. Prof. Dr. Stefan Rohde is thanked for providing MRI scans of the index case. This work was supported by the German Research Foundation (DFG FE432/9-1).

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Authors and Affiliations

  1. Department of Human Genetics, University Medicine Greifswald, and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, Fleischmannstraße 43, D-17475, Greifswald, Germany

    Stefanie Spiegler, Matthias Rath & Ute Felbor

  2. Department of Human Genetics, Ruhr-University, 44801, Bochum, Germany

    Sabine Hoffjan

  3. Department of Neurosurgery, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany

    Philipp Dammann & Ulrich Sure

  4. Department of Neuropathology, University Hospital Giessen and Marburg, 35043, Marburg, Germany

    Axel Pagenstecher

  5. Institute of Human Genetics, Technische Universität München, 81675, Munich, Germany

    Tim Strom

  6. Institute of Human Genetics, Helmholtz Zentrum München, 85764, Neuherberg, Germany

    Tim Strom

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  1. Stefanie Spiegler
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  2. Matthias Rath
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  3. Sabine Hoffjan
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  4. Philipp Dammann
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  5. Ulrich Sure
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  6. Axel Pagenstecher
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  7. Tim Strom
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  8. Ute Felbor
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Correspondence to Ute Felbor.

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Spiegler, S., Rath, M., Hoffjan, S. et al. First large genomic inversion in familial cerebral cavernous malformation identified by whole genome sequencing. Neurogenetics 19, 55–59 (2018). https://doi.org/10.1007/s10048-017-0531-7

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  • DOI: https://doi.org/10.1007/s10048-017-0531-7

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