Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Rahel T. Florian, Florian Kraft, Elsa Leitão, Sabine Kaya, Stephan Klebe, Eloi Magnin, Anne-Fleur van Rootselaar, Julien Buratti, Theresa Kühnel, Christopher Schröder, Sebastian Giesselmann, Nikolai Tschernoster, Janine Altmueller, Anaide Lamiral, Boris Keren, Caroline Nava, Delphine Bouteiller, Sylvie Forlani, Ludmila Jornea, Regina Kubica, Tao Ye, Damien Plassard, Bernard Jost, Vincent Meyer, Jean-François Deleuze, Yannick Delpu, Mario D. M. Avarello, Lisanne S. Vijfhuizen, Gabrielle Rudolf, Edouard Hirsch, Thessa Kroes, Philipp S. Reif, Felix Rosenow, Christos Ganos, Marie Vidailhet, Lionel Thivard, Alexandre Mathieu, Thomas Bourgeron, Ingo Kurth, Haloom Rafehi, Laura Steenpass, Bernhard Horsthemke, Eric LeGuern, Karl Martin Klein, Pierre Labauge, Mark F. Bennett, Melanie Bahlo, Jozef Gecz, Mark A. Corbett, Marina A. J. Tijssen, Arn M. J. M. van den Maagdenberg and Christel Depienne ()
Additional contact information
Rahel T. Florian: University Hospital Essen, University of Duisburg-Essen
Florian Kraft: RWTH Aachen University
Elsa Leitão: University Hospital Essen, University of Duisburg-Essen
Sabine Kaya: University Hospital Essen, University of Duisburg-Essen
Stephan Klebe: Universitätsklinikum Essen, Universität Duisburg-Essen
Eloi Magnin: CHU Jean Minjoz
Anne-Fleur van Rootselaar: Amsterdam UMC, University of Amsterdam
Julien Buratti: AP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique
Theresa Kühnel: University Hospital Essen, University of Duisburg-Essen
Christopher Schröder: University Hospital Essen, University of Duisburg-Essen
Sebastian Giesselmann: RWTH Aachen University
Nikolai Tschernoster: University of Cologne
Janine Altmueller: University of Cologne
Anaide Lamiral: CHU Jean Minjoz
Boris Keren: AP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique
Caroline Nava: AP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique
Delphine Bouteiller: Sorbonne Université, UMR S 1127, Inserm U1127, CNRS UMR 7225
Sylvie Forlani: Sorbonne Université, UMR S 1127, Inserm U1127, CNRS UMR 7225
Ludmila Jornea: Sorbonne Université, UMR S 1127, Inserm U1127, CNRS UMR 7225
Regina Kubica: University Hospital Essen, University of Duisburg-Essen
Tao Ye: IGBMC, CNRS UMR 7104/INSERM U1258/Université de Strasbourg
Damien Plassard: IGBMC, CNRS UMR 7104/INSERM U1258/Université de Strasbourg
Bernard Jost: IGBMC, CNRS UMR 7104/INSERM U1258/Université de Strasbourg
Vincent Meyer: Institut de Biologie François Jacob, CEA, Université Paris-Saclay
Jean-François Deleuze: Institut de Biologie François Jacob, CEA, Université Paris-Saclay
Yannick Delpu: Genomic Vision, 80 Rue des Meuniers
Mario D. M. Avarello: Genomic Vision, 80 Rue des Meuniers
Lisanne S. Vijfhuizen: Leiden University Medical Center
Gabrielle Rudolf: IGBMC, CNRS UMR 7104/INSERM U1258/Université de Strasbourg
Edouard Hirsch: University Hospital of Strasbourg
Thessa Kroes: The University of Adelaide
Philipp S. Reif: Goethe University and LOEWE Center for Personalized Translational Epilepsy Research (CePTER)
Felix Rosenow: Goethe University and LOEWE Center for Personalized Translational Epilepsy Research (CePTER)
Christos Ganos: Charité University Medicine Berlin
Marie Vidailhet: Sorbonne Université, UMR S 1127, Inserm U1127, CNRS UMR 7225
Lionel Thivard: APHP, Hôpital Pitié-Salpêtrière, Département de Neurologie
Alexandre Mathieu: UMR3571 CNRS, Université de Paris
Thomas Bourgeron: UMR3571 CNRS, Université de Paris
Ingo Kurth: RWTH Aachen University
Haloom Rafehi: The Walter and Eliza Hall Institute of Medical Research
Laura Steenpass: University Hospital Essen, University of Duisburg-Essen
Bernhard Horsthemke: University Hospital Essen, University of Duisburg-Essen
Eric LeGuern: AP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique
Karl Martin Klein: Goethe University and LOEWE Center for Personalized Translational Epilepsy Research (CePTER)
Pierre Labauge: Gui de Chauliac University Hospital
Mark F. Bennett: The Walter and Eliza Hall Institute of Medical Research
Melanie Bahlo: The Walter and Eliza Hall Institute of Medical Research
Jozef Gecz: The University of Adelaide
Mark A. Corbett: The University of Adelaide
Marina A. J. Tijssen: University Medical Center Groningen, University of Groningen
Arn M. J. M. van den Maagdenberg: Leiden University Medical Center
Christel Depienne: University Hospital Essen, University of Duisburg-Essen

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.

Date: 2019
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DOI: 10.1038/s41467-019-12763-9

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