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

Affiliation
Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45147, Essen, Germany.
Florian, Rahel T.;
ORCID
0000-0002-5324-9155
Affiliation
Institute of Human Genetics, Medical Faculty, RWTH Aachen University, 52062, Aachen, Germany.
Kraft, Florian;
ORCID
0000-0001-5051-9714
Affiliation
Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45147, Essen, Germany.
Leitão, Elsa;
Affiliation
Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45147, Essen, Germany.
Kaya, Sabine;
GND
123761743
Affiliation
Department of Neurology, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstraße 55, 45147, Essen, Germany.
Klebe, Stephan;
Affiliation
Department of Neurology, CHU Jean Minjoz, 25000, Besançon, France.
Magnin, Eloi;
ORCID
0000-0002-8376-9098
Affiliation
Departments of Neurology and Clinical Neurophysiology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands.
van Rootselaar, Anne-Fleur;
ORCID
0000-0002-0901-0905
Affiliation
AP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique, 75013, Paris, France.
Buratti, Julien;
GND
1216509018
Affiliation
Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45147, Essen, Germany.
Kühnel, Theresa;
Affiliation
Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45147, Essen, Germany.
Schröder, Christopher;
Affiliation
Institute of Human Genetics, Medical Faculty, RWTH Aachen University, 52062, Aachen, Germany.
Giesselmann, Sebastian;
Affiliation
Cologne Center for Genomics, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Weyertal 115b, 50931, Cologne, Germany.
Tschernoster, Nikolai;
Affiliation
Cologne Center for Genomics, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Weyertal 115b, 50931, Cologne, Germany.
Altmueller, Janine;
ORCID
0000-0001-7524-6222
Affiliation
Department of Neurology, CHU Jean Minjoz, 25000, Besançon, France.
Lamiral, Anaide;
Affiliation
AP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique, 75013, Paris, France.
Keren, Boris;
Affiliation
AP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique, 75013, Paris, France.
Nava, Caroline;
Affiliation
Institut du Cerveau et de la Moelle épinière (ICM), Sorbonne Université, UMR S 1127, Inserm U1127, CNRS UMR 7225, F-75013, Paris, France.
Bouteiller, Delphine;
Affiliation
Institut du Cerveau et de la Moelle épinière (ICM), Sorbonne Université, UMR S 1127, Inserm U1127, CNRS UMR 7225, F-75013, Paris, France.
Forlani, Sylvie;
Affiliation
Institut du Cerveau et de la Moelle épinière (ICM), Sorbonne Université, UMR S 1127, Inserm U1127, CNRS UMR 7225, F-75013, Paris, France.
Jornea, Ludmila;
Affiliation
Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45147, Essen, Germany.
Kubica, Regina;
ORCID
0000-0002-3394-2083
Affiliation
IGBMC, CNRS UMR 7104/INSERM U1258/Université de Strasbourg, 1 Rue Laurent Fries, 67400, Illkirch-Graffenstaden, France.
Ye, Tao;
ORCID
0000-0001-8569-6163
Affiliation
IGBMC, CNRS UMR 7104/INSERM U1258/Université de Strasbourg, 1 Rue Laurent Fries, 67400, Illkirch-Graffenstaden, France.
Plassard, Damien;
Affiliation
IGBMC, CNRS UMR 7104/INSERM U1258/Université de Strasbourg, 1 Rue Laurent Fries, 67400, Illkirch-Graffenstaden, France.
Jost, Bernard;
Affiliation
Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, F-91057, Evry, France.
Meyer, Vincent;
Affiliation
Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, F-91057, Evry, France.
Deleuze, Jean-François;
Affiliation
Genomic Vision, 80 Rue des Meuniers, 92220, Bagneux, France.
Delpu, Yannick;
Affiliation
Genomic Vision, 80 Rue des Meuniers, 92220, Bagneux, France.
Avarello, Mario D. M.;
Affiliation
Department of Human Genetics, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.
Vijfhuizen, Lisanne S.;
ORCID
0000-0002-2050-3911
Affiliation
IGBMC, CNRS UMR 7104/INSERM U1258/Université de Strasbourg, 1 Rue Laurent Fries, 67400, Illkirch-Graffenstaden, France.
Rudolf, Gabrielle;
Affiliation
Department of Neurology-centre de référence des epilepsies rares, University Hospital of Strasbourg, 1 Avenue Molière, 67200, Strasbourg, France.
Hirsch, Edouard;
Affiliation
School of Biological Sciences, School of Medicine and Robinson Research Institute, The University of Adelaide, Adelaide, 5005, SA, Australia.
Kroes, Thessa;
Affiliation
Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Goethe University and LOEWE Center for Personalized Translational Epilepsy Research (CePTER), 60323, Frankfurt am Main, Germany.
Reif, Philipp S.;
Affiliation
Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Goethe University and LOEWE Center for Personalized Translational Epilepsy Research (CePTER), 60323, Frankfurt am Main, Germany.
Rosenow, Felix;
Affiliation
Department of Neurology, Charité University Medicine Berlin, 10117, Berlin, Germany.
Ganos, Christos;
Affiliation
Institut du Cerveau et de la Moelle épinière (ICM), Sorbonne Université, UMR S 1127, Inserm U1127, CNRS UMR 7225, F-75013, Paris, France.
Vidailhet, Marie;
Affiliation
APHP, Hôpital Pitié-Salpêtrière, Département de Neurologie, 75013, Paris, France.
Thivard, Lionel;
Affiliation
Human Genetics and Cognitive Functions, Pasteur Institute, UMR3571 CNRS, Université de Paris, 75015, Paris, France.
Mathieu, Alexandre;
Affiliation
Human Genetics and Cognitive Functions, Pasteur Institute, UMR3571 CNRS, Université de Paris, 75015, Paris, France.
Bourgeron, Thomas;
ORCID
0000-0002-5642-8378
Affiliation
Institute of Human Genetics, Medical Faculty, RWTH Aachen University, 52062, Aachen, Germany.
Kurth, Ingo;
Affiliation
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, VIC, Australia.
Rafehi, Haloom;
Affiliation
Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45147, Essen, Germany.
Steenpaß, Laura;
GND
172144035
ORCID
0000-0002-8598-8147
LSF
14406
Affiliation
Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45147, Essen, Germany.
Horsthemke, Bernhard;
Affiliation
AP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique, 75013, Paris, France.
LeGuern, Eric;
ORCID
0000-0002-6654-1665
Affiliation
Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Goethe University and LOEWE Center for Personalized Translational Epilepsy Research (CePTER), 60323, Frankfurt am Main, Germany.
Klein, Karl Martin;
ORCID
0000-0001-7759-8555
Affiliation
Department of Neurology, Gui de Chauliac University Hospital, 34295, Montpellier, France.
Labauge, Pierre;
ORCID
0000-0002-3561-6804
Affiliation
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, VIC, Australia.
Bennett, Mark F.;
ORCID
0000-0001-5132-0774
Affiliation
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, VIC, Australia.
Bahlo, Melanie;
ORCID
0000-0002-7884-6861
Affiliation
School of Biological Sciences, School of Medicine and Robinson Research Institute, The University of Adelaide, Adelaide, 5005, SA, Australia.
Gecz, Jozef;
ORCID
0000-0001-9298-3072
Affiliation
School of Biological Sciences, School of Medicine and Robinson Research Institute, The University of Adelaide, Adelaide, 5005, SA, Australia.
Corbett, Mark A.;
ORCID
0000-0001-5783-571X
Affiliation
Department of Neurology, University Medical Center Groningen, University of Groningen, 9700, AB, Groningen, the Netherlands.
Tijssen, Marina A. J.;
Affiliation
Department of Human Genetics, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.
van den Maagdenberg, Arn M. J. M.;
ORCID
0000-0002-7212-9554
Affiliation
Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45147, Essen, Germany. christel.depienne@uni-due.de.
Depienne, Christel

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.

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Florian, R.T., Kraft, F., Leitão, E., Kaya, S., Klebe, S., Magnin, E., van Rootselaar, A.-F., Buratti, J., Kühnel, T., Schröder, C., Giesselmann, S., Tschernoster, N., Altmueller, J., Lamiral, A., Keren, B., Nava, C., Bouteiller, D., Forlani, S., Jornea, L., Kubica, R., Ye, T., Plassard, D., Jost, B., Meyer, V., Deleuze, J.-F., Delpu, Y., Avarello, M.D.M., Vijfhuizen, L.S., Rudolf, G., Hirsch, E., Kroes, T., Reif, P.S., Rosenow, F., Ganos, C., Vidailhet, M., Thivard, L., Mathieu, A., Bourgeron, T., Kurth, I., Rafehi, H., Steenpaß, L., Horsthemke, B., LeGuern, E., Klein, K.M., Labauge, P., Bennett, M.F., Bahlo, M., Gecz, J., Corbett, M.A., Tijssen, M.A.J., van den Maagdenberg, A.M.J.M., Depienne, C., 2019. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3. https://doi.org/10.1038/s41467-019-12763-9
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