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

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

  • Nat Commun. 2019 Oct 29;10(1):4919. doi: 10.1038/s41467-019-12763-9.
Rahel T Florian 1,  Florian Kraft 2,  Elsa Leitão 1,  Sabine Kaya 1,  Stephan Klebe 3,  Eloi Magnin 4,  Anne-Fleur van Rootselaar 5,  Julien Buratti 6,  Theresa Kühnel 1,  Christopher Schröder 1,  Sebastian Giesselmann 2,  Nikolai Tschernoster 7,  Janine Altmueller 7,  Anaide Lamiral 4,  Boris Keren 6,  Caroline Nava 6 8,  Delphine Bouteiller 8,  Sylvie Forlani 8,  Ludmila Jornea 8,  Regina Kubica 1,  Tao Ye 9,  Damien Plassard 9,  Bernard Jost 9,  Vincent Meyer 10,  Jean-François Deleuze 10,  Yannick Delpu 11,  Mario D M Avarello 11,  Lisanne S Vijfhuizen 12,  Gabrielle Rudolf 9 13,  Edouard Hirsch 13,  Thessa Kroes 14,  Philipp S Reif 15 16,  Felix Rosenow 15 16,  Christos Ganos 17,  Marie Vidailhet 8 18,  Lionel Thivard 18,  Alexandre Mathieu 19,  Thomas Bourgeron 19,  Ingo Kurth 2,  Haloom Rafehi 20 21 22,  Laura Steenpass 1,  Bernhard Horsthemke 1,  FAME consortium,  Eric LeGuern 6 8,  Karl Martin Klein 15 16 23,  Pierre Labauge 24,  Mark F Bennett 20 21 22,  Melanie Bahlo 20 21,  Jozef Gecz 14 25,  Mark A Corbett 14,  Marina A J Tijssen 26,  Arn M J M van den Maagdenberg 12 27,  Christel Depienne 28 29 30
Affiliations

Affiliations

  • 1 Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45147, Essen, Germany.
  • 2 Institute of Human Genetics, Medical Faculty, RWTH Aachen University, 52062, Aachen, Germany.
  • 3 Department of Neurology, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstraße 55, 45147, Essen, Germany.
  • 4 Department of Neurology, CHU Jean Minjoz, 25000, Besançon, France.
  • 5 Departments of Neurology and Clinical Neurophysiology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands.
  • 6 AP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique, 75013, Paris, France.
  • 7 Cologne Center for Genomics, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Weyertal 115b, 50931, Cologne, Germany.
  • 8 Institut du Cerveau et de la Moelle épinière (ICM), Sorbonne Université, UMR S 1127, Inserm U1127, CNRS UMR 7225, F-75013, Paris, France.
  • 9 IGBMC, CNRS UMR 7104/INSERM U1258/Université de Strasbourg, 1 Rue Laurent Fries, 67400, Illkirch-Graffenstaden, France.
  • 10 Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, F-91057, Evry, France.
  • 11 Genomic Vision, 80 Rue des Meuniers, 92220, Bagneux, France.
  • 12 Department of Human Genetics, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.
  • 13 Department of Neurology-centre de référence des epilepsies rares, University Hospital of Strasbourg, 1 Avenue Molière, 67200, Strasbourg, France.
  • 14 School of Biological Sciences, School of Medicine and Robinson Research Institute, The University of Adelaide, Adelaide, 5005, SA, Australia.
  • 15 Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Goethe University and LOEWE Center for Personalized Translational Epilepsy Research (CePTER), 60323, Frankfurt am Main, Germany.
  • 16 Department of Neurology, Epilepsy Center Hessen, Philipps University, 35037, Marburg, Germany.
  • 17 Department of Neurology, Charité University Medicine Berlin, 10117, Berlin, Germany.
  • 18 APHP, Hôpital Pitié-Salpêtrière, Département de Neurologie, 75013, Paris, France.
  • 19 Human Genetics and Cognitive Functions, Pasteur Institute, UMR3571 CNRS, Université de Paris, 75015, Paris, France.
  • 20 Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, VIC, Australia.
  • 21 Department of Medical Biology, University of Melbourne, Melbourne, 3010, VIC, Australia.
  • 22 Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, 3084, VIC, Australia.
  • 23 Departments of Clinical Neurosciences, Medical Genetics and Community Health Sciences, Hotchkiss Brain Institute & Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, 2500 University Dr NW, Calgary, AB, T2N 1N4, Canada.
  • 24 Department of Neurology, Gui de Chauliac University Hospital, 34295, Montpellier, France.
  • 25 South Australian Health and Medical Research Institute, The University of Adelaide, Adelaide, 5005, SA, Australia.
  • 26 Department of Neurology, University Medical Center Groningen, University of Groningen, 9700, AB, Groningen, the Netherlands.
  • 27 Department of Neurology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
  • 28 Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45147, Essen, Germany. [email protected].
  • 29 Institut du Cerveau et de la Moelle épinière (ICM), Sorbonne Université, UMR S 1127, Inserm U1127, CNRS UMR 7225, F-75013, Paris, France. [email protected].
  • 30 IGBMC, CNRS UMR 7104/INSERM U1258/Université de Strasbourg, 1 Rue Laurent Fries, 67400, Illkirch-Graffenstaden, France. [email protected].
PMID: 31664039 DOI: 10.1038/s41467-019-12763-9
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.

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