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

Author

Listed:
  • 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
    Sorbonne Université, UMR S 1127, Inserm U1127, CNRS UMR 7225)

  • 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
    University Hospital of 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)
    Epilepsy Center Hessen, Philipps University)

  • Felix Rosenow

    (Goethe University and LOEWE Center for Personalized Translational Epilepsy Research (CePTER)
    Epilepsy Center Hessen, Philipps University)

  • Christos Ganos

    (Charité University Medicine Berlin)

  • Marie Vidailhet

    (Sorbonne Université, UMR S 1127, Inserm U1127, CNRS UMR 7225
    APHP, Hôpital Pitié-Salpêtrière, Département de Neurologie)

  • 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
    University of Melbourne
    University of Melbourne, Austin Health)

  • 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
    Sorbonne Université, UMR S 1127, Inserm U1127, CNRS UMR 7225)

  • Karl Martin Klein

    (Goethe University and LOEWE Center for Personalized Translational Epilepsy Research (CePTER)
    Epilepsy Center Hessen, Philipps University
    Hotchkiss Brain Institute & Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary)

  • Pierre Labauge

    (Gui de Chauliac University Hospital)

  • Mark F. Bennett

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    University of Melbourne, Austin Health)

  • Melanie Bahlo

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Jozef Gecz

    (The University of Adelaide
    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
    Leiden University Medical Center)

  • Christel Depienne

    (University Hospital Essen, University of Duisburg-Essen
    Sorbonne Université, UMR S 1127, Inserm U1127, CNRS UMR 7225
    IGBMC, CNRS UMR 7104/INSERM U1258/Université de Strasbourg)

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.

Suggested Citation

  • 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 , 2019. "Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12763-9
    DOI: 10.1038/s41467-019-12763-9
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    Cited by:

    1. Lars Mohren & Friedrich Erdlenbruch & Elsa Leitão & Fabian Kilpert & G. Sebastian Hönes & Sabine Kaya & Christopher Schröder & Andreas Thieme & Marc Sturm & Joohyun Park & Agatha Schlüter & Montserrat, 2024. "Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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