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

Rahel Florian 1 Florian Kraft 2 Elsa Leitão 1 Sabine Kaya 1 Stephan Klebe 3, 4 Eloi Magnin 5 Anne-Fleur van Rootselaar 6, 7 Julien Buratti 8 Theresa Kühnel 1 Christopher Schröder 1 Sebastian Giesselmann 2 Nikolai Tschernoster 9, 10 Janine Altmueller 10, 9 Anaide Lamiral 5 Boris Keren 8 Caroline Nava 8, 11 Delphine Bouteiller 11 Sylvie Forlani 11 Ludmila Jornea 11 Regina Kubica 1 Tao Ye 12 Damien Plassard 12 Bernard Jost 12 Vincent Meyer 13, 14 Jean-François Deleuze 13, 14 Yannick Delpu 15 Mario Avarello 15 Lisanne Vijfhuizen 16 Gabrielle Rudolf 12, 17 Edouard Hirsch 18, 17 Thessa Kroes 19, 20 Philipp Reif 21, 22 Felix Rosenow 21, 22 Christos Ganos 23 Marie Vidailhet 11, 24 Lionel Thivard 24 Alexandre Mathieu 25 Thomas Bourgeron 25 Ingo Kurth 2 Haloom Rafehi 26, 27, 28 Laura Steenpass 1 Bernhard Horsthemke 1 Eric Leguern 8, 11 Karl Martin Klein 21, 22, 29 Pierre Labauge 30 Mark Bennett 26, 27, 28 Melanie Bahlo 26, 27 Jozef Gecz 20, 31 Mark Corbett 20 Marina Tijssen 32 Arn van den Maagdenberg 16 Christel Depienne 1, 11, 12
1 Institute of Human Genetics - Institut für Humangenetik [Essen]
2 RWTH Aachen University
3 Uniklinik Essen - Universitätsklinikum Essen [Universität Duisburg-Essen]
4 Universität Duisburg-Essen [Essen]
5 Hôpital Jean Minjoz
6 AMC - Academic Medical Center - Academisch Medisch Centrum [Amsterdam]
7 Amsterdam Neuroscience [Pays-Bas]
8 Service de génétique [CHU Pitié-Salpêtrière]
9 CMMC - Centre for Molecular Medicine Cologne [Cologne]
10 CCG - Cologne Center for Genomics [Cologne]
11 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
12 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
13 JACOB - Institut de Biologie François JACOB
14 CNG - Centre National de Génotypage
15 genomic vision
16 Leiden University Medical Center (LUMC)
17 CRéER - Centre de référence des épilepsies rares [CHRU Strasbourg]
18 Service de Neurologie [Strasbourg]
19 School of Biological Sciences [Adelaïde]
20 University of Adelaide
21 Goethe-University Frankfurt am Main
22 Philipps University of Marburg
23 Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin
24 Département de Neurologie [Paris]
25 GHFC (UMR_3571 / U-Pasteur_1) - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions
26 WEHI - The Walter and Eliza Hall Institute of Medical Research
27 University of Melbourne
28 Epilepsy Research Centre
29 University of Calgary
30 Hôpital Gui de Chauliac
31 SAHMRI - South Australian Health and Medical Research Institute [ Adelaide]
32 UMCG - University Medical Center Groningen [Groningen]
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.
Keywords : Neurodegenerative diseases Genomic instability Neurological disorders Epilepsy
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Rahel Florian, Florian Kraft, Elsa Leitão, Sabine Kaya, Stephan Klebe, et al.. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3. Nature Communications, Nature Publishing Group, 2019, 10 (1), pp.4919. ⟨10.1038/s41467-019-12763-9⟩. ⟨pasteur-02562487⟩

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