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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
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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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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