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 - Rheinisch-Westfälische Technische Hochschule Aachen University
3 Uniklinik Essen - Universitätsklinikum Essen [Universität Duisburg-Essen]
4 Universität Duisburg-Essen [Essen]
5 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
6 AMC - Academic Medical Center - Academisch Medisch Centrum [Amsterdam]
7 Amsterdam Neuroscience [Pays-Bas]
8 Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière]
9 CMMC - Centre for Molecular Medicine Cologne [Cologne]
10 CCG - Cologne Center for Genomics [Cologne]
11 ICM - Institut du Cerveau = Paris Brain 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 Universität Marburg = Philipps University of Marburg
23 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
24 Service de Neurologie [CHU Pitié-Salpêtrière]
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]

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; Neurological disorders; Epilepsy; Genomic instability

Domains: Life Sciences [q-bio]; Genetics; Life Sciences [q-bio]; Genetics; Human genetics

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, 2019, 10 (1), pp.4919. ⟨10.1038/s41467-019-12763-9⟩. ⟨pasteur-02562487⟩