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

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Item Type:Article
Title:Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3
Creators Name:Florian, R.T. and Kraft, F. and Leitão, E. and Kaya, S. and Klebe, S. and Magnin, E. and van Rootselaar, A.F. and Buratti, J. and Kühnel, T. and Schröder, C. and Giesselmann, S. and Tschernoster, N. and Altmüller, J. and Lamiral, A. and Keren, B. and Nava, C. and Bouteiller, D. and Forlani, S. and Jornea, L. and Kubica, R. and Ye, T. and Plassard, D. and Jost, B. and Meyer, V. and Deleuze, J.F. and Delpu, Y. and Avarello, M.D.M. and Vijfhuizen, L.S. and Rudolf, G. and Hirsch, E. and Kroes, T. and Reif, P.S. and Rosenow, F. and Ganos, C. and Vidailhet, M. and Thivard, L. and Mathieu, A. and Bourgeron, T. and Kurth, I. and Rafehi, H. and Steenpass, L. and Horsthemke, B. and LeGuern, E. and Klein, K.M. and Labauge, P. and Bennett, M.F. and Bahlo, M. and Gecz, J. and Corbett, M.A. and Tijssen, M.A.J and van den Maagdenberg, A.M.J.M. and Depienne, C.
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:Chromosome Mapping, DNA Repeat Expansion, Introns, Membrane Proteins, Myoclonic Epilepsies, Pedigree, Ubiquitin-Protein Ligases
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:4919
Date:29 October 2019
Official Publication:https://doi.org/10.1038/s41467-019-12763-9
PubMed:View item in PubMed

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