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

2019-10-29

Florian, Rahel T

Kraft, Florian

Leitão, Elsa

Kaya, Sabine

Klebe, Stephan

Magnin, Eloi

van Rootselaar, Anne-Fleur

Buratti, Julien

Kühnel, Theresa

Schröder, Christopher

Giesselmann, Sebastian

Tschernoster, Nikolai

Altmueller, Janine

Lamiral, Anaide

Keren, Boris

Nava, Caroline

Bouteiller, Delphine

Forlani, Sylvie

Jornea, Ludmila

Kubica, Regina

Ye, Tao

Plassard, Damien

Jost, Bernard

Meyer, Vincent

Deleuze, Jean-François

Delpu, Yannick

Avarello, Mario D M

Vijfhuizen, Lisanne S

Rudolf, Gabrielle

Hirsch, Edouard

Kroes, Thessa

Reif, Philipp S

Rosenow, Felix

Ganos, Christos

Vidailhet, Marie

Thivard, Lionel

Mathieu, Alexandre

Bourgeron, Thomas

Kurth, Ingo

Rafehi, Haloom

Steenpass, Laura

Horsthemke, Bernhard

LeGuern, Eric

Klein, Karl Martin

Labauge, Pierre

Bennett, Mark F

Bahlo, Melanie

Gecz, Jozef

Corbett, Mark A

Tijssen, Marina A J

van den Maagdenberg, Arn M J M

Depienne, Christel

Journal Article

0000-0002-5324-9155

0000-0001-5051-9714

0000-0002-8376-9098

0000-0002-0901-0905

0000-0001-7524-6222

0000-0002-3394-2083

0000-0001-8569-6163

0000-0002-2050-3911

0000-0002-5642-8378

0000-0002-8598-8147

0000-0002-6654-1665

0000-0001-7759-8555

0000-0002-3561-6804

0000-0001-5132-0774

0000-0002-7884-6861

0000-0001-9298-3072

0000-0001-5783-571X

0000-0002-7212-9554

10.1038/s41467-019-12763-9

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.

link

Nature Communications 2019; 10(1): 4919

Nature Communications