TY - JOUR
T1 - Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3
AU - FAME consortium
AU - Florian, Rahel T.
AU - Kraft, Florian
AU - Leitão, Elsa
AU - Kaya, Sabine
AU - Klebe, Stephan
AU - Magnin, Eloi
AU - van Rootselaar, Anne Fleur
AU - Buratti, Julien
AU - Kühnel, Theresa
AU - Schröder, Christopher
AU - Giesselmann, Sebastian
AU - Tschernoster, Nikolai
AU - Altmueller, Janine
AU - Lamiral, Anaide
AU - Keren, Boris
AU - Nava, Caroline
AU - Bouteiller, Delphine
AU - Forlani, Sylvie
AU - Jornea, Ludmila
AU - Kubica, Regina
AU - Ye, Tao
AU - Plassard, Damien
AU - Jost, Bernard
AU - Meyer, Vincent
AU - Deleuze, Jean François
AU - Delpu, Yannick
AU - Avarello, Mario D.M.
AU - Vijfhuizen, Lisanne S.
AU - Rudolf, Gabrielle
AU - Hirsch, Edouard
AU - Kroes, Thessa
AU - Reif, Philipp S.
AU - Rosenow, Felix
AU - Ganos, Christos
AU - Vidailhet, Marie
AU - Thivard, Lionel
AU - Mathieu, Alexandre
AU - Bourgeron, Thomas
AU - Kurth, Ingo
AU - Rafehi, Haloom
AU - Steenpass, Laura
AU - Bisulli, Francesca
AU - Brancati, Francesco
AU - Canafoglia, Laura
AU - Casari, Giorgio
AU - Guerrini, Renzo
AU - Licchetta, Laura
AU - Striano, Pasquale
AU - Tinuper, Paolo
AU - Zara, Federico
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85074285073&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85074285073&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-12763-9
DO - 10.1038/s41467-019-12763-9
M3 - Article
C2 - 31664039
AN - SCOPUS:85074285073
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4919
ER -