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A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD

Renton, Alan E., Majounie, Elisa ORCID:, Waite, Adrian James, Simón-Sánchez, Javier, Rollinson, Sara, Gibbs, J. Raphael, Schymick, Jennifer C., Laaksovirta, Hannu, van Swieten, John C., Myllykangas, Liisa, Kalimo, Hannu, Paetau, Anders, Abramzon, Yevgeniya, Remes, Anne M., Kaganovich, Alice, Scholz, Sonja W., Duckworth, Jamie, Ding, Jinhui, Harmer, Daniel W., Hernandez, Dena G., Johnson, Janel O., Mok, Kin, Ryten, Mina, Trabzuni, Danyah, Guerreiro, Rita J., Orrell, Richard W., Neal, James William, Murray, Alexandra, Pearson, Justin Peter, Jansen, Iris E., Sondervan, David, Seelaar, Harro, Blake, Derek J. ORCID:, Young, Kate, Halliwell, Nicola, Callister, Janis Bennion, Toulson, Greg, Richardson, Anna, Gerhard, Alex, Snowden, Julie, Mann, David, Neary, David, Nalls, Michael A., Peuralinna, Terhi, Jansson, Lilja, Isoviita, Veli-Matti, Kaivorinne, Anna-Lotta, Hölttä-Vuori, Maarit, Ikonen, Elina, Sulkava, Raimo, Benatar, Michael, Wuu, Joanne, Chiò, Adriano, Restagno, Gabriella, Borghero, Giuseppe, Sabatelli, Mario, Heckerman, David, Rogaeva, Ekaterina, Zinman, Lorne, Rothstein, Jeffrey D., Sendtner, Michael, Drepper, Carsten, Eichler, Evan E., Alkan, Can, Abdullaev, Ziedulla, Pack, Svetlana D., Dutra, Amalia, Pak, Evgenia, Hardy, John, Singleton, Andrew, Williams, Nigel Melville ORCID:, Heutink, Peter, Pickering-Brown, Stuart, Morris, Huw Rees, Tienari, Pentti J. and Traynor, Bryan J. 2011. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72 (2) , pp. 257-268. 10.1016/j.neuron.2011.09.010

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The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Neuroscience and Mental Health Research Institute (NMHRI)
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Publisher: Elsevier
ISSN: 0896-6273
Last Modified: 06 Nov 2022 13:10

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