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

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

Neuron (2011-09-29)
Alan E Renton, Elisa Majounie, Adrian Waite, Javier Simón-Sánchez, Sara Rollinson, J Raphael Gibbs, Jennifer C Schymick, Hannu Laaksovirta, John C van Swieten, Liisa Myllykangas, Hannu Kalimo, Anders Paetau, Yevgeniya Abramzon, Anne M Remes, Alice Kaganovich, Sonja W Scholz, Jamie Duckworth, Jinhui Ding, Daniel W Harmer, Dena G Hernandez, Janel O Johnson, Kin Mok, Mina Ryten, Danyah Trabzuni, Rita J Guerreiro, Richard W Orrell, James Neal, Alex Murray, Justin Pearson, Iris E Jansen, David Sondervan, Harro Seelaar, Derek Blake, Kate Young, Nicola Halliwell, Janis Bennion Callister, Greg Toulson, Anna Richardson, Alex Gerhard, Julie Snowden, David Mann, David Neary, Michael A Nalls, Terhi Peuralinna, Lilja Jansson, Veli-Matti Isoviita, Anna-Lotta Kaivorinne, Maarit Hölttä-Vuori, Elina Ikonen, Raimo Sulkava, Michael Benatar, Joanne Wuu, Adriano Chiò, Gabriella Restagno, Giuseppe Borghero, Mario Sabatelli, David Heckerman, Ekaterina Rogaeva, Lorne Zinman, Jeffrey D Rothstein, Michael Sendtner, Carsten Drepper, Evan E Eichler, Can Alkan, Ziedulla Abdullaev, Svetlana D Pack, Amalia Dutra, Evgenia Pak, John Hardy, Andrew Singleton, Nigel M Williams, Peter Heutink, Stuart Pickering-Brown, Huw R Morris, Pentti J Tienari, Bryan J Traynor
PMID21944779
ABSTRACT

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.