A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD
- Alan E. Renton ,
- Elisa Majounie ,
- Adrian Waite ,
- Javier Simon-Sanchez ,
- Sara Rollinson ,
- J. Raphael Gibbs ,
- Jennifer C Scymick ,
- 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 Isovaiita ,
- Anna-Lotta Kaivorinne ,
- Maarit Holtta-Vuori ,
- Elina Ikonen ,
- Raimo Sulkava ,
- MIchael Benatar ,
- Joanne Wuu ,
- Adriano Chio ,
- Garbiella Restagno ,
- Giuseppe Borghero ,
- Mario Sabatelli ,
- The ITALSGEN Consortium ,
- 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 ,
- Evengenia Pak ,
- John Hardy ,
- Andrew SIngleton ,
- Nigel M. Williams ,
- Peter Heutink ,
- Stuart Pickering-Brown ,
- Huw R. Morris ,
- Pentti J. Tienari ,
- Bryan J. Traynor
Neuron | , Vol 72(2): pp. 257-268
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.