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

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  • External authors:
  • 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
  • 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
  • Huw R. Morris
  • Pentti J. Tienari
  • Bryan J. Traynor


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. © 2011 Elsevier Inc.

Bibliographical metadata

Original languageEnglish
Pages (from-to)257-268
Number of pages11
Issue number2
Publication statusPublished - 20 Oct 2011

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