The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder

Bradley N Smith, Stephen Newhouse, Aleksey Shatunov, Caroline Vance, Simon Topp, Lauren Johnson, Jack Miller, Younbok Lee, Claire Troakes, Kirsten M Scott, Ashley Jones, Ian Gray, Jamie Wright, Tibor Hortobágyi, Safa Al-Sarraj, Boris Rogelj, John Powell, Michelle Lupton, Simon Lovestone, Peter C SappMarkus Weber, Peter J Nestor, Helenius J Schelhaas, Anneloor Alm Ten Asbroek, Vincenzo Silani, Cinzia Gellera, Franco Taroni, Nicola Ticozzi, Leonard Van den Berg, Jan Veldink, Phillip Van Damme, Wim Robberecht, Pamela J Shaw, Janine Kirby, Hardev Pall, Karen E Morrison, Alex Morris, Jacqueline de Belleroche, J M B Vianney de Jong, Frank Baas, Peter M Andersen, John Landers, Robert H Brown, Michael E Weale, Ammar Al-Chalabi, Christopher E Shaw

Research output: Contribution to journalArticlepeer-review

188 Citations (Scopus)


A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS+/−FTD from five European cohorts (totaln=1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n=434) and controls (n=856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/−FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/−FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P<10−8). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.
Original languageEnglish
Article numberN/A
Pages (from-to)102-108
Number of pages7
JournalEuropean Journal of Human Genetics
Issue number1
Early online date13 Jun 2012
Publication statusPublished - Jan 2013


  • Age of Onset
  • Amyotrophic Lateral Sclerosis
  • Cohort Studies
  • Europe
  • Founder Effect
  • Frontotemporal Dementia
  • Gene Frequency
  • Genomic Instability
  • Haplotypes
  • Humans
  • Mutation
  • Polymorphism, Single Nucleotide
  • Proteins
  • Repetitive Sequences, Nucleic Acid


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