Title: The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder
Authors: Smith, Bradley N ×
Newhouse, Stephen
Shatunov, Aleksey
Vance, Caroline
Topp, Simon
Johnson, Lauren
Miller, Jack
Lee, Younbok
Troakes, Claire
Scott, Kirsten M
Jones, Ashley
Gray, Ian
Wright, Jamie
Hortobágyi, Tibor
Al-Sarraj, Safa
Rogelj, Boris
Powell, John
Lupton, Michelle
Lovestone, Simon
Sapp, Peter C
Weber, Markus
Nestor, Peter J
Schelhaas, Helenius J
Asbroek, Anneloor Alm Ten
Silani, Vincenzo
Gellera, Cinzia
Taroni, Franco
Ticozzi, Nicola
Van den Berg, Leonard
Veldink, Jan
Van Damme, Phillip
Robberecht, Wim
Shaw, Pamela J
Kirby, Janine
Pall, Hardev
Morrison, Karen E
Morris, Alex
de Belleroche, Jacqueline
Vianney de Jong, J M B
Baas, Frank
Andersen, Peter M
Landers, John
Brown, Robert H
Weale, Michael E
Al-Chalabi, Ammar
Shaw, Christopher E #
Issue Date: Jan-2013
Publisher: Karger
Series Title: European Journal of Human Genetics vol:21 issue:1 pages:102-8
Article number: 10.1038/ejhg.2012.98
Abstract: A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has 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 (total n=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.European Journal of Human Genetics advance online publication, 13 June 2012; doi:10.1038/ejhg.2012.98.
ISSN: 1018-4813
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for Neurobiology
× corresponding author
# (joint) last author

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