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

The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder
The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder
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.
1018-4813
102-108
Smith, Bradley N.
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Newhouse, Stephen
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Shatunov, Aleksey
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Vance, Caroline
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Hortobágyi, Tibor
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Lovestone, Simon
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Sapp, Peter C.
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Shaw, Pamela J.
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Pall, Hardev
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Morrison, Karen E.
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Morris, Alex
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de Belleroche, Jacqueline
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Vianney de Jong, J.M.B.
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Baas, Frank
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Andersen, Peter M.
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Landers, John
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Brown, Robert H.
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Weale, Michael E.
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Al-Chalabi, Ammar
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Shaw, Christopher E.
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Smith, Bradley N.
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Newhouse, Stephen
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Shatunov, Aleksey
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Vance, Caroline
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Topp, Simon
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Johnson, Lauren
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Miller, Jack
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Lee, Younbok
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Troakes, Claire
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Scott, Kirsten M.
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Jones, Ashley
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Gray, Ian
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Wright, Jamie
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Hortobágyi, Tibor
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Al-Sarraj, Safa
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Rogelj, Boris
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Powell, John
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Lupton, Michelle
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Lovestone, Simon
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Sapp, Peter C.
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Nestor, Peter J.
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Schelhaas, Helenius J.
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Silani, Vincenzo
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Gellera, Cinzia
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Taroni, Franco
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Ticozzi, Nicola
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Van den Berg, Leonard
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Veldink, Jan
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Van Damme, Phillip
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Robberecht, Wim
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Shaw, Pamela J.
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Kirby, Janine
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Pall, Hardev
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Morrison, Karen E.
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Morris, Alex
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de Belleroche, Jacqueline
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Vianney de Jong, J.M.B.
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Baas, Frank
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Andersen, Peter M.
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Landers, John
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Brown, Robert H.
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Weale, Michael E.
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Al-Chalabi, Ammar
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Shaw, Christopher E.
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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 and Shaw, Christopher E. (2013) The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder. European Journal of Human Genetics, 21 (1), 102-108. (doi:10.1038/ejhg.2012.98). (PMID:22692064)

Record type: Article

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.

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Accepted/In Press date: 24 April 2012
e-pub ahead of print date: 13 June 2012
Published date: January 2013
Organisations: Medical Education

Identifiers

Local EPrints ID: 398479
URI: http://eprints.soton.ac.uk/id/eprint/398479
ISSN: 1018-4813
PURE UUID: a71fea55-0c88-480b-835d-4b432861f4d9
ORCID for Karen E. Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 25 Jul 2016 14:26
Last modified: 17 Dec 2019 01:32

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Contributors

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

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