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 Sapp; Markus 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

doi:10.1038/ejhg.2012.98

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 journal › Article › peer-review

192 Citations (Scopus)

Abstract

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 language	English
Article number	N/A
Pages (from-to)	102-108
Number of pages	7
Journal	European Journal of Human Genetics
Volume	21
Issue number	1
Early online date	13 Jun 2012
DOIs	https://doi.org/10.1038/ejhg.2012.98
Publication status	Published - Jan 2013

Keywords

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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10.1038/ejhg.2012.98

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@article{2364731d64d74a7fa7a0684c914c77e4,

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

abstract = "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.",

keywords = "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",

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

year = "2013",

month = jan,

doi = "10.1038/ejhg.2012.98",

language = "English",

volume = "21",

pages = "102--108",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

publisher = "Nature Publishing Group",

number = "1",

}

Smith, BN , Newhouse, S , Shatunov, A , Vance, C , Topp, S , Johnson, L , Miller, J , Lee, Y , Troakes, C, Scott, KM, Jones, A, Gray, I, Wright, J, Hortobágyi, T , Al-Sarraj, S , Rogelj, B , Powell, J , Lupton, M , Lovestone, S, Sapp, PC, Weber, M, Nestor, PJ, Schelhaas, HJ, Asbroek, AAT, Silani, V, Gellera, C, Taroni, F, Ticozzi, N, Van den Berg, L, Veldink, J, Van Damme, P, Robberecht, W, Shaw, PJ, Kirby, J, Pall, H, Morrison, KE, Morris, A, de Belleroche, J, Vianney de Jong, JMB, Baas, F, Andersen, PM, Landers, J, Brown, RH, Weale, ME , Al-Chalabi, A & Shaw, CE 2013, 'The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder', European Journal of Human Genetics, vol. 21, no. 1, N/A, pp. 102-108. https://doi.org/10.1038/ejhg.2012.98

TY - JOUR

T1 - The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder

AU - Smith, Bradley N

AU - Newhouse, Stephen

AU - Shatunov, Aleksey

AU - Vance, Caroline

AU - Topp, Simon

AU - Johnson, Lauren

AU - Miller, Jack

AU - Lee, Younbok

AU - Troakes, Claire

AU - Scott, Kirsten M

AU - Jones, Ashley

AU - Gray, Ian

AU - Wright, Jamie

AU - Hortobágyi, Tibor

AU - Al-Sarraj, Safa

AU - Rogelj, Boris

AU - Powell, John

AU - Lupton, Michelle

AU - Lovestone, Simon

AU - Sapp, Peter C

AU - Weber, Markus

AU - Nestor, Peter J

AU - Schelhaas, Helenius J

AU - Asbroek, Anneloor Alm Ten

AU - Silani, Vincenzo

AU - Gellera, Cinzia

AU - Taroni, Franco

AU - Ticozzi, Nicola

AU - Van den Berg, Leonard

AU - Veldink, Jan

AU - Van Damme, Phillip

AU - Robberecht, Wim

AU - Shaw, Pamela J

AU - Kirby, Janine

AU - Pall, Hardev

AU - Morrison, Karen E

AU - Morris, Alex

AU - de Belleroche, Jacqueline

AU - Vianney de Jong, J M B

AU - Baas, Frank

AU - Andersen, Peter M

AU - Landers, John

AU - Brown, Robert H

AU - Weale, Michael E

AU - Al-Chalabi, Ammar

AU - Shaw, Christopher E

PY - 2013/1

Y1 - 2013/1

N2 - 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.

AB - 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.

KW - Age of Onset

KW - Amyotrophic Lateral Sclerosis

KW - Cohort Studies

KW - Europe

KW - Founder Effect

KW - Frontotemporal Dementia

KW - Gene Frequency

KW - Genomic Instability

KW - Haplotypes

KW - Humans

KW - Mutation

KW - Polymorphism, Single Nucleotide

KW - Proteins

KW - Repetitive Sequences, Nucleic Acid

U2 - 10.1038/ejhg.2012.98

DO - 10.1038/ejhg.2012.98

M3 - Article

C2 - 22692064

SN - 1018-4813

VL - 21

SP - 102

EP - 108

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 1

M1 - N/A

ER -

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

Abstract

Keywords

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