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.
Department of Clinical Neurosciences, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, Kings College London, London, UK.
Bradley N
BN
Smith
Stephen
S
Newhouse
Aleksey
A
Shatunov
Caroline
C
Vance
Simon
S
Topp
Lauren
L
Johnson
Jack
J
Miller
Younbok
Y
Lee
Claire
C
Troakes
Kirsten M
KM
Scott
Ashley
A
Jones
Ian
I
Gray
Jamie
J
Wright
Tibor
T
Hortobágyi
Safa
S
Al-Sarraj
Boris
B
Rogelj
John
J
Powell
Michelle
M
Lupton
Simon
S
Lovestone
Peter C
PC
Sapp
Markus
M
Weber
Peter J
PJ
Nestor
Helenius J
HJ
Schelhaas
Anneloor Alm Ten
AA
Asbroek
Vincenzo
V
Silani
Cinzia
C
Gellera
Franco
F
Taroni
Nicola
N
Ticozzi
Leonard
L
Van den Berg
Jan
J
Veldink
Phillip
P
Van Damme
Wim
W
Robberecht
Pamela J
PJ
Shaw
Janine
J
Kirby
Hardev
H
Pall
Karen E
KE
Morrison
Alex
A
Morris
Jacqueline
J
de Belleroche
J M B
JM
Vianney de Jong
Frank
F
Baas
Peter M
PM
Andersen
John
J
Landers
Robert H
RH
Brown
Michael E
ME
Weale
Ammar
A
Al-Chalabi
Christopher E
CE
Shaw
D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology / Q000235:genetics*; D000073885:C9orf72 Protein; D015331:Cohort Studies; D005060:Europe / Q000453:epidemiology; D018703:Founder Effect; D057180:Frontotemporal Dementia / Q000453:epidemiology / Q000235:genetics*; D005787:Gene Frequency; D042822:Genomic Instability; D006239:Haplotypes; D006801:Humans; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid
D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins