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.
102-108
Smith, Bradley N.
d707ebcc-5728-47c9-a143-d6a5a2906055
Newhouse, Stephen
9d597b4a-be0c-4b1d-8e7f-f1a460174aec
Shatunov, Aleksey
e4422e0f-4878-404a-8e9e-fc45b4d5d9bd
Vance, Caroline
abed10a7-4433-4d85-918d-d3d1d73d2a98
Topp, Simon
87c7e700-3d61-445d-995c-32e756371526
Johnson, Lauren
9faa9932-b329-484e-be24-5ff3077355e3
Miller, Jack
920a813e-f63b-492a-b6ad-b0f13fe640a4
Lee, Younbok
c681f436-828f-4501-8b14-61b561f369f1
Troakes, Claire
872c40b7-a327-4a98-a682-a9fd7f3ec255
Scott, Kirsten M.
9ba43ead-63c9-4558-a23b-d38ef2235d59
Jones, Ashley
88875ff8-f810-4186-b815-a243a80bbc77
Gray, Ian
65518b18-4b80-441e-a820-a36559ed2226
Wright, Jamie
0b4f4371-c95a-4a3f-8a97-afc0e77ae57b
Hortobágyi, Tibor
61c9dcee-3c4e-4797-89d4-6ed47ec6201a
Al-Sarraj, Safa
bad034e5-2bfa-421e-9278-10656553c023
Rogelj, Boris
871dd1f2-62a2-4774-9212-2c89cf07da14
Powell, John
0616c5bf-0ce6-48ef-9b89-45a72529beb1
Lupton, Michelle
00083587-2d9a-4341-9155-39117708ab53
Lovestone, Simon
8c74cdb9-c6cc-4f60-8ad4-beaf5b526040
Sapp, Peter C.
60a7159c-1a1b-46e6-b0f5-c701d52254e5
Weber, Markus
b9015b0d-f973-4def-bab4-93da562e72b4
Nestor, Peter J.
1bb15a95-8f2a-4ebb-9ae8-03757f0b5902
Schelhaas, Helenius J.
240fb4c5-e110-496e-9afa-6433df8d4728
Asbroek, Anneloor ALM ten
45a9045e-1736-4c15-99ec-062b46fd347e
Silani, Vincenzo
14b98cfa-849f-4072-903f-5ff9077f2105
Gellera, Cinzia
83f42af0-2cf1-4380-87d2-b2f4aff5fbb7
Taroni, Franco
b1070d9b-d505-4ddc-b773-0b90ba2f7e22
Ticozzi, Nicola
d80e92fc-0775-4d73-9be9-974a56957076
Van den Berg, Leonard
be593907-70e2-4a69-b7ce-40fe1f8fcb33
Veldink, Jan
09b110af-7e3c-4000-8834-36055dd148b9
Van Damme, Phillip
10010134-4a1b-4d45-9585-51c596115985
Robberecht, Wim
d91a4719-00b2-4a40-99ef-04bcdff6cae5
Shaw, Pamela J.
3d0a5c6f-9610-45be-a0bc-5b6888003028
Kirby, Janine
59b4a438-0185-46a5-a76c-9f96b0ea3fe2
Pall, Hardev
940b7c3a-7b6f-4ede-8cf4-cd0e2497e752
Morrison, Karen E.
f00890f0-2fde-4dbd-a73b-7422e1b0ede8
Morris, Alex
84e423a7-350b-4fc5-ae0f-b41902840283
de Belleroche, Jacqueline
a062f08e-ed99-4aee-a470-2850af237c63
Vianney de Jong, J.M.B.
e8bfa3c5-883e-458b-a14f-b80470c393d4
Baas, Frank
59626a53-6490-406f-99a5-02d2622e8032
Andersen, Peter M.
8035638e-0eb6-4ab3-a2c2-70e8f59e0d96
Landers, John
29da3a55-c26a-4beb-9686-e577bdf43521
Brown, Robert H.
53461f4a-ed23-40f5-b339-0e4c7991991e
Weale, Michael E.
08e9259c-f52a-4279-925a-dfcecb60ad34
Al-Chalabi, Ammar
db16bbda-7684-49b4-9b2d-9799c7dba33c
Shaw, Christopher E.
ad432fe6-4928-445b-a3e1-aaba83c6a530
January 2013
Smith, Bradley N.
d707ebcc-5728-47c9-a143-d6a5a2906055
Newhouse, Stephen
9d597b4a-be0c-4b1d-8e7f-f1a460174aec
Shatunov, Aleksey
e4422e0f-4878-404a-8e9e-fc45b4d5d9bd
Vance, Caroline
abed10a7-4433-4d85-918d-d3d1d73d2a98
Topp, Simon
87c7e700-3d61-445d-995c-32e756371526
Johnson, Lauren
9faa9932-b329-484e-be24-5ff3077355e3
Miller, Jack
920a813e-f63b-492a-b6ad-b0f13fe640a4
Lee, Younbok
c681f436-828f-4501-8b14-61b561f369f1
Troakes, Claire
872c40b7-a327-4a98-a682-a9fd7f3ec255
Scott, Kirsten M.
9ba43ead-63c9-4558-a23b-d38ef2235d59
Jones, Ashley
88875ff8-f810-4186-b815-a243a80bbc77
Gray, Ian
65518b18-4b80-441e-a820-a36559ed2226
Wright, Jamie
0b4f4371-c95a-4a3f-8a97-afc0e77ae57b
Hortobágyi, Tibor
61c9dcee-3c4e-4797-89d4-6ed47ec6201a
Al-Sarraj, Safa
bad034e5-2bfa-421e-9278-10656553c023
Rogelj, Boris
871dd1f2-62a2-4774-9212-2c89cf07da14
Powell, John
0616c5bf-0ce6-48ef-9b89-45a72529beb1
Lupton, Michelle
00083587-2d9a-4341-9155-39117708ab53
Lovestone, Simon
8c74cdb9-c6cc-4f60-8ad4-beaf5b526040
Sapp, Peter C.
60a7159c-1a1b-46e6-b0f5-c701d52254e5
Weber, Markus
b9015b0d-f973-4def-bab4-93da562e72b4
Nestor, Peter J.
1bb15a95-8f2a-4ebb-9ae8-03757f0b5902
Schelhaas, Helenius J.
240fb4c5-e110-496e-9afa-6433df8d4728
Asbroek, Anneloor ALM ten
45a9045e-1736-4c15-99ec-062b46fd347e
Silani, Vincenzo
14b98cfa-849f-4072-903f-5ff9077f2105
Gellera, Cinzia
83f42af0-2cf1-4380-87d2-b2f4aff5fbb7
Taroni, Franco
b1070d9b-d505-4ddc-b773-0b90ba2f7e22
Ticozzi, Nicola
d80e92fc-0775-4d73-9be9-974a56957076
Van den Berg, Leonard
be593907-70e2-4a69-b7ce-40fe1f8fcb33
Veldink, Jan
09b110af-7e3c-4000-8834-36055dd148b9
Van Damme, Phillip
10010134-4a1b-4d45-9585-51c596115985
Robberecht, Wim
d91a4719-00b2-4a40-99ef-04bcdff6cae5
Shaw, Pamela J.
3d0a5c6f-9610-45be-a0bc-5b6888003028
Kirby, Janine
59b4a438-0185-46a5-a76c-9f96b0ea3fe2
Pall, Hardev
940b7c3a-7b6f-4ede-8cf4-cd0e2497e752
Morrison, Karen E.
f00890f0-2fde-4dbd-a73b-7422e1b0ede8
Morris, Alex
84e423a7-350b-4fc5-ae0f-b41902840283
de Belleroche, Jacqueline
a062f08e-ed99-4aee-a470-2850af237c63
Vianney de Jong, J.M.B.
e8bfa3c5-883e-458b-a14f-b80470c393d4
Baas, Frank
59626a53-6490-406f-99a5-02d2622e8032
Andersen, Peter M.
8035638e-0eb6-4ab3-a2c2-70e8f59e0d96
Landers, John
29da3a55-c26a-4beb-9686-e577bdf43521
Brown, Robert H.
53461f4a-ed23-40f5-b339-0e4c7991991e
Weale, Michael E.
08e9259c-f52a-4279-925a-dfcecb60ad34
Al-Chalabi, Ammar
db16bbda-7684-49b4-9b2d-9799c7dba33c
Shaw, Christopher E.
ad432fe6-4928-445b-a3e1-aaba83c6a530