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A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study

Ilse Gijselinck, Tim Van Langenhove, Julie van der Zee, Kristel Sleegers, Stephanie Philtjens, Gernot Kleinberger, Jonathan Janssens, Karolien Bettens, Caroline Van Cauwenberghe and Sandra Pereson, et al. (2012) LANCET NEUROLOGY. 11(1). p.54-65
abstract
Background Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are extremes of a clinically, pathologically, and genetically overlapping disease spectrum. A locus on chromosome 9p21 has been associated with both disorders, and we aimed to identify the causal gene within this region. Methods We studied 305 patients with FTLD, 137 with ALS, and 23 with concomitant FTLD and ALS (FTLD-ALS) and 856 controls from Flanders (Belgium); patients were identified from a hospital-based cohort and were negative for mutations in known FTLD and ALS genes. We also examined the family of one patient with FTLD-ALS previously linked to 9p21 (family DR14). We analysed 130 kbp at 9p21 in association and segregation studies, genomic sequencing, repeat genotyping, and expression studies to identify the causal mutation. We compared genotype-phenotype correlations between mutation carriers and non-carriers. Findings In the patient-control cohort, the single-nucleotide polymorphism rs28140707 within the 130 kbp region of 9p21 was associated with disease (odds ratio [OR] 2.6,95% CI 1.5-4.7; p=0.001). A GGGGCC repeat expansion in C9orf72 completely co-segregated with disease in family DR14. The association of rs28140707 with disease in the patient-control cohort was abolished when we excluded GGGGCC repeat expansion carriers. In patients with familial disease, six (86%) of seven with FTLD-ALS, seven (47%) of 15 with ALS, and 12 (16%) of 75 with FTLD had the repeat expansion. In patients without known familial disease, one (6%) of 16 with FTLD-ALS, six (5%) of 122 with ALS, and nine (4%) of 230 with FTLD had the repeat expansion. Mutation carriers primarily presented with classic ALS (10 of 11 individuals) or behavioural variant FTLD (14 of 15 individuals). Mean age at onset of FTLD was 55.3 years (SD 8.4) in 21 mutation carriers and 63.2 years (9.6) in 284 non-carriers (p=0.001); mean age at onset of ALS was 54.5 years (9.9) in 13 carriers and 60.4 years (11.4) in 124 non-carriers. Postmortem neuropathological analysis of the brains of three mutation carriers with FTLD showed a notably low TDP-43 load. In brain at postmortem, C9orf72 expression was reduced by nearly 50% in two carriers compared with nine controls (p=0.034). In familial patients, 14% of FTLD-ALS, 50% of ALS, and 62% of FTLD was not accounted for by known disease genes. Interpretation We identified a pathogenic GGGGCC repeat expansion in C9orf72 on chromosome 9p21, as recently also reported in two other studies. The GGGGCC repeat expansion is highly penetrant, explaining all of the contribution of chromosome 9p21 to FTLD and ALS in the Flanders-Belgian cohort. Decreased expression of C9orf72 in brain suggests haploinsufficiency as an underlying disease mechanism. Unidentified genes probably also contribute to the FTLD-ALS disease spectrum.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
MUTATIONS, INCLUSIONS, PREVALENCE, SUSCEPTIBILITY, FAMILIES, DEMENTIA, ALS, CHROMOSOME 9P, HEXANUCLEOTIDE REPEAT, MOTOR-NEURON DISEASE
journal title
LANCET NEUROLOGY
Lancet Neurol.
volume
11
issue
1
pages
54 - 65
Web of Science type
Article
Web of Science id
000298513700019
JCR category
CLINICAL NEUROLOGY
JCR impact factor
23.917 (2012)
JCR rank
1/190 (2012)
JCR quartile
1 (2012)
ISSN
1474-4422
DOI
10.1016/S1474-4422(11)70261-7
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2016739
handle
http://hdl.handle.net/1854/LU-2016739
date created
2012-02-02 16:03:29
date last changed
2013-01-23 10:37:51
@article{2016739,
  abstract     = {Background Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are extremes of a clinically, pathologically, and genetically overlapping disease spectrum. A locus on chromosome 9p21 has been associated with both disorders, and we aimed to identify the causal gene within this region. 
Methods We studied 305 patients with FTLD, 137 with ALS, and 23 with concomitant FTLD and ALS (FTLD-ALS) and 856 controls from Flanders (Belgium); patients were identified from a hospital-based cohort and were negative for mutations in known FTLD and ALS genes. We also examined the family of one patient with FTLD-ALS previously linked to 9p21 (family DR14). We analysed 130 kbp at 9p21 in association and segregation studies, genomic sequencing, repeat genotyping, and expression studies to identify the causal mutation. We compared genotype-phenotype correlations between mutation carriers and non-carriers. 
Findings In the patient-control cohort, the single-nucleotide polymorphism rs28140707 within the 130 kbp region of 9p21 was associated with disease (odds ratio [OR] 2.6,95\% CI 1.5-4.7; p=0.001). A GGGGCC repeat expansion in C9orf72 completely co-segregated with disease in family DR14. The association of rs28140707 with disease in the patient-control cohort was abolished when we excluded GGGGCC repeat expansion carriers. In patients with familial disease, six (86\%) of seven with FTLD-ALS, seven (47\%) of 15 with ALS, and 12 (16\%) of 75 with FTLD had the repeat expansion. In patients without known familial disease, one (6\%) of 16 with FTLD-ALS, six (5\%) of 122 with ALS, and nine (4\%) of 230 with FTLD had the repeat expansion. Mutation carriers primarily presented with classic ALS (10 of 11 individuals) or behavioural variant FTLD (14 of 15 individuals). Mean age at onset of FTLD was 55.3 years (SD 8.4) in 21 mutation carriers and 63.2 years (9.6) in 284 non-carriers (p=0.001); mean age at onset of ALS was 54.5 years (9.9) in 13 carriers and 60.4 years (11.4) in 124 non-carriers. Postmortem neuropathological analysis of the brains of three mutation carriers with FTLD showed a notably low TDP-43 load. In brain at postmortem, C9orf72 expression was reduced by nearly 50\% in two carriers compared with nine controls (p=0.034). In familial patients, 14\% of FTLD-ALS, 50\% of ALS, and 62\% of FTLD was not accounted for by known disease genes. 
Interpretation We identified a pathogenic GGGGCC repeat expansion in C9orf72 on chromosome 9p21, as recently also reported in two other studies. The GGGGCC repeat expansion is highly penetrant, explaining all of the contribution of chromosome 9p21 to FTLD and ALS in the Flanders-Belgian cohort. Decreased expression of C9orf72 in brain suggests haploinsufficiency as an underlying disease mechanism. Unidentified genes probably also contribute to the FTLD-ALS disease spectrum.},
  author       = {Gijselinck, Ilse  and Van Langenhove, Tim and van der Zee, Julie and Sleegers, Kristel and Philtjens, Stephanie and Kleinberger, Gernot and Janssens, Jonathan and Bettens, Karolien and Van Cauwenberghe, Caroline and Pereson, Sandra and Engelborghs, Sebastiaan  and SIEBEN, ANNE and De Jonghe, Peter and Vandenberghe, Rik and Santens, Patrick and De Bleecker, Jan and Maes, Githa and Baumer, Veerle and Dillen, Lubina and Joris, Geert and Cuijt, Ivy and Corsmit, Ellen  and Elinck, Ellen and Van Dongen, Jasper and Vermeulen, Steven and Van Den Broeck, Marleen and Vaerenberg, Carolien and Mattheijssens, Maria and Peeters, Karin and Robberecht, Wim and Cras, Patrick and Martin, Jean-Jacques and De Deyn, Peter and Cruts, Marc and Van Broeckhoven, Christine},
  issn         = {1474-4422},
  journal      = {LANCET NEUROLOGY},
  keyword      = {MUTATIONS,INCLUSIONS,PREVALENCE,SUSCEPTIBILITY,FAMILIES,DEMENTIA,ALS,CHROMOSOME 9P,HEXANUCLEOTIDE REPEAT,MOTOR-NEURON DISEASE},
  language     = {eng},
  number       = {1},
  pages        = {54--65},
  title        = {A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study},
  url          = {http://dx.doi.org/10.1016/S1474-4422(11)70261-7},
  volume       = {11},
  year         = {2012},
}

Chicago
Gijselinck, Ilse , Tim Van Langenhove, Julie van der Zee, Kristel Sleegers, Stephanie Philtjens, Gernot Kleinberger, Jonathan Janssens, et al. 2012. “A C9orf72 Promoter Repeat Expansion in a Flanders-Belgian Cohort with Disorders of the Frontotemporal Lobar Degeneration-amyotrophic Lateral Sclerosis Spectrum: a Gene Identification Study.” Lancet Neurology 11 (1): 54–65.
APA
Gijselinck, I., Van Langenhove, T., van der Zee, J., Sleegers, K., Philtjens, S., Kleinberger, G., Janssens, J., et al. (2012). A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. LANCET NEUROLOGY, 11(1), 54–65.
Vancouver
1.
Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G, et al. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. LANCET NEUROLOGY. 2012;11(1):54–65.
MLA
Gijselinck, Ilse , Tim Van Langenhove, Julie van der Zee, et al. “A C9orf72 Promoter Repeat Expansion in a Flanders-Belgian Cohort with Disorders of the Frontotemporal Lobar Degeneration-amyotrophic Lateral Sclerosis Spectrum: a Gene Identification Study.” LANCET NEUROLOGY 11.1 (2012): 54–65. Print.