Back to Search
Start Over
Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study
- Source :
- The Lancet Neurology; Vol 11, Majounie, E, Renton, A E, Mok, K, Dopper, E G P, Waite, A, Rollinson, S, Chio, A, Restagno, G, Nicolaou, N, Simon-Sanchez, J, van Swieten, J C, Abramzon, Y, Johnson, J O, Sendtner, M, Pamphlett, R, Orrell, R W, Mead, S, Sidle, K C, Houlden, H, Rohrer, J D, Morrison, K E, Pall, H, Talbot, K, Ansorge, O, Hernandez, D G, Arepalli, S, Sabatelli, M, Mora, G, Corbo, M, Giannini, F, Calvo, A, Englund, E, Borghero, G, Foris, G L, Remes, A M, Laaksovirta, H, McCluskey, L, Trojanowski, J Q, Van Deerlin, V M, Schellenberg, G D, Nalls, M A, Drory, V E, Lu, C S, Yeh, T H, Ishiura, H, Takahashi, Y, Tsuji, S, Le Ber, I, Brice, A, Drepper, C, Williams, N, Kirby, J, Shaw, P, Hardy, J, Tienari, P J, Heutink, P, Morris, H R, Pickering-Brown, S & Traynor, B J 2012, ' Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study ', Lancet Neurology, vol. 11, no. 4, pp. 323-330 . https://doi.org/10.1016/S1474-4422(12)70043-1, Lancet Neurology, 11(4), 323-330. Lancet Publishing Group, Nature Communications, Nature Communications, Nature Publishing Group, 2012, 11 (4), pp.323-30. ⟨10.1016/S1474-4422(12)70043-1⟩, Nature Communications, 2012, 11 (4), pp.323-30. ⟨10.1016/S1474-4422(12)70043-1⟩, Lancet Neurology; 11(4), pp 323-330 (2012)
- Publication Year :
- 2012
- Publisher :
- Elsevier BV, 2012.
-
Abstract
- International audience; BACKGROUND: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). METHODS: We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. FINDINGS: In patients with sporadic ALS, we identified the repeat expansion in 236 (7*0%) of 3377 white individuals from the USA, Europe, and Australia, two (4*1%) of 49 black individuals from the USA, and six (8*3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39*3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6*0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24*8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. INTERPRETATION: A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).
- Subjects :
- MESH: Signal Transduction
Male
MESH: Vesicular Transport Proteins
MESH: Membrane Glycoproteins
MESH: DNA Repeat Expansion
MESH: Genotype
Cohort Studies
MESH: Protein Structure, Tertiary
MESH: Aged, 80 and over
MESH: Interferon Regulatory Factor-3
0302 clinical medicine
C9orf72
MESH: Child
MESH: RNA, Small Interfering
80 and over
genetics
Age of Onset
Child
MESH: Cohort Studies
MESH: Amyotrophic Lateral Sclerosis
MESH: Aged
Genetics
Aged, 80 and over
0303 health sciences
MESH: Middle Aged
DNA Repeat Expansion
MESH: Toll-Like Receptor 4
Middle Aged
Penetrance
3. Good health
Settore MED/26 - NEUROLOGIA
Neurology
MESH: Young Adult
MESH: HEK293 Cells
Child, Preschool
Frontotemporal Dementia
Female
Sample collection
Chromosomes, Human, Pair 9
MESH: Myeloid Differentiation Factor 88
Frontotemporal dementia
Human
Pair 9
Adult
MESH: Protein Transport
medicine.medical_specialty
Adolescent
Genotype
MESH: Age of Onset
MESH: RNA Interference
Clinical Neurology
MESH: Frontotemporal Dementia
MESH: Genetic Loci
TARDBP
Chromosomes
03 medical and health sciences
Open Reading Frames
Young Adult
MESH: Cross-Sectional Studies
Internal medicine
medicine
MESH: Chemokine CCL5
Humans
ddc:610
Preschool
MESH: Adaptor Proteins, Signal Transducing
030304 developmental biology
Aged
MESH: Adolescent
MESH: Humans
business.industry
MESH: Transfection
MESH: Child, Preschool
Haplotype
Amyotrophic Lateral Sclerosis
MESH: Adult
MESH: Adaptor Proteins, Vesicular Transport
MESH: Open Reading Frames
medicine.disease
MESH: Male
MESH: Cell Line
C9orf72 Protein
Cross-Sectional Studies
MESH: Endosomes
Genetic Loci
[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Neurology (clinical)
MESH: Lipopolysaccharides
MESH: Chromosomes, Human, Pair 9
business
Trinucleotide repeat expansion
MESH: Female
Adolescent, Adult, Age of Onset, Aged, Aged
80 and over, Amyotrophic Lateral Sclerosis
genetics, Child, Child
Preschool, Chromosomes
genetics, Cohort Studies, Cross-Sectional Studies, DNA Repeat Expansion
genetics, Female, Frontotemporal Dementia
genetics, Genetic Loci, Genotype, Humans, Male, Middle Aged, Open Reading Frames
genetics, Young Adult
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 14744422, 20411723, and 14744465
- Volume :
- 11
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- The Lancet Neurology
- Accession number :
- edsair.doi.dedup.....8784206eb3366edf49dc1cda0e6ce09f
- Full Text :
- https://doi.org/10.1016/s1474-4422(12)70043-1