Investigation of C9orf72 in 4 neurodegenerative disorders
Author
dc.contributor.author
Xi, Zhengrui
Author
dc.contributor.author
Zinman, Lorne
Author
dc.contributor.author
Grinberg, Yakov
Author
dc.contributor.author
Moreno, Danielle
Author
dc.contributor.author
Sato, Christine
Author
dc.contributor.author
Bilbao, Juan M.
Author
dc.contributor.author
Ghani, Mahdi
Author
dc.contributor.author
Hernańdez, Isabel
Author
dc.contributor.author
Ruiz, Agustín
Author
dc.contributor.author
Boada, Mercè
Author
dc.contributor.author
Morón, Francisco J.
Author
dc.contributor.author
Lang, Anthony E.
Author
dc.contributor.author
Marras, Connie
Author
dc.contributor.author
Bruni, Amalia
Author
dc.contributor.author
Colao, Rosanna
Author
dc.contributor.author
Maletta, Raffaele G.
Author
dc.contributor.author
Puccio, Gianfranco
Author
dc.contributor.author
Rainero, Innocenzo
Author
dc.contributor.author
Pinessi, Lorenzo
Author
dc.contributor.author
Galimberti, Daniela
Author
dc.contributor.author
Morrison, Karen E.
Author
dc.contributor.author
Moorby, Catriona
Author
dc.contributor.author
Stockton, Joanne D.
Author
dc.contributor.author
Masellis, Mario
Author
dc.contributor.author
Black, Sandra E.
Author
dc.contributor.author
Hazrati, Lili-Naz
Author
dc.contributor.author
Liang, Yan
Author
dc.contributor.author
Haersma de With, Jan van
Author
dc.contributor.author
Fornazzari, Luis
Author
dc.contributor.author
Villagra, Roque
Author
dc.contributor.author
Rojas-Garcia, Ricardo
Author
dc.contributor.author
Clarimón, Jordi
Author
dc.contributor.author
Mayeux, Richard
Author
dc.contributor.author
Robertson, Janice
Author
dc.contributor.author
St George-Hyslop, Peter
Author
dc.contributor.author
Rogaeva, Ekaterina
Admission date
dc.date.accessioned
2019-01-29T13:56:01Z
Available date
dc.date.available
2019-01-29T13:56:01Z
Publication date
dc.date.issued
2012
Cita de ítem
dc.identifier.citation
Archives of Neurology, Volumen 69, Issue 12, 2012, Pages 1583-1590
Identifier
dc.identifier.issn
00039942
Identifier
dc.identifier.issn
15383687
Identifier
dc.identifier.other
10.1001/archneurol.2012.2016
Identifier
dc.identifier.uri
https://repositorio.uchile.cl/handle/2250/160035
Abstract
dc.description.abstract
Objective: To estimate the allele frequency of C9orf72 (G4C 2) repeats in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer disease (AD), and Parkinson disease (PD). Design: The number of repeats was estimated by a 2-step genotyping strategy. For expansion carriers, we sequenced the repeat flanking regions and obtained APOE genotypes and MAPT H1/H2 haplotypes. Setting: Hospitals specializing in neurodegenerative disorders. Subjects: We analyzed 520 patients with FTLD, 389 patients with ALS, 424 patients with AD, 289 patients with PD, 602 controls, 18 families, and 29 patients with PD with the LRRK2 G2019S mutation. Main Outcome Measure: The expansion frequency. Results: Based on a prior cutoff (>30 repeats), the expansion was detected in 9.3% of patients with ALS, 5.2% of patients with FTLD, and 0.7% of patients with PD but not in controls or patients with AD. It was significantly associated with family history of ALS or FTLD and age at onset of FTLD. Phenotype variation (ALS vs FTLD)
was not associated with MAPT, APOE, or variability in
the repeat flanking regions. Two patients with PD were
carriers of 39 and 32 repeats with questionable pathological significance, since the 39-repeat allele does not
segregate with PD. No expansion or intermediate alleles
(20-29 repeats) were found among the G2019S carriers
and AD cases with TAR DNA-binding protein 43–
positive inclusions. Surprisingly, the frequency of the 10-
repeat allele was marginally increased in all 4 neurodegenerative diseases compared with controls, indicating
the presence of an unknown risk variation in the C9orf72
locus.
Conclusions: The C9orf72 expansion is a common cause
of ALS and FTLD, but not of AD or PD. Our study raises
concern about a reliable cutoff for the pathological repeat number, which is important in the utility of genetic
screening.