Analysis of the<i>C</i><i>9orf72</i>Gene in Patients with Amyotrophic Lateral Sclerosis in Spain and Different Populations Worldwide

García‐Redondo, Alberto; Dols‐Icardo, Oriol; Rojas‐García, Ricard; Esteban-Pérez, Jesús; Cordero-Vázquez, Pilar; Jl, Muñoz-Blanco; I, Catalina; González‐Muñoz, Miguel; Varona, L.; Sarasola, E.; Povedano, Mònica; Sevilla, Teresa; Guerrero, Antonio; Pardo, Julio; A, López de Munain; Márquez-Infante, Celedonio; Fj, de Rivera; Pástor, Pau; Jericó, Ivonne; Aá, de Arcaya; Js, Mora; Clarimón, Jordi; Jf, Gonzalo-Martínez; Juárez-Rufián, Alexandra; Atencia, Gabriela; Jiménez-Bautista, R; Moran, Yeinmy; Mascías, Javier; Hernández-Barral, María; Kapetanovic, Solange; García-Barcina, María; Alcalá, Concepción Martínez; Vela, A.; Ramírez-Ramos, C; Galán, Lucía; Pérez‐Tur, Jordi; Quintáns, Beatriz; Mj, Sobrido; Fernández‐Torrón, Roberto; Jj, Poza; Gorostidi, Ana; Paradas, Carmen; Villoslada, Pablo; Larrodé, P; Jl, Capablo; Pascual-Calvet, Jordi; Goñi, Mario; Morgado, Y; Guitart, Míriam; Moreno-Laguna, S; Rueda, Antonio; Martín-Estefanía, C; Cemillán, Carlos; Blesa, Rafael; Lleó, Alberto

doi:10.1002/humu.22211

Cited by 86 publications

(74 citation statements)

References 18 publications

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“…unlikely (p < 10 À8 ), and we conclude that methylation is the result of GGGGCC expansion. The frequency of the C9orf72 HRE in several Caucasian ALS cohorts range from 10.95% to 47% in fALS and 3.20%e21.1% in sALS (Garcia-Redondo et al, 2013;Gijselinck et al, 2012;Majounie et al, 2012;Millecamps et al, 2012;Mok K.Y. et al, 2012;Ratti et al, 2012;Sabatelli et al, 2012).…”

Section: Discussionmentioning

confidence: 98%

C9orf72 hexanucleotide repeat expansions in Chinese sporadic amyotrophic lateral sclerosis

Tang

Benyamin

et al. 2015

Neurobiology of Aging

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A hexanucleotide repeat expansion (HRE) in the C9orf72 gene has been identified as the most common mutation in amyotrophic lateral sclerosis (ALS) among Caucasian populations. We sought to comprehensively evaluate genetic and epigenetic variants of C9orf72 and the contribution of the HRE in Chinese ALS cases. We performed fragment-length and repeat-primed polymerase chain reaction to determine GGGGCC copy number and expansion within the C9orf72 gene in 1092 sporadic ALS (sALS) and 1062 controls from China. We performed haplotype analysis of 23 single-nucleotide polymorphisms within and surrounding C9orf72. The C9orf72 HRE was found in 3 sALS patients (0.3%) but not in control subjects (p = 0.25). For 2 of the cases with the HRE, genotypes of 8 single-nucleotide polymorphisms flanking the HRE were inconsistent with the haplotype reported to be strongly associated with ALS in Caucasian populations. For these 2 individuals, we found hypermethylation of the CpG island upstream of the repeat, an observation not detected in other sALS patients (p< 10(-8)) or controls. The detailed analysis of the C9orf72 locus in a large cohort of Chinese samples provides robust evidence that may not be consistent with a single Caucasian founder event. Both the Caucasian and Chinese haplotypes associated with HRE were highly associated with repeat lengths >8 repeats implying that both haplotypes may confer instability of repeat length.

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Section: Discussionmentioning

confidence: 98%

C9orf72 hexanucleotide repeat expansions in Chinese sporadic amyotrophic lateral sclerosis

Tang

Benyamin

et al. 2015

Neurobiology of Aging

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“…We approached this question by comparing baseline demographic and clinical features of C9Pos to C9Neg patients from a cohort of 781 patients with ALS to determine whether these 2 groups are clinically distinct, adding to published reports from European cohorts. 21,22 This was a clinic-based series of patients with ALS, which allowed us to avoid bias in patient selection. All patients at the Emory ALS Center are asked to donate DNA for research purposes, and thus the only criteria for inclusion were the diagnosis of ALS and the consent to donate blood for research.…”

Section: Demographic and Clinical Information Acquisitionmentioning

confidence: 99%

Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population

Umoh

Fournier

et al. 2016

Neurology

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Objective: We investigated whether the C9orf72 expansion mutation in patients with amyotrophic lateral sclerosis (ALS) is associated with unique demographic and clinical features.Methods: Between 2001 and, approximately half of all patients attending the Emory ALS Clinic agreed to donate DNA for research. This research cohort of 781 patients was screened for the C9orf72 expansion, and demographic and clinical data were compared between those with and without the C9orf72 mutation. For mutation carriers without a family history of ALS, we sought further family history of dementia and other non-ALS neurodegenerative diseases in first-degree relatives.Results: The C9orf72 expansion was identified in 61 patients (7.8%). Compared to those without the expansion mutation, these patients did not differ in race, age, or site of onset. As expected, C9orf72 patients were more likely to have a family history of ALS (59% vs 7.9%) and to present with comorbid frontotemporal dementia (FTD) (14.8% vs 1.7%). Survival was shorter in patients with the expansion (log-rank x 2 [1] 5 45.323, p , 0.001). Further investigation in 28 patients initially categorized as having no known family history of ALS identified a family history of dementia in 16 cases; 6 of these had characteristics suggestive of FTD. Conclusions:Comparing the C9orf72 ALS population to the general ALS population, there were no differences in race, age at onset, or proportion of patients with bulbar onset disease. Differences identified in patients with the C9orf72 mutation included shortened survival and an equal proportion of men and women. In addition, we found that assessing family history for dementia may identify other family members likely to be carrying the C9orf72 expansion, reduce the number of sporadic cases, and thus increase our understanding of disease penetrance.

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“…This is not the case for SOD1, FUS, or TARDBP mutations, which have been reported at similar percentages in a wide array of patient populations. On the other hand, the C9orf72 repeat expansion, which is a less penetrant mutation, is the most common mutation in studies of pan-European and North American patient populations [43,44], as well as in a recent study in a Turkish cohort [102], but is not as common among Chinese, Korean, and Japanese ALS patients [103][104][105].…”

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confidence: 95%

Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD)

et al. 2015

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Analysis of theC9orf72Gene in Patients with Amyotrophic Lateral Sclerosis in Spain and Different Populations Worldwide

Cited by 86 publications

References 18 publications

C9orf72 hexanucleotide repeat expansions in Chinese sporadic amyotrophic lateral sclerosis

C9orf72 hexanucleotide repeat expansions in Chinese sporadic amyotrophic lateral sclerosis

Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population

Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD)

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