Screening for C9ORF72 repeat expansion in FTLD

Ferrari, Raffaele; Mok, Kin Y.; Moreno, Jorge; Cosentino, Stephanie; Goldman, Jill; Pietrini, Pietro; Mayeux, Richard; Tierney, Michael; Kapogiannis, Dimitrios; Jicha, Gregory A.; Murrell, Jill R.; Ghetti, Bernardino; Wassermann, Eric M.; Grafman, Jordan; Hardy, John; Huey, Edward D.; Momeni, Parastoo

doi:10.1016/j.neurobiolaging.2012.02.017

Cited by 44 publications

(50 citation statements)

References 24 publications

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“…Small repeat sizes of 20-22 were reportedly pathogenic in FTD, 8 Eight studies found no significant difference in mean repeat lengths between expansion-negative FTD cases and controls. [10][11][12][13][14][15][16][17] Sporadic FTD cases appear to show similar allele frequency distribution as controls, with the two-unit repeat being the most common, followed by the 5-repeat, 6-repeat, 7-repeat or 8-repeat unit. [12][13][14][15][16][17][18][19] Repeat range was higher in a Dutch study of 363 FTD patients where…”

Section: Introductionmentioning

confidence: 99%

Intermediate C9orf72 alleles in neurological disorders: does size really matter?

Tan

2017

J Med Genet

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C9orf72 repeat expansions is a major cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. Sizes of <20 hexanucleotide repeats are observed in controls, while up to thousands associate with disease. Intermediate C9orf72 repeat lengths, however, remain uncertain. We systematically reviewed the role of intermediate C9orf72 alleles in C9orf72-related neurological disorders. We identified 49 studies with adequate available data on normal or intermediate C9orf72 repeat length, involving subjects with FTD, ALS, Parkinson’s disease (PD), atypical parkinsonism, Alzheimer’s disease (AD) and other aetiologies. We found that, overall, normal or intermediate C9orf72 repeat lengths are not associated with higher disease risk across these disorders, but intermediate allele sizes appear to associate more frequently with neuropsychiatric phenotypes. Intermediate sizes were detected in subjects with personal or family history of FTD and/or psychiatric illness, parkinsonism complicated by psychosis and rarely in psychiatric cohorts. Length of the hexanucleotide repeat may be influenced by ethnicity (with Asian controls displaying shorter normal repeat lengths compared with Caucasians) and underlying haplotype, with more patients and controls carrying the ‘risk’ haplotype rs3849942 displaying intermediate alleles. There is some evidence that intermediate alleles display increased methylation levels and affect normal transcriptional activity of the C9orf72 promoter, but the ‘critical’ repeat size required for initiation of neurodegeneration remains unknown and requires further study. In common neurological diseases, intermediate C9orf72 repeats do not influence disease risk but may associate with higher frequency of neuropsychiatric symptoms. This has important clinical relevance as intermediate carriers pose a challenge for genetic counselling.

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Section: Introductionmentioning

confidence: 99%

Intermediate C9orf72 alleles in neurological disorders: does size really matter?

Tan

2017

J Med Genet

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“…6 The p.Y294C GRN variant is novel, and has not been detected in other patients or in controls; it was present in a patient with behavioral variant FTD and it is predicted to be damaging. 24 The p.A239T MAPT variant was also identified in a patient with behavioral variant FTD. 6 She had 2 brothers with C9ORF72 expansions without the MAPT variant, who demonstrated signs of MND.…”

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confidence: 97%

“…Interestingly, 2 patients have already been described with both C9ORF72 repeat expansions and a GRN variant (p.Y294C), 24 or a MAPT variant (p.A239T). 6 The p.Y294C GRN variant is novel, and has not been detected in other patients or in controls; it was present in a patient with behavioral variant FTD and it is predicted to be damaging.…”

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confidence: 99%

C9ORF72 repeat expansions in cases with previously identified pathogenic mutations

et al. 2013

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Objective: To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases.Methods: A 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72. For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology.Results: We detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin (GRN: p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau (MAPT: p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (.3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations. Conclusions:Our findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members. Neurology

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“…In a small number of FTD/ALS cases, coexistent mutations have been found in GRN, TARDBP, and MAPT. Ferrari et al (2012) reported two missense mutations, in GRN and in PSEN2, in two FTD hexanucleotide expansion carriers. Recently, Kaivorinne et al (2014) found the p. Ser292del variant and the C9orf72 expansion in two siblings with typical bvFTD without ALS signs, although a direct pathogenic role of the p. Ser292del variant cannot be demonstrated.…”

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Neuroimaging features inC9orf72andTARDBPdouble mutation with FTD phenotype

et al. 2014

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Increasing evidence has shown that morphological and functional neuroimaging may help to understand the pathophysiological mechanisms leading to behavioral disturbances in patients with genetic or sporadic frontotemporal dementia (FTD). The C9orf72 expansion was found in association with the N267S TARDBP mutation in two siblings with behavioral-variant FTD (bvFTD). In one of them with very mild dementia, MRI showed symmetric atrophy of temporal, inferolateral and orbital frontal cortex, while [18F]FDG-PET disclosed more extended hypometabolism in dorsolateral and inferolateral frontal cortex, anterior cingulate, and caudate nucleus. Hypometabolism in right lateral and orbital frontal cortex was confirmed also in comparison with a group of sporadic bvFTD patients. These findings appear as the neuroimaging hallmark of double C9orf72 and TARDBP gene mutation with a bvFTD phenotype.

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Screening for C9ORF72 repeat expansion in FTLD

Cited by 44 publications

References 24 publications

Intermediate C9orf72 alleles in neurological disorders: does size really matter?

Intermediate C9orf72 alleles in neurological disorders: does size really matter?

C9ORF72 repeat expansions in cases with previously identified pathogenic mutations

Neuroimaging features inC9orf72andTARDBPdouble mutation with FTD phenotype

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