Abstract
Expansion of a hexanucleotide repeat in the C9ORF72 gene has been identified as the most common pathogenic mutation in families with autosomal dominant frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis. Herein we investigated frequency and penetrance of the C9ORF72 hexanucleotide repeat pathological expansion in a large cohort of familial and sporadic FTLD and related disorders (FTLD and related disorders, n = 388; Controls, n = 201). Moreover, we weighed the impact of C9ORF72 genotype on clinical phenotype taking into account the hexanucleotide repeat units number as a possible disease modifier. In our cohort, the C9ORF72 pathological expansion: i) showed a prevalence of 7.5%; ii) showed a full penetrance by the age of 80; iii) was rarely found in sporadic patients; iv) was solely associated with FTLD; v) was mainly associated with bvFTD clinical subtype; and vi) was associated with earlier age of onset in the youngest generation compared with the previous generation within a pedigree. Interestingly, intermediate C9ORF72 expansion had a risk effect in familial/sporadic FTLD. Eventually, the C9ORF72 repeat units number influenced the disease phenotype in terms of age of onset and associated clinical subtype. Genome-wide studies in well characterized clinical cohorts will be essential in order to decipher pathways of disease expression in C9ORF72-associated neurodegeneration.
| Original language | English |
|---|---|
| Pages (from-to) | 799-808 |
| Number of pages | 10 |
| Journal | Journal of Alzheimer's Disease |
| Volume | 38 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2014 |
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Keywords
- C9ORF72 repeat units number
- Endophenotype
- Frontotemporal dementia
- Genetic testing
- Mutation penetrance
- Mutation prevalence
- Pedigree
ASJC Scopus subject areas
- Psychiatry and Mental health
- Geriatrics and Gerontology
- Clinical Psychology
Cite this
C9ORF72 hexanucleotide repeat number in frontotemporal lobar degeneration : A genotype-phenotype correlation study. / Benussi, Luisa; Rossi, Giacomina; Glionna, Michela; Tonoli, Elisa; Piccoli, Elena; Fostinelli, Silvia; Paterlini, Anna; Flocco, Rosa; Albani, Diego; Pantieri, Roberta; Cereda, Cristina; Forloni, Gianluigi; Tagliavini, Fabrizio; Binetti, Giuliano; Ghidoni, Roberta.
In: Journal of Alzheimer's Disease, Vol. 38, No. 4, 2014, p. 799-808.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - C9ORF72 hexanucleotide repeat number in frontotemporal lobar degeneration
T2 - A genotype-phenotype correlation study
AU - Benussi, Luisa
AU - Rossi, Giacomina
AU - Glionna, Michela
AU - Tonoli, Elisa
AU - Piccoli, Elena
AU - Fostinelli, Silvia
AU - Paterlini, Anna
AU - Flocco, Rosa
AU - Albani, Diego
AU - Pantieri, Roberta
AU - Cereda, Cristina
AU - Forloni, Gianluigi
AU - Tagliavini, Fabrizio
AU - Binetti, Giuliano
AU - Ghidoni, Roberta
PY - 2014
Y1 - 2014
N2 - Expansion of a hexanucleotide repeat in the C9ORF72 gene has been identified as the most common pathogenic mutation in families with autosomal dominant frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis. Herein we investigated frequency and penetrance of the C9ORF72 hexanucleotide repeat pathological expansion in a large cohort of familial and sporadic FTLD and related disorders (FTLD and related disorders, n = 388; Controls, n = 201). Moreover, we weighed the impact of C9ORF72 genotype on clinical phenotype taking into account the hexanucleotide repeat units number as a possible disease modifier. In our cohort, the C9ORF72 pathological expansion: i) showed a prevalence of 7.5%; ii) showed a full penetrance by the age of 80; iii) was rarely found in sporadic patients; iv) was solely associated with FTLD; v) was mainly associated with bvFTD clinical subtype; and vi) was associated with earlier age of onset in the youngest generation compared with the previous generation within a pedigree. Interestingly, intermediate C9ORF72 expansion had a risk effect in familial/sporadic FTLD. Eventually, the C9ORF72 repeat units number influenced the disease phenotype in terms of age of onset and associated clinical subtype. Genome-wide studies in well characterized clinical cohorts will be essential in order to decipher pathways of disease expression in C9ORF72-associated neurodegeneration.
AB - Expansion of a hexanucleotide repeat in the C9ORF72 gene has been identified as the most common pathogenic mutation in families with autosomal dominant frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis. Herein we investigated frequency and penetrance of the C9ORF72 hexanucleotide repeat pathological expansion in a large cohort of familial and sporadic FTLD and related disorders (FTLD and related disorders, n = 388; Controls, n = 201). Moreover, we weighed the impact of C9ORF72 genotype on clinical phenotype taking into account the hexanucleotide repeat units number as a possible disease modifier. In our cohort, the C9ORF72 pathological expansion: i) showed a prevalence of 7.5%; ii) showed a full penetrance by the age of 80; iii) was rarely found in sporadic patients; iv) was solely associated with FTLD; v) was mainly associated with bvFTD clinical subtype; and vi) was associated with earlier age of onset in the youngest generation compared with the previous generation within a pedigree. Interestingly, intermediate C9ORF72 expansion had a risk effect in familial/sporadic FTLD. Eventually, the C9ORF72 repeat units number influenced the disease phenotype in terms of age of onset and associated clinical subtype. Genome-wide studies in well characterized clinical cohorts will be essential in order to decipher pathways of disease expression in C9ORF72-associated neurodegeneration.
KW - C9ORF72 repeat units number
KW - Endophenotype
KW - Frontotemporal dementia
KW - Genetic testing
KW - Mutation penetrance
KW - Mutation prevalence
KW - Pedigree
UR - http://www.scopus.com/inward/record.url?scp=84890464112&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84890464112&partnerID=8YFLogxK
U2 - 10.3233/JAD-131028
DO - 10.3233/JAD-131028
M3 - Article
VL - 38
SP - 799
EP - 808
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
SN - 1387-2877
IS - 4
ER -