C9ORF72 hexanucleotide repeat number in frontotemporal lobar degeneration

A genotype-phenotype correlation study

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 languageEnglish
Pages (from-to)799-808
Number of pages10
JournalJournal of Alzheimer's Disease
Volume38
Issue number4
DOIs
Publication statusPublished - 2014

Fingerprint

Frontotemporal Lobar Degeneration
Genetic Association Studies
Penetrance
Age of Onset
Phenotype
Amyotrophic Lateral Sclerosis
Pedigree
Genotype
Genome
Mutation
Genes

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

@article{e036e5a3b8d049caababbb9630c8d0f8,
title = "C9ORF72 hexanucleotide repeat number in frontotemporal lobar degeneration: A genotype-phenotype correlation study",
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.",
keywords = "C9ORF72 repeat units number, Endophenotype, Frontotemporal dementia, Genetic testing, Mutation penetrance, Mutation prevalence, Pedigree",
author = "Luisa Benussi and Giacomina Rossi and Michela Glionna and Elisa Tonoli and Elena Piccoli and Silvia Fostinelli and Anna Paterlini and Rosa Flocco and Diego Albani and Roberta Pantieri and Cristina Cereda and Gianluigi Forloni and Fabrizio Tagliavini and Giuliano Binetti and Roberta Ghidoni",
year = "2014",
doi = "10.3233/JAD-131028",
language = "English",
volume = "38",
pages = "799--808",
journal = "Journal of Alzheimer's Disease",
issn = "1387-2877",
publisher = "IOS Press",
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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

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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 -