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C9ORF72 hexanucleotide repeat number in frontotemporal lobar degeneration: a genotype-phenotype correlation study.
Luisa Benussi1, Giacomina Rossi, Michela Glionna
1NeuroBioGen Lab-Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
Journal of Alzheimer'S Disease : JAD
|September 26, 2013
Summary
The C9ORF72 gene expansion is a common cause of frontotemporal lobar degeneration (FTLD). This study found it in 7.5% of FTLD patients, with full penetrance by age 80, and it influences disease presentation.
Area of Science:
- Neurogenetics
- Neurodegenerative Diseases
- Molecular Biology
Background:
- Expansion of a hexanucleotide repeat in the C9ORF72 gene is the most frequent mutation in familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis.
- Understanding the frequency, penetrance, and clinical impact of this mutation is crucial for diagnosing and managing these disorders.
Purpose of the Study:
- To investigate the prevalence and penetrance of the C9ORF72 hexanucleotide repeat expansion in a large cohort of familial and sporadic FTLD and related disorders.
- To evaluate the impact of C9ORF72 genotype, including repeat unit number, on the clinical phenotype of FTLD.
- To explore the potential disease-modifying role of C9ORF72 repeat expansions.
Main Methods:
- Genotyping of a large cohort (n=388) of FTLD patients and controls (n=201) for C9ORF72 hexanucleotide repeat expansions.
- Clinical phenotyping of patients, including subtype classification (e.g., behavioral FTD) and age of onset.
- Analysis of the correlation between C9ORF72 repeat unit number and clinical presentation, including age of onset and subtype.
Main Results:
- The C9ORF72 pathological expansion was present in 7.5% of the FTLD cohort.
- The expansion demonstrated full penetrance by age 80 and was rarely observed in sporadic cases.
- The mutation was exclusively associated with FTLD, predominantly the behavioral variant (bvFTD), and linked to an earlier age of onset in younger generations within pedigrees.
- Intermediate C9ORF72 expansions showed a risk effect in familial/sporadic FTLD.
- The number of C9ORF72 repeat units significantly influenced the age of onset and clinical subtype.
Conclusions:
- The C9ORF72 hexanucleotide repeat expansion is a significant genetic factor in FTLD, particularly in familial cases.
- The repeat unit number acts as a disease modifier, affecting clinical phenotype and age of onset.
- Further genome-wide studies are needed to elucidate the pathways involved in C9ORF72-associated neurodegeneration.
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