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Abstract
A pathogenic hexanucleotide repeat expansion within the C9orf72 gene has been identified as the major cause of two neurodegenerative syndromes, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This mutation is known to have incomplete penetrance, with some patients developing disease in their twenties and a small portion of carriers surviving to their ninth decade without developing symptoms. Describing penetrance by age among C9orf72 carriers and identifying parameters that alter onset age are essential to better understanding this locus and to enhance predictive counseling. To do so, data from 1,170 individuals were used to model penetrance. Our analysis showed that the penetrance was incomplete and age-dependent. Additionally, familial and sporadic penetrance did not significantly differ from one another; ALS cases exhibited earlier age of onset than FTD cases; and individuals with spinal-onset exhibited earlier age of onset than those with bulbar-onset. The older age of onset among female cases in general, and among female bulbar-onset cases in particular, was the most striking finding, and there may be an environmental, lifestyle, or hormonal factor that is influencing these penetrance patterns. These results will have important applications for future clinical research, the identification of disease modifiers, and genetic counseling.
Highlights
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by rapidly progressive paralysis and death due to respiratory failure, typically within 2–4 years of onset
The variable phenotype associated with this mutation complicates these clinical trial efforts, especially future studies testing the ability of therapies to delay disease onset among asymptomatic carriers
We found that the penetrance of C9orf[72] repeat expansion exhibits incomplete, age-dependent penetrance, which confirms our previous findings and those of other groups[6, 9]. This more complete picture of C9orf[72] repeat expansion age-dependent penetrance will aid in the design and execution of clinical trials, and may be important – hopefully – in the future for decisions related to timing and administration of preventative therapy
Summary
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by rapidly progressive paralysis and death due to respiratory failure, typically within 2–4 years of onset. The C9orf[72] repeat expansion accounts for 1 in 10 of every ALS case among European-ancestry populations[5, 6]. This represents the first time that a large non-coding repeat expansion has been implicated in either of these neurodegenerative diseases. We previously published age-related estimates of C9orf[72] penetrance based on a relatively small cohort of carriers[6]. A better understanding of the age-related penetrance of the C9orf[72] repeat expansion will help in clinical trial design, and in determining at what stage to initiate neuroprotective therapy, should it become available in the future
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