Age-related penetrance of the C9orf72 repeat expansion

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.

Figure 1

Relationship between gender and site of onset in C9orf72 repeat expansion carriers. Donut chart showing the site of symptom onset and age at onset among male and female C9orf72 carriers. Inner layer shows the proportion of males (52.6%) and females (47.4%) in the cohort. The middle layer shows the site of onset within males and females. The outer histogram layer shows the age distribution within each subset. The y-axis of this outer histogram represents the number of patients at each age, whereas the x-axis represents age at symptom onset ranging from 25 to 83 years of age. The graph was created using Circos (version 0.67, available at www.circos.ca) and FusionCharts (www.jsfiddle.net/fusioncharts/J7svz).

Figure 2

Age-related penetrance of the pathogenic C9orf72 repeat expansion. The black curve shows age-related penetrance of 1,147 symptomatic patients and 23 asymptomatic individuals carrying the C9orf72 repeat expansion. The shading represents the 95% confidence interval and censored individuals (i.e. asymptomatic) are indicated by crosses. The red curve represents model data in which the proportion of asymptomatic individuals is artificially increased to 20% (n = 316).

Figure 3

Age-related penetrance of the pathogenic C9orf72 repeat expansion classified by subtype. (A) Age-related penetrance based on familial (n = 555) and sporadic (n = 544) status; (B) age-related penetrance curves based on ALS (n = 734) and FTD (n = 303) clinical phenotype; (C) age-related penetrance curves comparing male (n = 612) and female (n = 543) cases of ALS and FTD; (D) age-related penetrance curves among ALS patients based on bulbar (n = 270) or spinal (n = 481) site of symptom onset. The shading represents the 95% confidence interval and censored individuals (i.e. asymptomatic) are indicated by crosses.

Figure 4

Density plots of age of onset among pathogenic C9orf72 repeat expansion carriers. Density plot showing age of onset frequency distribution (A) among male (n = 393) and female (n = 357) ALS cases; (B) bulbar-onset (n = 256) and spinal-onset ALS cases (n = 481); (C) bulbar-onset male (n = 111) and bulbar-onset female (n = 111) ALS cases; (D) spinal-onset male (n = 273) and spinal-onset female (n = 208) cases. Shaded area represents differences between compared subgroups, and the dotted vertical line indicates median age of onset in the overall cohort (58.0 years of age).