Assessment of risk of ALS conferred by the GGGGCC hexanucleotide repeat expansion in C9orf72 among first-degree relatives of patients with ALS carrying the repeat expansion

Abstract

Objectives

We aimed to estimate the age-related risk of ALS in first-degree relatives of patients with ALS carrying the C9orf72 repeat expansion.

Methods

We included all patients with ALS carrying a C9orf72 repeat expansion in The Netherlands. Using structured questionnaires, we determined the number of first-degree relatives, their age at death due to ALS or another cause, or age at time of questionnaire. The cumulative incidence of ALS among first-degree relatives was estimated, while accounting for death from other causes. Variability in ALS risk between families was evaluated using a random effects hazards model. We used a second, distinct approach to estimate the risk of ALS and FTD in the general population, using previously published data.

Results

In total, 214 of the 2,486 (9.2%) patients with ALS carried the C9orf72 repeat expansion. The mean risk of ALS at age 80 for first-degree relatives carrying the repeat expansion was 24.1%, but ranged between individual families from 16.0 to 60.6%. Using the second approach, we found the risk of ALS and FTD combined was 28.7% (95% CI 17.8%–54.3%) for carriers in the general population.

Conclusions

On average, our estimated risk of ALS in the C9orf72 repeat expansion was lower compared to historical estimates. We showed, however, that the risk of ALS likely varies between families and one overall penetrance estimate may not be sufficient to describe ALS risk. This warrants a tailor-made, patient-specific approach in testing. Further studies are needed to assess the risk of FTD in the C9orf72 repeat expansion.

Keywords:

• penetrance
• c9orf72

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

LHvdB reports grants from the Netherlands ALS Foundation, The Netherlands Organization for Health Research and Development (Vici scheme), The European Community’s Health Seventh Framework Programme (grant number 259867; EuroMOTOR), and The Netherlands Organization for Health Research and Development (STRENGTH project) which was funded through the EU Joint Programme—Neurodegenerative Disease Research (JPND), during the conduct of the study; and ad hoc consultancy services to Biogen, Ferrer, Amylyx, Takeda and Argenx, for which their employer receives a fee for service, outside the submitted work. JHV reports this project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement n° 772376 - EScORIAL, and to have sponsored research agreements with Biogen and Astra Zeneca.