Age-Based Risk Estimates for C9orf72 RE-related Diseases: Theoretical Developments and Added Value for Genetic Counselling

The C9orf72 RE hexanucleotide repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). In genetic council, children of carriers of the mutation are often told they have a 50% risk of carrying the mutation, but this figure ignores the fact that the penetrance is age-related, with a unimodal distribution of the age of onset of the disease around 58 years. We have developed the theory to calculate the probability of carrying the mutation for asymptomatic relatives (children/siblings and grandchildren/niblings) and the probability of declaring ALS/FTD within a given time frame, based on their age. We have also built an online simulator to compute these probabilities using published data of age-related penetrance. The probabilities found can be markedly different from the Mendelian values. For example, a 70-year-old asymptomatic child of the carrier has a risk of about 6% of being a carrier, far from 50%. For grandchildren, taking into account jointly their age and the parental age also leads to figures much lower than those given if their age alone were considered. For consultands, the choice to undergo a test is partly based on the risk estimates. In this regard, the refined estimates and the simulator we propose can prove to be valuable tools for genetic counselling to families affected by C9orf72 RE -related ALS/FTD. Furthermore, the formulas used in this study could also be used to calculate risk estimates for other diseases caused by autosomal dominant mutations with age-dependent penetrance.