Age-based risk estimates for C9orf72RE-related diseases: Theoretical developments and added value for genetic...

The C9orf72 hexanucleotide repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). In genetic counseling, children of mutation carriers are often told that they have a 50% risk of carrying the mutation, but this figure does not take into account the fact that penetrance is age-related, with a unimodal distribution of disease onset around 58 years of age. Using a Bayesian approach, we developed a theory to calculate the probability of carrying the mutation for asymptomatic relatives (children/siblings and grandchildren/niblings) as well as the probability of developing ALS/FDT within a given time frame, based on their age. Using published data on age-related penetrance, we then calculated these probabilities and developed an online simulator that makes it easy to calculate them on a case-by-case basis. The conditional probabilities obtained can be very different from Mendelian values. For example, a 70-year-old asymptomatic child born to a carrier has approximately a 6% risk of being a carrier, which is far from 50%. For grandchildren, taking into account both their age and that of their parents also leads to figures that are much lower than those obtained if only their age were considered. For consultands, the decision to undergo testing is based in part on risk estimates. In this regard, the refined estimates and simulator we propose may prove to be valuable tools for genetic counseling for families affected by ALS/FTD linked to the C9orf72RE mutation. In addition, 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.