Bayesian model refines age-dependent risk estimates for C9orf72 repeat expansion carriers
A new theoretical framework published in PLOS Genetics uses age-specific penetrance data to improve on the standard 50% carrier-risk figure given to relatives of C9orf72 mutation carriers.
Dominique de Vienne and Damien M. de Vienne, writing in PLOS Genetics, have developed a Bayesian framework for calculating the probability that an asymptomatic relative carries the C9orf72 hexanucleotide repeat expansion — the most common single genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
The standard figure quoted in genetic counselling is 50%, reflecting simple Mendelian transmission from an affected parent. The new model adjusts this estimate by incorporating the age-related penetrance of the expansion, which follows a unimodal distribution with onset clustering around 58 years of age. Because someone who has passed their peak-risk age without symptoms is less likely to carry the expansion than a young adult in the same family, the static 50% figure can misrepresent the actual probability at a given age.
Using the Bayesian approach, the authors derive age-stratified carrier-probability curves and demonstrate the added informational value these provide over the conventional estimate. The framework is positioned as a theoretical and educational advance intended to inform genetic counselling practice, rather than as a clinical tool in its own right.
The work is directly relevant to genetic counsellors and genetic nurses supporting families affected by ALS or FTD, and to researchers working on penetrance modelling for repeat-expansion disorders. It builds on existing published penetrance data rather than generating new empirical cohort data.
Plain-language version
For patients, families, and general readers. Educational only — not medical advice.
The C9orf72 gene change is the most common genetic cause of two serious brain conditions: ALS (also called motor neurone disease) and frontotemporal dementia (FTD). When a parent carries this change, their children are traditionally told there is a 50% chance they have inherited it too.
Researchers publishing in the journal PLOS Genetics have developed a new mathematical approach that takes age into account. Because this gene change tends to cause illness most often around age 58, someone who is already in their 60s or 70s without any symptoms is statistically less likely to carry it than a younger relative — so a flat 50% figure may not tell the full story.
The researchers have produced updated, age-adjusted probability estimates that they suggest could help genetic counsellors give families a more nuanced picture. This work is a theoretical development based on existing data; it does not change current clinical guidance on its own.
This is an educational summary, not medical advice. If anything here raises questions for you, please speak with your GP or a clinical professional.
Sources
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Primary source PLOS Genetics · 2026-07-13Age-based risk estimates for C9orf72RE-related diseases: Theoretical developments and added value for genetic counseling