A tool for ALS or FTD gene carriers.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases. A significant number of cases are linked to a hexanucleotide repeat expansion in the C9orf72 gene, making it the most common known genetic cause of both conditions.
Genetic counseling is essential in informing families about their risk, especially for those with a family history of the disease. Currently, children of C9orf72 mutation carriers are often told they have a 50% chance of inheriting the mutation. While technically correct based on Mendelian inheritance, this figure overlooks a critical factor: age-related penetrance.
Penetrance describes the likelihood that someone carrying a disease-causing gene will develop the disease. In cases of C9orf72-related ALS/FTD, penetrance increases with age, peaking around 58 years old. This means that simply knowing you carry the mutation does not give the full picture of your personal risk.
A new study addresses this limitation by developing a more precise method for calculating risk and providing an online tool for families.
The tool is available here: https://lbbeshiny.univ-lyon1.fr/ftd-als/
While other research has focused on identifying genetic modifiers of disease risk, this study centers on a readily available and easily measurable factor: age.
The researchers used a Bayesian approach, a statistical method that updates probabilities with new evidence. In this case, the evidence includes the individual's age and family history. By integrating age-related penetrance data, the researchers created a model to estimate the probability of carrying the C9orf72 mutation and developing ALS or FTD within a specific timeframe. This approach is especially relevant for asymptomatic relatives, such as children, siblings, grandchildren, and niblings of mutation carriers.
Importance of this work:
This research is significant because it moves beyond the simplified 50% risk figure, offering a more personalized and accurate risk assessment for individuals at risk of C9orf72-related ALS/FTD. It helps inform decisions about genetic testing and could influence lifestyle choices or participation in clinical trials. As testing for C9orf72 becomes more common, the need for nuanced interpretation of results increases. The findings are highly relevant for families affected by ALS/FTD, providing a more realistic understanding of their individual risk profiles.
Originality:
The study offers original insights beyond the basic concept. Although age-related penetrance is a known idea, this research presents a concrete, mathematically sound method to incorporate it into risk calculations. The online simulator further enhances its practical use. The novelty is in applying a Bayesian framework to refine risk estimates in C9orf72-related ALS/FTD, providing a more sophisticated and personalized approach than traditional Mendelian risk assessments.
Conclusion:
This study makes a valuable contribution to ALS/FTD genetics. By offering a more detailed and personalized risk assessment, it can improve genetic counseling, aid in clinical trial recruitment, and deepen the understanding of the disease. The online simulator makes this complex information accessible to clinicians and families, increasing its practical impact.