BackgroundC9orf72hexanucleotide repeat expansions are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in European populations. Variable disease penetrance between families presents a challenge for genetic counselling of at-risk relatives and reduces the predictive utility of testing asymptomatic relatives. We have developed a novel model for estimating penetrance in individual families affected byC9orf72using available family history information, allowing the calculation of personalised risk estimates.MethodsPublished aggregated age-of-onset data forC9orf72-related ALS/FTD were used to generate age-related cumulative relative risks for at-risk relatives within pedigrees. Age-related relative risks are combined with a priori chance of individuals carrying an expansion based on known pedigree information. Penetrance is calculated as a number of affected individuals divided by the sum of cumulative age-related risks of relatives being affected by 80 years.ResultsThis method allows family-specific penetrance to be estimated from family history and at-risk relatives’ personalised age-related ALS/FTD risks to be calculated and illustrated graphically. Penetrance reduces as the number and age of at-risk unaffected relatives increases.ConclusionsFamily history remains the best indicator of penetrance inC9orf72expansion carriers. Calculating family-specific penetrance can aid genetic counselling by allowing at-risk relatives a more accurate understanding of their individual risk.
Journal article
BMJ Neurology Open
BMJ
09/2024
6
e000792 - e000792