P32 Penetrance of neurodegenerative disorders in C9orf72 families: A C9orf72 national (ACORN) study

Background Hexanucleotide GGGGCC repeat expansion in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, family history of ALS and/or FTD may be absent, indicating that disease penetrance varies. Objective To determine the range and distribution of disease penetrance in families with C9orf72 expansions. Methods Pedigrees were analysed from participants of ‘A C9orf72 National (ACORN) Study’. Number of affected relatives and number and age of unaffected at-risk relatives was used to determine family-specific penetrance, taking into account a priori likelihood of relatives being carriers of C9orf72. Penetrance estimates were modelled using beta distributions. Results 52 families comprising 758 informative relatives were assessed. Neurodegeneration affected 177 people: 131 (75%) ALS, 27 (15%) FTD, 13 (7%) Alzheimer’s disease, 7 (4%) Parkinson’s disease and 58 (33%) dementia of any kind. Overall penetrance by 80 years was 64% (per-family penetrance range 27%-100%). Discussion This study confirms family-specific disease penetrance in C9orf72 families and illustrates how disease risk can be individualised. The high proportion of ALS may reflect recruitment bias but also suggests existence of genetic factors that specifically increase ALS risk. We now hope to investigate the causes of variable penetrance to identify protective therapeutic factors.