Oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling and therapeutic implications

Background Despite several studies suggesting a potential oligogenic risk model in amyotrophic lateral sclerosis (ALS), case–control statistical evidence implicating oligogenicity with disease risk or clinical outcomes is limited. Considering its direct clinical and therapeutic implications, we aim to perform a large-scale robust investigation of oligogenicity in ALS risk and in the disease clinical course. Methods We leveraged Project MinE genome sequencing datasets (6711 cases and 2391 controls) to identify associations between oligogenicity in known ALS genes and disease risk, as well as clinical outcomes. Results In both the discovery and replication cohorts, we observed that the risk imparted from carrying multiple ALS rare variants was significantly greater than the risk associated with carrying only a single rare variant, both in the presence and absence of variants in the most well-established ALS genes. However, in contrast to risk, the relationships between oligogenicity and ALS clinical outcomes, such as age of onset and survival, did not follow the same pattern. Conclusions Our findings represent the first large-scale, case–control assessment of oligogenicity in ALS and show that oligogenic events involving known ALS risk genes are relevant for disease risk in ~6% of ALS but not necessarily for disease onset and survival. This must be considered in genetic counselling and testing by ensuring to use comprehensive gene panels even when a pathogenic variant has already been identified. Moreover, in the age of stratified medication and gene therapy, it supports the need for a complete genetic profile for the correct choice of therapy in all ALS patients.