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.