| Title: |
Oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling and therapeutic implications |
| Authors: |
Iacoangeli,Alfredo; Dilliott,Allison A.; Al Khleifat,Ahmad; Andersen,Peter M.; Başak,Nazli A.; Cooper-Knock,Johnathan; Corcia,Philippe; Couratier,Philippe; Decarvalho,Mamede; Drory,Vivian E.; Glass,Jonathan D.; Gotkine,Marc; Lerner,Yosef M.; Hardiman,Orla; Landers,John E.; McLaughlin, Russell L.; Pardina,Jesus S.Mora; Morrison,Karen; Pinto,Susana; Povedano,Monica; Shaw,Christopher E.; Shaw,Pamela J.; Silani,Vincenzo; Ticozzi,Nicola; Van Damme,Philip; Van Den Berg, Leonard H.; Vourc'H,Patrick; Weber,Markus; Veldink, Jan Herman; Dobson,Richard; Rouleau,Guy A.; Al-Chalabi,Ammar; Farhan,Sali M.K.; Project MinE ALS Sequencing Consortium; Neurologen; Projectafdeling ALS; Brain; Genetic Risks |
| Publication Year: |
2025 |
| Subject Terms: |
ALS; GENETICS; MOTOR NEURON DISEASE; Surgery; Clinical Neurology; Psychiatry and Mental health |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISSN: |
0022-3050 |
| Relation: |
https://dspace.library.uu.nl/handle/1874/465510 |
| Availability: |
https://dspace.library.uu.nl/handle/1874/465510 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.9E079A5A |
| Database: |
BASE |