Clinical trajectories of genetic variants in ALS: a European observational study within PRECISION-ALS

To investigate the association between C9orf72, SOD1, FUS and TARDBP variants on the clinical trajectory of ALS patients in Europe.

Nine ALS centers with population-based registries provided data on demographic and disease characteristics - at diagnosis and longitudinally - as part of PRECISION ALS. These data were harmonized and collated for analysis.

21,820 ALS patients were identified, 9,887 underwent genetic testing for at least one of the 4 genes of interest. 9.8% of patients carried a hexanucleotide expansion in C9orf72; 2.9% carried a pathogenic variant in SOD1; 1.4% carried a pathogenic variant in TARDBP; and 0.8% carried a pathogenic variant in FUS. Only one p.A5V variant was identified in this dataset. The most frequently identified SOD1 variant was p.D91A, with evidence of other variant clusters in Belgium, Italy and the United Kingdom. TARDBP variants were clustered in the Netherlands and Italy. Earlier ages of onset were demonstrated compared to wild-type populations; C9orf72 59.58 (IQR 62.5, p < 2.2e-16), SOD1 54.19 (IQR 19.4, p = 6.304e-14), TARDBP 58.30 (IQR 16.23, p = 0.00024) and FUS 51.16 (IQR 25.08, p = 1.58e-06). C9orf72 was more bulbar (p < 0.0001) in onset and SOD1 more spinal (p < 0.0001). Those carrying variants spent distinctly different periods in each of the King's stages.

Genetic forms of ALS have an earlier age of onset, have distinct patterns in their sites of disease onset, and progress differently as compared to populations without such major-effect genes. There is also evidence of disease clusters across Europe suggestive of founder effects.