Coexistence of variants in TBK1 and in other ALS-related genes elucidates an oligogenic model of pathogenesis in sporadic ALS

Variants in TBK1 are responsible for a significant proportion of ALS cases. In the present study, we analysed variants in TBK1 extracted by targeted sequencing of 32 genes in a group of 406 Italian ALS patients. We identified 7 different TBK1 variants in 7 sporadic cases, resulting in a frequency of 1.7%. Three patients had missense variants (p.R357Q, p.R358H and p.R724C), one patient had a small deletion (p.E618del) and three had truncating variants (p.Y482*, p.R229*, p.N681*). Notably, we found that 4 patients had an additional variant in ALS related genes: two in OPTN and two in the 3’UTR region of FUS. By studying an independent group of 7 TBK1 mutated patients previously reported, we found another variant in the 3’UTR region of FUS in one patient. The presence of a second variant in TBK1 variant carriers is an interesting finding that needs to be investigated in larger cohorts of patients. These findings suggest that TBK1 belongs to the category of genes conferring a significantly increased risk, but not sufficient to cause disease.