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Variants in tank-binding kinase 1 (TBK1) are responsible for a significant proportion of amyotrophic lateral sclerosis (ALS) cases. In the present study, we analyzed variants in TBK1 extracted by targeted sequencing of 32 genes in a group of 406 Italian patients with ALS. 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 3 had truncating variants (p.Y482*, p.R229*, and p.N681*). Notably, we found that 4 patients had an additional variant in ALS-related genes: 2 in OPTN and 2 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. • Variants in tank-binding kinase 1 (TBK1) gene are present in 1.7% of Italian patients with amyotrophic lateral sclerosis. • The pathogenic mechanism of TBK1 variants is based on haploinsufficiency, through nonsense-mediated decay. • All the 17 Italian patients with TBK1 variants described to date have a sporadic disease. • A second variant in another amyotrophic lateral sclerosis–related gene is present in one-third of the TBK1- mutated patients. • Loss of function variants in TBK1 are likely to work as partner through an oligogenic model. [ABSTRACT FROM AUTHOR]