We report mutation frequency of pathogenic TBK1 mutations in FTD, ALS and FTD-ALS patients. We detail phenotypic and genetic characteristics of Belgian mutation carriers. We also present a pedigree segregating a new, previously unknown LOF mutation with autosomal dominant inheritance. Lastly, we describe phenotypes of genetic TBK1 variants with uncertain significance.

Pathogenic TBK1 mutations are associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS).

We screened TBK1 in Belgian FTD (n = 678), ALS (n = 220) and FTD-ALS (n = 46) cohorts. We identified 18 carriers of pathogenic mutations and 1 carrier of a novel LOF mutation. We sampled and screened family members, totalling a carrier cohort of 40. Another 6 patients carried missense mutations of uncertain significance. We collected data on clinical characteristics, biomarkers and neuropathology.

TBK1 LOF mutation frequency was 1.3% in FTD, 3.6% in ALS and 4.3% in FTD-ALS. Among 40 carriers, 23 were affected: FTD (n = 8; 7 bvFTD, 1 PPA), ALS (n = 7), unspecified dementia (n = 5), FTD-ALS (n = 2), Alzheimer’s disease (n = 1). Mean onset age and disease duration were 62.8 and 6.5 years (ranges 41-86 and 0-24 years). ALS patients had significantly shorter disease duration averaging 2.6 year. Neuropathology confirmed FTLD-TDP B. TBK1 missense mutations of uncertain significance were present in 3 ALS and 3 FTD patients (1 svPPA, 2 bvFTD).