Neuropathological characterisation of a novel TBK1 loss of function mutation associated with amyotrophic lateral sclerosis.

Aims Mutations in TANK binding kinase gene (TBK1) are causative in amyotrophic lateral sclerosis (ALS), however correlations between clinical features and TBK1 mutations have not been fully elucidated. We aimed to identify and compare TBK1 mutations to clinical features in a cohort of ALS patients from Northern England. Methods TBK1 mutations were analysed in 290 ALS cases. Immunohistochemistry was performed in brain and spinal cord of one case with a novel in-frame deletion. Results Seven TBK1 variants were identified, including one novel in-frame deletion (p.85delIle). In silico analysis and literature suggested four variants were pathogenic, and three were variants of uncertain significance or benign. Post-mortem immunohistochemistry established an individual with the novel in-frame deletion had classical ALS and Type B FTLD-TDP pathology, with no changes in TBK1 staining or interferon regulatory factor IRF3. Conclusions TBK1 mutations were present in 1.38% of our cohort, and screening showed no clear genotype-phenotype associations compared to other genetic and sporadic ALS cases. TBK1 immunohistochemistry was consistent with previously published literature and we are the first to show no differential expression of interferon regulatory factor IRF3, a downstream effector of TBK1 in the immune pathway, in the TBK1-mutant tissue, compared to controls.