TBK1 p.Y153Qfs*9 variant may be associated with young-onset, rapidly progressive amyotrophic lateral sclerosis through a haploinsufficiency mechanism.

Background: TBK1 variants have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia spectrum disorder. The current study elucidated the clinical and molecular genetic features of a novel TBK1 variant identified in a patient with young-onset, rapidly progressive ALS.

Methods: The coding regions of TBK1 , SOD1 , TARDBP , and FUS were genetically analyzed using Sanger sequencing. Repeat-primed polymerase chain reaction (PCR) was used to survey the GGGGCC repeat in C9ORF72 . The study participant underwent a comprehensive clinical evaluation. The functional effects of the TBK1 variant were analyzed through in vitro transfection studies.

Results: We identified a novel frameshift truncating TBK1 variant, c.456_457delGT (p.Y153Qfs*9), in a man with ALS. The disease initially manifested as right hand weakness at the age of 39 years but progressed rapidly, with the revised ALS Functional Rating Scale score declining at an average monthly rate of 1.92 points in the first year after diagnosis. The patient had no cognitive dysfunction. However, Technetium-99m single photon emission tomography indicated hypoperfusion in his bilateral superior and middle frontal cortices. In vitro studies revealed that the p.Y153Qfs*9 variant resulted in a truncated TBK1 protein product, reduced TBK1 protein expression, loss of kinase function, reduced interaction with optineurin, and impaired dimerization.

Conclusion: The heterozygous TBK1 p.Y153Qfs*9 variant may be associated with young-onset, rapidly progressive ALS through a haploinsufficiency mechanism.