FUS mutations dominate TBK1 mutations in FUS/TBK1 double-mutant ALS/FTD pedigrees

Mutations in FUS and TBK1 often cause aggressive early-onset amyotrophic lateral sclerosis (ALS) or a late-onset ALS and/or frontotemporal dementia (FTD) phenotype, respectively.

Co-occurrence of mutations in two or more Mendelian ALS/FTD genes has been repeatedly reported.

However, little is known how two pathogenic ALS/FTD mutations in the same patient interact to shape the final phenotype.

We screened 28 ALS patients with a known FUS mutation by whole-exome sequencing and targeted evaluation for mutations in other known ALS genes followed by genotype–phenotype correlation analysis of FUS/TBK1 double-mutant patients.

We report on new and summarize previously published FUS and TBK1 double-mutant ALS/FTD patients and their families.

We found that, within a family, mutations in FUS cause ALS while TBK1 single mutations are observed in FTD patients.

FUS/TBK1 double mutations manifested as ALS and without a manifest difference regarding age at onset and disease duration when compared to FUS single-mutant individuals.

In conclusion, TBK1 and FUS variants do not seem to interact in a simple additive way.

Rather, the phenotype of FUS/TBK1 double-mutant patients appears to be dominated by the FUS mutation.