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.

FUS和TBK1的突变通常分别导致侵袭性早发性肌萎缩侧索硬化症 (ALS) 或迟发性 ALS 和/或额颞叶痴呆 (FTD) 表型。已反复报道了两个或多个孟德尔 ALS/FTD 基因同时发生突变。然而，鲜为人知的是，同一患者中的两种致病性 ALS/FTD 突变如何相互作用以形成最终表型。我们通过全外显子组测序筛选了 28 名已知FUS突变的ALS 患者，并对其他已知 ALS 基因的突变进行靶向评估，然后对FUS/TBK1双突变患者进行基因型-表型相关性分析。我们报告新的并总结以前发布的FUS和TBK1双突变 ALS/FTD 患者及其家属。我们发现，在一个家族中，FUS突变导致 ALS，而在 FTD 患者中观察到TBK1单突变。FUS/TBK1双突变表现为 ALS，与FUS单突变个体相比，在发病年龄和疾病持续时间方面没有明显差异。总之，TBK1和FUS变体似乎并没有以简单的相加方式相互作用。相反，FUS/TBK1双突变患者的表型似乎以FUS突变为主。