Submission Details

Autosomal dominant

11/07/2019

The FUS gene is located on chromosome 16 at 16p11.2 and encodes the FUS RNA binding protein which is predominantly located in the nucleus and involved in the regulation of many cellular processes, including RNA metabolism, regulation of translation, and stress response. The FUS gene was first reported in relation to autosomal dominant amyotrophic lateral sclerosis, with or without frontotemporal dementia in 2009 (19251627: Kwaitkowski et al. 2009); 19251628: Vance et al. 2009). At least 18 unique missense, stop gained and frameshift variants have been reported in ClinVar. Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. Variants in this gene have been reported in at least ten probands in six publications (19251628: Vance et al. 2009; 20668259: Yan et al. 2010; 20660363: Waibel et al. 2010; 24439481; Calvo et al. 2014; 25457557: Kim et al. 2015; 26362943; Hubers et al. 2015). Vance et al. (2009) reported segregation of disease with a FUS variant in six affected family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by studies in patient derived cell lines and at least two transgenic mouse models which recapitulate key features of disease (23867462: Shelkobnikova et al. 2013; 26795035: Lim et al. 2016; 30344044: Lopez Erauskin 2018). In summary, FUS is definitively associated with autosomal dominant amyotrophic lateral sclerosis, with or without frontotemporal dementia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

25457557 24439481 26362943 19251628 20668259 20660363 31626953 26795035 23867462 30344044