FUS

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0017593

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0011951

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: Illumina

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.

Inheritance Pattern: AD

Disease ID:MONDO:0011951

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0013888

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0011951

Submitter: ClinGen

FUS was first reported in relation to autosomal dominant amyotrophic lateral sclerosis 6 (ALS) in 2009 (Kwiatkowski TJ, et al., 2009, PMID: 19251627 and Vance C, et al., 2009, PMID: 19251628). ALS is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. FUS encodes a nucleoprotein that functions in DNA and RNA metabolism, including DNA repair, and the regulation of transcription, RNA splicing, and export to the cytoplasm. It’s proposed that the FALS-associated FUS mutations alter the liquid-solid phase transition in FUS and thereby dominantly interfere with the ability of wild type FUS in DNA damage repair and RNA splicing, leading to both structural and functional defects in dendritic/axonal growth and synaptic transmission (PMID: 27033831). Evidence supporting this gene-disease relationship includes case-level data and experimental data. More than 50 mutations in FUS have been associated with ALS, the majority of which are dominant, missense changes clustered in and around the C-terminal nuclear localization signal, as well as some nonsense, splicing, and frameshift variants (reviewed in PMID: 27033831). This curation includes 26 variants in this gene that have been reported in 26 probands in 7 publications (PMIDs: 19251627, 19251628, 19741215, 20232451, 26362943, 22057404, and 20668259). Experimentally, this gene-disease relationship is supported the alterations observed in cells expressing FUS variants, showing mislocalization to the cytoplasm and association with stress granules (PMID: 23474818) as well as decreased DNA repair (PMID: 24036913). Further support is provided by several animal models (at least 6 transgenic strains, reviewed in PMID: 27033831) including mouse (PMID: 26842965) and rat models (PMID: 21408206), which recapitulate features of ALS. In summary FUS is definitively associated with autosomal dominant amyotrophic lateral sclerosis 6. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen ALS GCEP on 10/12/2021 (SOPv8). Of note, FUS has also been reported in relation to autosomal dominant hereditary essential tremor 4. This will be curated separately from ALS per criteria outlined by the ClinGen Lumping and Splitting working group; there is a difference in molecular mechanism (gain of toxicity vs loss of function) and phenotype.

Inheritance Pattern: Unknown

Disease ID:MONDO:0013888

Submitter: Labcorp Genetics (formerly Invitae)