Submission Details

UBQLN2 was first reported in relation to X-linked dominant amyotrophic lateral sclerosis 15 (ALS) in 2011 (Deng HX, et al., 2011, PMID: 21857683). UBQLN2 encodes ubiquilin 2, which is mainly involved in protein homeostasis, directing misfolded or redundant proteins towards the proteasome. 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. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. At least 29 missense variants have been reported in relation to ALS. Variants in this gene have been reported in at least 30 probands in 13 publications (PMIDs: 21857683, 23138764, 22717235, 24771548, 28716533, 23312802, 22892309, 22560112, 31475037, 23582661, 24684794, 25179229, 25681989), and segregated with disease in at least 21 additional family member. Experimentally, this gene-disease relationship is supported by its role in the ubiquitin-dependent protein catabolic process (PMID: 15147878), which is altered in cells expressing variants (PMID: 26075709). Additionally, its role in autophagy is also altered in patient cells (PMID: 28716533) and it interacts in stress granules with additional ALS-implicated genes FUS and TIA1 (PMID: 30442662). Further support is provided by several animal models (drosophila, rat, and mouse) including at least two knock-in mouse models (PMID: 27834214), which recapitulate features of ALS. In summary UBQLN2 is definitively associated with X-linked dominant amyotrophic lateral sclerosis 15. 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 04/13/2021 (SOPv8).