Submission Details

SOD1 was first reported in relation to autosomal dominant amyotrophic lateral sclerosis 1 (ALS) in 1993 (Rosen DR, et al., 1993, PMID: 8446170). Genetic linkage analysis performed with 13 ALS families for 10 DNA markers confirmed the presence of a FALS gene on chromosome 21. The highest total 2-point LOD score for all families was 4.33, obtained at a distance of 10 CM from the marker D21S223 and a multipoint score of 6.50 was obtained with the markers D21S213, D21S223, D21S167, and FALS for 5 chromosome 21- linked ALS families (PMID: 7913294). 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. SOD1 encodes superoxide dismutase which has a tendency to form aggregates, and recent work has highlighted oligomers, specifically trimeric forms as the neurotoxic species (PMID: 26719414). Evidence supporting this gene-disease relationship includes case-level data and experimental data. More than 155 mutations in SOD1 have been found and associated with ALS, including single point mutations, truncations, deletions, and insertions in the protein (reviewed in PMID: 2368712). This curation includes 35 variants in this gene that have been reported in 35 probands in 3 publications (PMIDs: 8446170, 22292843, 8004110). A few mechanisms of disease implicated with SOD1 mutations are protein misfolding, proteasome impairment, oxidative stress, oligodendrocyte degeneration, and mitochondrial dysfunction. Experimentally, this gene-disease relationship is supported by the alterations observed in cells expressing SOD1 variants, which support the disease mechanism or association, including the formation of trimers (PMID: 26719414), or aggregates (PMID: 19483195), and the accumulation of misfolded or unfolded proteins in the endoplasmic reticulum which induces stress (PMID: 12659845). Further support is provided by several animal models (at least 12 transgenic strains, reviewed in PMID: 21706386) including mouse (PMID: 8209258) and rat models (PMID: 11717358), which recapitulate features of ALS. More genetic and experimental evidence is available in the literature, however the maximum score of 18pts has been reached. In summary SOD1 is definitively associated with autosomal dominant amyotrophic lateral sclerosis 1. 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 07/13/2021 (SOPv8).

Of note, SOD1 has also been reported in relation to progressive spastic tetraplegia and axial hypotonia. 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), phenotype (adult onset motor disease vs pediatric onset pan-neurodegenerative disease), and inheritance pattern (autosomal dominant vs recessive). Additionally, ALS has also been reported with biallelic SOD1 variants, specifically Scandinavian founder variant D90A, which shows both autosomal dominant and recessive patterns in different populations (Andersen et al., 1995; Al-Chalabi et al., 1998; Aguirre et al., 1999; Hand et al., 2001; Pasinelli and Brown, 2006). However, this variant may be considered a risk allele, only resulting in disease when biallelic or in combination with another risk factor, and only dominant cases were considered within this curation.