SOD-1 Variants in Amyotrophic Lateral Sclerosis: Systematic Re-Evaluation According to ACMG-AMP Guidelines

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common type of motor neuron disease whose causes are unclear. The first ALS gene associated with the autosomal dominant form of the disease was SOD1. This gene has a high rate of rare variants, and an appropriate classification is essential for a correct ALS diagnosis. In this study, we re-evaluated the classification of all previously reported SOD1 variants (n = 202) from ALSoD, project MinE, and in-house databases by applying the ACMG-AMP criteria to ALS. New bioinformatics analysis, frequency rating, and a thorough search for functional studies were performed. We also proposed adjusting criteria strength describing how to apply them to SOD1 variants. Most of the previously reported variants have been reclassified as likely pathogenic and pathogenic based on the modified weight of the PS3 criterion, highlighting how in vivo or in vitro functional studies are determining their interpretation and classification. Furthermore, this study reveals the concordance and discordance of annotations between open databases, indicating the need for expert review to adapt the study of variants to a specific disease. Indeed, in complex diseases, such as ALS, the oligogenic inheritance, the presence of genes that act as risk factors and the reduced penetration must be considered. Overall, the diagnosis of ALS remains clinical, and improving variant classification could support genetic data as diagnostic criteria.

Single cell sequencing as a general variant interpretation assay

“…Moreover, SOD1 variants observed in human populations were predominantly very rare and contained a high proportion of pathogenic variants (40%; Figure S5C), hindering their use as putatively benign variants. We therefore benchmarked the scores on the task of distinguishing between ClinVar pathogenic variants and variants that were not annotated as potentially pathogenic in any other database or cohort (Abel et al, 2012; Chen et al, 2021; McCann et al, 2021; Opie-Martin et al, 2022; Ruffo et al, 2022; Yamashita and Ando, 2015). While proliferation alone (i.e., effects on enzymatic activity) was not informative for classifying ALS pathogenic variants (ROC AUC = 0.507), regressing out these effects from PrimateAI-3D and other computational predictions indeed consistently improved ALS variant classification (Figures 5K, S5D and S5E, ROC AUC = 0.713 for the residual score vs. 0.623 for the raw score).…”

Clinical and molecular features of patients with amyotrophic lateral sclerosis and SOD1 mutations: a monocentric study

“…A different substitution in the same amino acid position (p.Pro67Ser) has been reported in seven ALS cases, of whom four were familial, with a heterogenous age at onset (21–72 years) and survival between 6 and 48 months ( 12 , 22 , 33–36 ). Similarly, p.Pro67Ala and p.Pro67Arg have been associated with a slow progression and a long disease duration ( 37–39 ). Recently, a compound heterozygous p.Pro67Ser/Asp91Ala was found in a 69-year-old ALS patient with a facial onset and slow progression ( 40 ).…”

New SOD1 Mutation Causing Rapid Amyotrophic Lateral Sclerosis with Nerve Root Enhancement

“…4,5 Another publication assessing SOD1 variants according to ACMG criteria similarly concluded the variant is likely pathogenic. 6 Autopsy, completed 1 month after the last clinical examination, supported a final diagnosis of ALS given both upper and lower motor neuron involvement and p62 (a marker for proteins destined for degradation) positive neuronal inclusions in anterior horn cells, primary motor cortex, and brainstem motor nuclei. Notably, neuronal loss, gliosis, and chromatolytic changes were noted in the anterior horn, primary motor cortex, and two cranial nerves.…”

“…4,5 Another publication assessing SOD1 variants according to ACMG criteria similarly concluded the variant is likely pathogenic. 6…”