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.
摘要：
肌萎缩侧索硬化症（ALS）是最常见的运动神经元疾病，其原因尚不清楚。与该疾病的常染色体显性形式有关的第一个ALS基因是SOD1。这个基因有很高的罕见变异率，正确的分类对ALS诊断至关重要.在这项研究中,我们重新评估了所有先前报道的来自ALSoD的SOD1变体（n=202）的分类，MinE项目，和内部数据库，通过将ACMG-AMP标准应用于ALS。新的生物信息学分析，频率额定值，并对功能研究进行了彻底的搜索。我们还提出了调整标准强度，描述了如何将其应用于SOD1变体。根据PS3标准的修改权重，大多数先前报道的变体已被重新分类为可能的致病性和致病性。强调体内或体外功能研究如何确定其解释和分类。此外，这项研究揭示了开放数据库之间注释的一致性和不一致性，表明需要专家审查，以适应特定疾病的变异研究。的确,在复杂的疾病中，比如ALS,寡基因遗传，必须考虑作为危险因素的基因的存在和渗透的减少。总的来说,ALS的诊断仍然是临床的，改进变异分类可以支持遗传数据作为诊断标准。
