Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia.
School of Biological Sciences, Centre for Brain Research, University of Auckland, Auckland, New Zealand.
J Neuromuscul Dis. 2023;10(6):1127-1141. doi: 10.3233/JND-230148.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with genetic and phenotypic heterogeneity. Pathogenic genetic variants remain the only validated cause of disease, the majority of which were discovered in familial ALS patients. While causal gene variants are a lesser contributor to sporadic ALS, an increasing number of risk alleles (low penetrance genetic variants associated with a small increase in disease risk) and variants of uncertain significance have been reported.
To examine the pathogenic potential of genetic variation in ALS, we sought to characterise variant- and gene-level attributes of previously reported ALS-implicated variants.
A list of 1,087 genetic variants reported in ALS to March 2021 was compiled through comprehensive literature review. Individual variants were annotated using in silico tools and databases across variant features including pathogenicity scores, localisation to protein domains, evolutionary conservation, and minor allele frequencies. Gene level attributes of genic tolerance, gene expression in ALS-relevant tissues and gene ontology terms were assessed for 33 ALS genes. Statistical analysis was performed for each characteristic, and we compared the most penetrant variants found in familial cases with risk alleles exclusive to sporadic cases, to explore genetic variant features that associate with disease penetrance.
We provide spreadsheet (hg19 and GRCh38) and variant call format (GRCh38) resources for all 1,087 reported ALS-implicated variants, including detailed summaries for each attribute. We demonstrate that the characteristics of variants found exclusively in sporadic ALS cases are less severe than those observed in familial ALS.
We provide a comprehensive, literature-derived catalogue of genetic variation in ALS thus far and reveal crucial attributes that contribute to ALS pathogenicity. Our variant- and gene-level observations highlight the complexity of genetic variation in ALS, and we discuss important implications and considerations for novel variant interpretation.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，具有遗传和表型异质性。致病性遗传变异仍然是唯一被证实的疾病原因，其中大多数是在家族性 ALS 患者中发现的。虽然因果基因变异对散发性 ALS 的贡献较小，但越来越多的风险等位基因（与疾病风险略有增加相关的低外显率遗传变异）和意义不确定的变异已被报道。
为了研究 ALS 中遗传变异的致病潜力，我们试图描述先前报道的 ALS 相关变异的变异体和基因水平特征。
通过全面的文献回顾，编制了一份截至 2021 年 3 月在 ALS 中报道的 1087 种遗传变异的清单。使用各种变异特征（包括致病性评分、蛋白质结构域定位、进化保守性和次要等位基因频率）的计算工具和数据库对个体变异进行注释。对 33 个 ALS 基因的基因耐受性、ALS 相关组织中的基因表达和基因本体论术语的基因水平属性进行了评估。对每个特征进行了统计分析，并比较了在家族性病例中发现的最具穿透性的变异与仅在散发性病例中发现的风险等位基因，以探讨与疾病穿透性相关的遗传变异特征。
我们提供了所有 1087 个报告的 ALS 相关变异的电子表格（hg19 和 GRCh38）和变异调用格式（GRCh38）资源，包括每个属性的详细摘要。我们表明，仅在散发性 ALS 病例中发现的变异的特征比在家族性 ALS 中观察到的变异的特征不那么严重。
我们提供了迄今为止 ALS 中遗传变异的全面、文献衍生目录，并揭示了导致 ALS 致病性的关键属性。我们的变异体和基因水平观察结果突出了 ALS 遗传变异的复杂性，我们讨论了对新型变异解释的重要影响和考虑因素。
