Rare missense variants play a crucial role in amyotrophic lateral sclerosis (ALS) pathophysiology. We report rare/novel missense variants from 154 Indian ALS patients, identified through targeted sequencing of 25 ALS-associated genes. As pathogenic variants could explain only a small percentage of ALS pathophysiology in our cohort, we investigated the frequency of tolerated and benign novel/rare variants, which could be potentially ALS susceptible. These variants were identified in 5.36% (8/149) of sporadic ALS (sALS) cases; with one novel variant each in ERBB4, SETX, DCTN1, and MATR3; four rare variants, one each in PON2 and ANG and two different rare variants in SETX. Identified variants were either absent or present at extremely rare frequencies (MAF < 0.01) in large population databases and were absent in 50 healthy controls sequenced through Sanger method. Furthermore, an oligogenic basis of ALS was observed in three sALS, with co-occurrence of intermediate-length repeat expansions in ATXN2 and a rare/novel variant in DCTN1 and SETX genes. Additionally, molecular dynamics and biochemical functional analysis of an angiogenin variant (R21G) identified from our cohort demonstrated loss of ribonucleolytic and nuclear translocation activities. Our findings suggest that rare variants could be potentially pathogenic and functional studies are warranted to decisively establish the pathogenic mechanisms associated with them.

中文翻译：

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印度肌萎缩性侧索硬化症患者中新型和罕见的易感变异体的鉴定和表征。

稀有的错义变体在肌萎缩性侧索硬化症（ALS）的病理生理中起着至关重要的作用。我们报告了来自154位印度ALS患者的稀有/新颖错义变异体，这些变异体是通过对25个与ALS相关的基因进行靶向测序而确定的。由于致病性变异仅能解释我们队列中ALS病理生理的一小部分，因此我们研究了耐受性和良性新型/罕见变异的频率，这些变异可能是ALS易感的。5.3％（8/149）的散发性ALS（sALS）病例中发现了这些变异；在ERBB4，SETX，DCTN1和MATR3中有一个新的变种; 四个稀有变体，分别在PON2和ANG中一个，以及两个不同的稀有变体在SETX中。在大型人群数据库中，已鉴定的变体不存在或以极少的频率出现（MAF <0.01），并且在通过Sanger方法测序的50个健康对照中不存在。此外，在三个SALS观察ALS的寡基因的基础上，在中间长度的重复扩张的共同出现ATXN2和在稀有/新颖变体DCTN1和SETX基因。此外，从我们的队列研究中确定的血管生成素变体（R21G）的分子动力学和生化功能分析证明了核糖核酸溶解和核转运活性的丧失。我们的研究结果表明，稀有变体可能具有潜在的致病性，因此有必要进行功能性研究以确定与它们相关的致病机制。