Burden of rare variants in causative genes for amyotrophic lateral sclerosis (ALS) accelerates age at onset of ALS
Burden of rare variants in causative genes for amyotrophic lateral sclerosis (ALS) accelerates age at onset of ALS
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DOI：
10.1136/jnnp-2018-318568
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发表时间：
2019-05-01
影响因子：
11
通讯作者：
Tsuji, Shoji
中科院分区：
文献类型：
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作者：
Naruse, Hiroya;Ishiura, Hiroyuki;Tsuji, Shoji
目的 评估日本病例系列中肌萎缩侧索硬化症 (ALS) 致病基因中罕见变异对 ALS 发病年龄的影响。方法 我们对 89 个家族性 ALS (FALS) 家庭和 410 名散发性 ALS (SALS) 患者进行全外显子组测序分析，以鉴定 ALS 致病基因中已知的致病突变或罕见的功能预测有害变异。罕见变异（次要等位基因频率 20 被定义为罕见的功能预测有害变异。根据致病性和/或罕见功能预测有害变异的数量对 ALS 患者进行分类，并比较分类组之间的发病年龄。结果 全外显子组测序分析显示 56 个 FALS 家族（62.9%）和 87 名 SALS 患者中 ALS 致病基因存在已知致病突变或罕见功能预测有害变异(21.2%) 在 7 名 FALS 先证者和 8 名 SALS 患者中发现了这种多基因变异，具有多种变异的 ALS 患者的发病年龄明显早于其他 ALS 患者。在日本 ALS 系列中，ALS 致病基因影响发病年龄。
Objectives To evaluate the burden of rare variants in the causative genes for amyotrophic lateral sclerosis (ALS) on the age at onset of ALS in a Japanese case series.Methods We conducted whole-exome sequencing analysis of 89 families with familial ALS (FALS) and 410 patients with sporadic ALS (SALS) to identify known pathogenic mutations or rare functionally predicted deleterious variants in the causative genes for ALS. Rare variants (minor allele frequency 20 were defined as rare functionally predicted deleterious variants. The patients with ALS were classified on the basis of the number of pathogenic and/or rare functionally predicted deleterious variants, and the age at onset was compared among the classified groups.Results Whole-exome sequencing analysis revealed known pathogenic mutations or rare functionally predicted deleterious variants in causative genes for ALS in 56 families with FALS (62.9%) and 87 patients with SALS (21.2%). Such variants in multiple genes were identified in seven probands with FALS and eight patients with SALS. The ages at onset in the patients with ALS with multiple variants were significantly earlier than those in other patients with ALS. Even when the patients with known pathogenic mutations were excluded, a significantly earlier onset of the disease was still observed in patients with multiple rare functionally predicted deleterious variants.Conclusions A substantial number of patients carried rare variants in multiple genes, and the burden of rare variants in the known causative genes for ALS affects the age at onset in the Japanese ALS series.