Loss-of-function (LoF) variants in NEK1 have recently been reported to be associated with amyotrophic lateral sclerosis (ALS). In this study, we investigated the association of NEK1 LoF variants with an increased risk of sporadic ALS (SALS) and the clinical characteristics of patients with SALS carrying LoF variants in a Japanese case series. Whole-exome sequencing analysis was performed for a series of 446 SALS patients in whom pathogenic variants in familial ALS-causative genes have not been identified and 1163 healthy control subjects in our Japanese series. We evaluated LoF variants, defined as nonsense, splice-site disrupting single-nucleotide variants (SNVs), or short insertion/deletion (indel) variants predicted to cause frameshifts in NEK1. We identified seven NEK1 LoF variants in patients with SALS (1.57%), whereas only one was identified in control subjects (0.086%) (P = 0.00073, Fisher’s exact test). This finding is consistent with those in recent reports from other regions in the world. In conclusion, we demonstrated that NEK1 LoF variants are also associated with an increased risk of SALS in the Japanese population.

丧失功能（LOF）的变种NEK1最近被报道与肌萎缩侧索硬化症（ALS）相关联。在这项研究中，我们调查了日本病例系列中NEK1 LoF变异与散发性ALS（SALS）风险增加以及携带LoF变异的SALS患者的临床特征之间的关系。对我们的446例SALS患者进行了全外显子测序分析，这些患者中尚未发现家族性ALS致病基因的致病变异，以及我们的日语系列中的1163例健康对照者。我们评估了LoF变体，定义为无意义的剪接位点破坏单核苷酸变体（SNV）或短插入/缺失（indel）变体，预计会导致NEK1移码。我们在SALS患者中鉴定出7种NEK1 LoF变异体（1.57％），而在对照受试者中仅鉴定出1种（0.086％）（P  = 0.00073，Fisher精确检验）。这一发现与来自世界其他地区的最新报告相一致。总之，我们证明了NEK1 LoF变体也与日本人群中SALS的风险增加有关。