Our objective was to investigate the frequency of KIF5A variants in amyotrophic lateral sclerosis (ALS) and the clinical characteristics of familial ALS (FALS) associated with variants in KIF5A. Whole-exome sequence analysis was performed for a Japanese series of 43 families with FALS and 444 patients with sporadic ALS (SALS), in whom causative variants had not been identified. We compared the frequencies of rare variants (MAF < 0.01) in KIF5A, including missense and loss of function (LoF) variants, between ALS and control subjects (n = 1163). Clinical characteristics of patients with FALS carrying pathogenic variants in KIF5A were also described. LoF variants were identified only in the probands of two families with FALS, both of which were 3′ splice-site variants leading to exon skipping and an altered C-terminal domain, located in the mutational hotspot causing FALS, and were considered to be pathogenic for FALS. Rare missense variants in KIF5A were identified in five patients with SALS (1.13%) and 11 control subjects (0.95%, carrier frequency), which were not significantly different. Consequently, the pathogenic LoF variants in KIF5A accounted for 2.1% of all FALS families in this study. These patients suffered from ALS characteristically associated with the predominant involvement of upper motor neuron. In conclusion, we identified two pathogenic splice-site variants in KIF5A in the probands in two Japanese families with FALS, which altered the C-terminal region of KIF5A. Our findings broaden the phenotype spectrum of ALS associated with variants in KIF5A in the Japanese series.

我们的目的是调查的频率KIF5A在肌萎缩侧索硬化症（ALS）和与变体相关联的家族性ALS（FALS）的临床特征的变体KIF5A。对日本的 43 个 FALS 家族和 444 名散发性 ALS (SALS) 患者进行了全外显子组序列分析，其中的致病变异尚未确定。我们比较了KIF5A中罕见变异 (MAF < 0.01) 的频率，包括错义和功能丧失 (LoF) 变异，在 ALS 和对照受试者之间 ( n  = 1163)。携带KIF5A致病性变异的 FALS 患者的临床特征也进行了描述。LoF 变异仅在两个 FALS 家族的先证者中发现，这两个家族都是 3' 剪接位点变异导致外显子跳跃和 C 端结构域改变，位于导致 FALS 的突变热点，被认为是致病性的对于 FALS。在 5 名 SALS 患者 (1.13%) 和 11 名对照受试者 (0.95%，载波频率) 中发现了KIF5A中的罕见错义变异，两者没有显着差异。因此，在本研究中，KIF5A 中的致病性 LoF 变异占所有 FALS 家族的 2.1%。这些患者患有 ALS，其特征是与上运动神经元的主要受累有关。总之，我们在KIF5A 中发现了两个致病性剪接位点变异在两个患有 FALS 的日本家庭的先证者中，这改变了 KIF5A 的 C 端区域。我们的发现拓宽了与日本系列中KIF5A变异相关的 ALS 表型谱。