Splice-site mutations inKIF5Ain the Japanese case series of amyotrophic lateral sclerosis

Our objective was to investigate the frequency ofKIF5Avariants in amyotrophic lateral sclerosis (ALS) and the clinical characteristics of familial ALS (FALS) associated with variants inKIF5A. 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) inKIF5A, including missense and loss of function (LoF) variants, between ALS and control subjects (n = 1163). Clinical characteristics of patients with FALS carrying pathogenic variants inKIF5Awere 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 inKIF5Awere 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 inKIF5Aaccounted 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 inKIF5Ain 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 inKIF5Ain the Japanese series.

Automated summary

The study revealed that LoF variants in the KIF5A gene accounted for 2.1% of all FALS families, while the frequency of missense variants in SALS patients and controls did not show a significant difference. FALS patients carrying pathogenic KIF5A variants exhibited ALS characterized by predominant involvement of upper motor neurons.