Hand-onset weakness is a common feature of ALS patients with a NEK1 loss-of-function variant.

Objective: The NEK1 gene has been recently implicated in amyotrophic lateral sclerosis (ALS). This study aims to assess the influence of NEK1 variants on the occurrence of ALS and investigate the spectrum and clinical features of NEK1 loss-of-function (LOF) variants in a Taiwanese ALS cohort.
Methods: We screened 325 unrelated ALS patients for coding variants in NEK1 by targeted resequencing and queried the Taiwan Biobank database for NEK1 coding variants in 1000 Taiwanese healthy individuals. The clinical features of the patients with a NEK1 LOF variant were analyzed.
Results: Six patients and two healthy individuals carried NEK1 LOF variants. The rare missense variants with minor allele frequencies <0.1% in Taiwanese population were present in 2.8% of the ALS patients and 1.6% of the healthy subjects. NEK1 LOF variants, but not rare missense variants, are significantly enriched in the ALS patients (P = 0.0037 and 0.24, Fisher's exact test). The odds ratio of an individual carrying a NEK1 LOF variant to develop ALS is 9.39 (95% confidence interval: 1.88-46.7). All the six patients carrying a NEK1 LOF variant had a hand-onset ALS with an onset age from 52 to 64 years. Comparing with ALS patients without a NEK1 LOF variant, patients with a NEK1 LOF variant tend to have a hand-onset disease (P = 0.0008, Fisher's exact test).
Interpretation: Our study supports the pathogenic role of NEK1 LOF variants and demonstrates their spectrum and clinical features in a Taiwanese cohort with ALS.
(© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)