NEK1 Variants in a Cohort of Italian Patients With Amyotrophic Lateral Sclerosis

Nilo Riva; Laura Pozzi; Tommaso Russo; Giovanni Battista Pipitone; Paride Schito; Teuta Domi; Federica Agosta; Angelo Quattrini; Paola Carrera; Massimo Filippi

doi:10.3389/fnins.2022.833051

NEK1 Variants in a Cohort of Italian Patients With Amyotrophic Lateral Sclerosis

Front Neurosci. 2022 Apr 14:16:833051. doi: 10.3389/fnins.2022.833051. eCollection 2022.

Authors

Nilo Riva^{1

2

3}, Laura Pozzi¹, Tommaso Russo^{1

2}, Giovanni Battista Pipitone⁴, Paride Schito^{1

2}, Teuta Domi¹, Federica Agosta^{5

6}, Angelo Quattrini¹, Paola Carrera⁴, Massimo Filippi^{2

3

5

6

7}

Affiliations

¹ Neuropathology Unit, Division of Neuroscience, Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, Milan, Italy.
² Neurology Unit, San Raffaele Scientific Institute, Milan, Italy.
³ Neurorehabilitation Unit, San Raffaele Scientific Institute, Milan, Italy.
⁴ Unit of Genomics for Human Disease Diagnosis, San Raffaele Scientific Institute, Milan, Italy.
⁵ Neuroimaging Research Unit, Division of Neuroscience, Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, Milan, Italy.
⁶ Vita-Salute San Raffaele University, Milan, Italy.
⁷ Neurophysiology Service, San Raffaele Scientific Institute, Milan, Italy.

Abstract

Introduction: In the last few years, different studies highlighted a significant enrichment of NEK1 loss of function (LoF) variants in amyotrophic lateral sclerosis (ALS), and an additional role for the p.Arg261His missense variant in the disease susceptibility. Several other missense variants have been described so far, whose pathogenic relevance remains however unclear since many of them have been reported in both patients and controls. This study aimed to investigate the presence of NEK1 variants and their correlation with phenotype in a cohort of Italian patients with ALS.

Methods: We sequenced a cohort of 350 unrelated Italian patients with ALS by next-generation sequencing (NGS) and then we analyzed the clinical features of NEK1 carriers.

Results: We detected 20 different NEK1 rare variants (four LoF and 16 missense) in 33 unrelated patients with sporadic ALS (sALS). The four LoF variants (two frameshift and two splice-site variants) were all novel. The p.Arg261His missense variant was enriched in the patients' cohort (p < 0.001). Excluding this variant from counting, the difference in the frequency of NEK1 rare missense variants between patients and controls was not statistically significant. NEK1 carriers had a higher frequency of flail arm (FA) phenotype compared with the other patients of the cohort (29.2% vs. 6.4%). Nine NEK1 carriers (37.5%) also harbored variants in other ALS-related genes.

Conclusion: This study confirms that NEK1 LoF and p.Arg261. His missense variants are associated with ALS in an Italian ALS cohort and suggests a correlation between the presence of NEK1 variants and FA phenotype.

Keywords: ALS phenotype; flail arm; frontotemporal dementia; genetics; motor neuron disease; neurodegenerative disorders; neuromuscular diseases; never in mitosis a (NIMA)-related kinase 1.