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Background <p>Mutations in <i>NEK1</i>, encoding for a serine/threonine kinase which regulates several biological processes, are associated with amyotrophic lateral sclerosis (ALS).</p> Methods <p><i>NEK1</i> was analysed by amplicon deep sequencing in a cohort of 1016 Italian sporadic and familial ALS patients previously screened for <i>C9orf72</i>, <i>SOD1</i>, <i>TARDBP</i> and <i>FUS</i> mutations.</p> Results <p>We identified 28 rare <i>NEK1</i> variants in 29 patients (2.85%) of whom 20/782 were sporadic (2.5%), 6/107 familial (5%) and 3/127 of unknown aetiology (2.3%). Variants were classified as pathogenic (<i>P</i>; <i>n</i> = 1), likely pathogenic (LP; <i>n</i> = 6 in 7 patients) and of unknown significance (VUS; <i>n</i> = 21) according the American College of Medical Genetics and Genomics criteria. Notably, 64% of the identified variants (18/28, including 4 LP and 14 VUS) were novel. Among the 29 patients with rare <i>NEK1</i> variants, 7 (of whom 5 were familial cases) had additional variants in one of the four main ALS causative genes. Moreover, 23 patients carried the already reported <i>NEK1</i> p.Arg261His risk variant (VUS) alone or in addition to <i>SOD1</i> mutations (<i>n</i> = 1) or <i>C9orf72</i> repeat expansion (<i>n</i> = 2) and to the <i>NEK1</i> p.Asp128Val variant (<i>n</i> = 1). Genotype–phenotype correlation analysis showed no significant differences in age at onset or survival in <i>NEK1</i> variant carriers, independently on the variant type. No flail arm phenotype, but atypical features, including sensory symptoms, were present in <i>NEK1</i> carriers.</p> Conclusion <p>Our study further expands <i>NEK1</i> genetic variability by identifying novel rare variants and confirming ALS oligogenic nature since 19.6% of <i>NEK1</i> patients also carried mutations in one of the four main ALS-associated genes.</p>

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Exploring NEK1 genetic variability in Italian amyotrophic lateral sclerosis patients

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  • 发表日期：

    2025年6月19日

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  • Viviana Pensato,
  • Silvia Peverelli,
  • Cinzia Tiloca,
  • Stefania Magri,
  • Alberto Brusati,
  • Monica Pingue,
  • Claudia Morelli,
  • Eleonora Dalla Bella,
  • Arianna Manini,
  • Pierpaola Tannorella,
  • Alberto Doretti,
  • Jessica Mandrioli,
  • Fabrizia Terenghi,
  • Alessandro Prelle,
  • Nilo Riva,
  • Federico Verde,
  • Roberto Eleopra,
  • Franco Taroni,
  • Giuseppe Lauria Pinter,
  • Vincenzo Silani,
  • Nicola Ticozzi,
  • Cinzia Gellera,
  • Antonia Ratti

摘要

Background

Mutations in NEK1, encoding for a serine/threonine kinase which regulates several biological processes, are associated with amyotrophic lateral sclerosis (ALS).

Methods

NEK1 was analysed by amplicon deep sequencing in a cohort of 1016 Italian sporadic and familial ALS patients previously screened for C9orf72, SOD1, TARDBP and FUS mutations.

Results

We identified 28 rare NEK1 variants in 29 patients (2.85%) of whom 20/782 were sporadic (2.5%), 6/107 familial (5%) and 3/127 of unknown aetiology (2.3%). Variants were classified as pathogenic (P; n = 1), likely pathogenic (LP; n = 6 in 7 patients) and of unknown significance (VUS; n = 21) according the American College of Medical Genetics and Genomics criteria. Notably, 64% of the identified variants (18/28, including 4 LP and 14 VUS) were novel. Among the 29 patients with rare NEK1 variants, 7 (of whom 5 were familial cases) had additional variants in one of the four main ALS causative genes. Moreover, 23 patients carried the already reported NEK1 p.Arg261His risk variant (VUS) alone or in addition to SOD1 mutations (n = 1) or C9orf72 repeat expansion (n = 2) and to the NEK1 p.Asp128Val variant (n = 1). Genotype–phenotype correlation analysis showed no significant differences in age at onset or survival in NEK1 variant carriers, independently on the variant type. No flail arm phenotype, but atypical features, including sensory symptoms, were present in NEK1 carriers.

Conclusion

Our study further expands NEK1 genetic variability by identifying novel rare variants and confirming ALS oligogenic nature since 19.6% of NEK1 patients also carried mutations in one of the four main ALS-associated genes.