Exploring NEK1 genetic variability in Italian amyotrophic lateral sclerosis patients

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Mutations in NEK1, a gene encoding a serine/threonine kinase, are associated with amyotrophic lateral sclerosis (ALS).
• NEK1 plays a role in regulating various biological processes relevant to neuronal function and survival.

Purpose of the Study:

• To investigate the frequency and spectrum of rare NEK1 variants in a large cohort of Italian ALS patients.
• To analyze the genetic contribution of NEK1 in conjunction with other known ALS-associated genes.

Main Methods:

• Amplicon deep sequencing of the NEK1 gene was performed on 1016 Italian ALS patients.
• Patients were pre-screened for mutations in C9orf72, SOD1, TARDBP, and FUS genes.
• Variants were classified according to American College of Medical Genetics and Genomics (ACMG) criteria.

Main Results:

• Twenty-eight rare NEK1 variants were identified in 29 patients (2.85%), including sporadic and familial cases.
• Six variants were classified as likely pathogenic (LP), and 21 as variants of unknown significance (VUS); one was pathogenic (P).
• Notably, 64% of identified variants were novel. 19.6% of patients with NEK1 variants also carried mutations in other major ALS genes, suggesting an oligogenic nature of ALS.

Conclusions:

• The study expands the known genetic variability of NEK1 in ALS.
• It confirms the oligogenic model of ALS, where multiple genetic factors can contribute to disease development.
• No significant genotype-phenotype correlation was observed for NEK1 variants regarding age at onset or survival, though atypical features were noted.