Genetic overlap between ALS and other neurodegenerative or neuromuscular disorders

Amyotroph Lateral Scler Frontotemporal Degener. 2024 Feb;25(1-2):177-187. doi: 10.1080/21678421.2023.2270705. Epub 2024 Jan 23.

Abstract

Objective: In Norway, 89% of patients with Amyotrophic lateral sclerosis (ALS) lacks a genetic diagnose. ALS genes and genes that cause other neuromuscular or neurodegenerative disorders extensively overlap. This population-based study examined whether patients with ALS have a family history of neurological disorders and explored the occurrence of rare genetic variants associated with other neurodegenerative or neuromuscular disorders.

Methods: During a two-year period, blood samples and clinical data from patients with ALS were collected from all 17 neurological departments in Norway. Our genetic analysis involved exome sequencing and bioinformatics filtering of 510 genes associated with neurodegenerative and neuromuscular disorders. The variants were interpreted using genotype-phenotype correlations and bioinformatics tools.

Results: A total of 279 patients from a Norwegian population-based ALS cohort participated in this study. Thirty-one percent of the patients had first- or second-degree relatives with other neurodegenerative disorders, most commonly dementia and Parkinson's disease. The genetic analysis identified 20 possible pathogenic variants, in ATL3, AFG3L2, ATP7A, BICD2, HARS1, KIF1A, LRRK2, MSTO1, NEK1, NEFH, and SORL1, in 25 patients. NEK1 risk variants were present in 2.5% of this ALS cohort. Only four of the 25 patients reported relatives with other neurodegenerative or neuromuscular disorders.

Conclusion: Gene variants known to cause other neurodegenerative or neuromuscular disorders, most frequently in NEK1, were identified in 9% of the patients with ALS. Most of these patients had no family history of other neurodegenerative or neuromuscular disorders. Our findings indicated that AFG3L2, ATP7A, BICD2, KIF1A, and MSTO1 should be further explored as potential ALS-causing genes.

Keywords: Amyotrophic lateral sclerosis; amyotrophic lateral sclerosis susceptibility; genetic analysis; pleiotropy.

MeSH terms

  • ATP-Dependent Proteases / genetics
  • ATPases Associated with Diverse Cellular Activities / genetics
  • Amyotrophic Lateral Sclerosis* / epidemiology
  • Amyotrophic Lateral Sclerosis* / genetics
  • Cell Cycle Proteins*
  • Cytoskeletal Proteins / genetics
  • Family
  • Genetic Association Studies
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Kinesins / genetics
  • LDL-Receptor Related Proteins / genetics
  • Membrane Transport Proteins / genetics
  • Neurodegenerative Diseases* / epidemiology
  • Neurodegenerative Diseases* / genetics

Substances

  • AFG3L2 protein, human
  • ATPases Associated with Diverse Cellular Activities
  • ATP-Dependent Proteases
  • SORL1 protein, human
  • LDL-Receptor Related Proteins
  • Membrane Transport Proteins
  • KIF1A protein, human
  • Kinesins
  • MSTO1 protein, human
  • Cytoskeletal Proteins
  • Cell Cycle Proteins