Systematic evaluation of genetic mutations in ALS: a population-based study

Maurizio Grassano*, Andrea Calvo, Cristina Moglia, Luca Sbaiz, Maura Brunetti, Marco Barberis, Federico Casale, Umberto Manera, Rosario Vasta, Antonio Canosa, Sandra D'Alfonso, Lucia Corrado, Letizia Mazzini, Clifton Dalgard, Ramita Karra, Ruth Chia, Bryan Traynor, Adriano Chiò

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


Background A genetic diagnosis in Amyotrophic Lateral Sclerosis (ALS) can inform genetic counselling, prognosis and, in the light of incoming gene-targeted therapy, management. However, conventional genetic testing strategies are often costly and time-consuming. Objective To evaluate the diagnostic yield and advantages of whole-genome sequencing (WGS) as a standard diagnostic genetic test for ALS. Methods In this population-based cohort study, 1043 ALS patients from the Piemonte and Valle d'Aosta Register for ALS and 755 healthy individuals were screened by WGS for variants in 42 ALS-related genes and for repeated-expansions in C9orf72 and ATXN2. Results A total of 279 ALS cases (26.9%) received a genetic diagnosis, namely 75.2% of patients with a family history of ALS and 21.5% of sporadic cases. The mutation rate among early-onset ALS patients was 43.9%, compared with 19.7% of late-onset patients. An additional 14.6% of the cohort carried a genetic factor that worsen prognosis. Conclusions Our results suggest that, because of its high diagnostic yield and increasingly competitive costs, along with the possibility of retrospectively reassessing newly described genes, WGS should be considered as standard genetic testing for all ALS patients. Additionally, our results provide a detailed picture of the genetic basis of ALS in the general population.

Original languageEnglish
Pages (from-to)1190-1193
Number of pages4
JournalJournal of Neurology, Neurosurgery and Psychiatry
Issue number11
StatePublished - 27 Jul 2022
Externally publishedYes


  • ALS
  • C9ORF


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