• 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, and Adriano Chiò.
• Department of Neuroscience, University of Turin, Torino, Italy grassano.maurizio@gmail.com.
• J. Neurol. Neurosurg. Psychiatr. 2022 Jul 27; 93 (11): 119011931190-3.

BackgroundA 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.ObjectiveTo evaluate the diagnostic yield and advantages of whole-genome sequencing (WGS) as a standard diagnostic genetic test for ALS.MethodsIn 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.ResultsA 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.ConclusionsOur 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.© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

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