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Updated: Nov 29, 2025
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Mutational Analysis of Known ALS Genes in an Italian Population-Based Cohort
Maurizio Grassano1, Andrea Calvo2, Cristina Moglia2
1From "Rita Levi Montalcini" Department of Neuroscience (M.G., A. Calvo, C.M., A. Canosa, U.M., R.V., A. Chiò), University of Turin, Italy; Biocomputational Group (J.D., R.J.G.) and Neuromuscular Diseases Research Section (M.G., R.C., B.J.T.), Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD; Laboratory of Genetics, Department of Clinical Pathology (M. Brunetti, M. Barberis, L.S.), Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin; Department of Health Sciences Interdisciplinary Research Center of Autoimmune Diseases (L.C., S.D.), "Amedeo Avogadro" University of Eastern Piedmont; ALS Center (L.M.), Department of Neurology, Azienda Ospedaliera Universitaria Maggiore della Carità, Novara, Italy; Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics (S.W.S.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; Department of Neurology (S.W.S., B.J.T.), Johns Hopkins University Medical Center; Department of Anatomy, Physiology & Genetics (C.D.), and The American Genome Center, Collaborative Health Initiative Research Program (C.D.), Uniformed Services University of the Health Sciences, Bethesda, MD; and Institute of Cognitive Sciences and Technologies (A. Chiò), National Council of Research, Rome, Italy. grassano.maurizio@gmail.com.
Objective:
To assess the burden of rare genetic variants and to estimate the contribution of known amyotrophic lateral sclerosis (ALS) genes in an Italian population-based cohort, we performed whole genome sequencing in 959 patients with ALS and 677 matched healthy controls.
Methods:
We performed genome sequencing in a population-based cohort (Piemonte and Valle d'Aosta Registry for ALS [PARALS]). A panel of 40 ALS genes was analyzed to identify potential disease-causing genetic variants and to evaluate the gene-wide burden of rare variants among our population.
Results:
A total of 959 patients with ALS were compared with 677 healthy controls from the same geographical area. Gene-wide association tests demonstrated a strong association with SOD1, whose rare variants are the second most common cause of disease after C9orf72 expansion. A lower signal was observed for TARDBP, proving that its effect on our cohort is driven by a few known causal variants. We detected rare variants in other known ALS genes that did not surpass statistical significance in gene-wise tests, thus highlighting that their contribution to disease risk in our cohort is limited.
Conclusions:
We identified potential disease-causing variants in 11.9% of our patients. We identified the genes most frequently involved in our cohort and confirmed the contribution of rare variants in disease risk. Our results provide further insight into the pathologic mechanism of the disease and demonstrate the importance of genome-wide sequencing as a diagnostic tool.
