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. 2025 Aug 22;272(9):587.
doi: 10.1007/s00415-025-13328-1.

Whole genome sequencing analysis in primary lateral sclerosis (PLS) patients reveals mutations in neurological diseases-causing genes

Arianna Manini #  1 , Alberto Brusati #  2 , Maurizio Grassano  3   4 , Giulia Scacciatella  5 , Silvia Peverelli  6 , Jacopo Spagliardi  5 , Viviana Pensato  7 , Alberto Doretti  6 , Rosario Vasta  3 , Umberto Manera  3   4 , Antonio Canosa  3   4 , Maura Brunetti  3 , Davide Gentilini  8   9 , Stefano Messina  6 , Federico Verde  6 , Cristina Moglia  3   4 , Claudia Morelli  6 , Eleonora Dalla Bella  10 , Pamela J Keagle  2 , John E Landers  2   11 , Cinzia Gellera  7 , Giuseppe Lauria Pinter  10   12 , Adriano Chiò  3   4   13 , Antonia Ratti  6   12 , Andrea Calvo  3   4 , Vincenzo Silani #  1   6 , Nicola Ticozzi #  14   15
Affiliations

Whole genome sequencing analysis in primary lateral sclerosis (PLS) patients reveals mutations in neurological diseases-causing genes

Arianna Manini et al. J Neurol. .

Abstract

Background: Primary Lateral Sclerosis (PLS) is a rare, adult-onset neurodegenerative disease that predominantly affects upper motor neurons. Despite being considered mostly sporadic, familial cases and rare genetic variants in genes associated with amyotrophic lateral sclerosis, hereditary spastic paraplegia and other neurological disorders have been reported in some PLS cases. Due to its rare prevalence among general population, large genetic studies of PLS are lacking.

Methods: Fifty patients diagnosed with PLS based on consensus criteria were enrolled between 2013 and 2022 for comprehensive phenotypic and genotypic analysis using whole genome sequencing. We analyzed rare single nucleotide variants (SNVs), deemed pathogenic, likely pathogenic or of uncertain significance (VUS) based on the American College of Medical Genetics and Genomics criteria, and repeat expansions (REs) exceeding the pathogenic threshold, in 290 genes involved in neurological disorders.

Results: We identified mutations in 7 patients (13.7%), specifically SNVs in CAPN1 (Spastic paraplegia 76), TBK1 (amyotrophic lateral sclerosis/frontotemporal dementia, ALS4/FTD), LITAF (Charcot-Marie-Tooth disease 1C), POLG (chronic progressive external ophthalmoplegia), APP (Alzheimer's disease) and OPTN (ALS12 ± FTD), and one RE in ATXN8OS (spinocerebellar ataxia 8). Additionally, two VUS were found in ANTXR2, a candidate gene for PLS recently identified via truncating variant collapsing analysis, but none of them was loss-of-function (one synonymous and one in-frame insertion).

Conclusions: Our study demonstrates a notable genetic intersection between PLS and various neurological disorders, including motor neuron diseases, neuropathies, mitochondrial disorders, ataxias, and dementias. These findings underscore the relevance of further investigation in larger cohorts to fully elucidate PLS genetic architecture and highlight the need to reconsider the role of genetic testing in its diagnostic criteria.

Keywords: Ataxia; Hereditary; Mitochondrial diseases; Motor neuron disease; Neurodegenerative diseases; Peripheral nervous system diseases; Primary lateral sclerosis; Sequence analysis; Spastic paraplegia; Tandem repeat sequences; Whole genome sequencing.

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Conflict of interest statement

Declarations. Conflicts of interest: VS received compensation for consulting services and/or speaking activities from AveXis, Cytokinetics, Italfarmaco, Liquidweb Srl, Novartis Pharma AG and Zambon Biotech SA. He is on the Editorial Board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, European Neurology, American Journal of Neurodegenerative Diseases, Frontiers in Neurology and Exploration of Neuroprotective Therapy. NT received compensation for consulting services from Amylyx Pharmaceuticals, Biogen, Italfarmaco and Zambon Biotech SA. He is Associate Editor for Frontiers in Aging Neuroscience. AD received compensation for consulting services and/or speaking activities from Abbvie, Eli Lilly, Teva, Lundbeck, Pfizer, IPSEN, Merz, Exeltis, Novartis, Zambon, Neopharmed Gentili, Piam. Ethical approval: The study was approved by the Ethics Committee of the IRCCS Instituto Auxologico Italiano (2021_05_18) and by the Ethics Committee of the Turin ALS Center (Comitato Etico Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Torino). Written informed consent was obtained from each patient at the time of evaluation to use semi-anonymized clinical data for research purposes. The study was conducted in accordance with the principles of the Declaration of Helsinki.

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