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Background <p>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.</p> Methods <p>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.</p> Results <p>We identified mutations in 7 patients (13.7%), specifically SNVs in <i>CAPN1</i> (Spastic paraplegia 76), <i>TBK1</i> (amyotrophic lateral sclerosis/frontotemporal dementia, ALS4/FTD), <i>LITAF</i> (Charcot-Marie-Tooth disease 1C), <i>POLG</i> (chronic progressive external ophthalmoplegia), <i>APP</i> (Alzheimer's disease) and <i>OPTN</i> (ALS12 ± FTD), and one RE in <i>ATXN8OS</i> (spinocerebellar ataxia 8). Additionally, two VUS were found in <i>ANTXR2</i>, 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).</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年8月22日

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  • Arianna Manini,
  • Alberto Brusati,
  • Maurizio Grassano,
  • Giulia Scacciatella,
  • Silvia Peverelli,
  • Jacopo Spagliardi,
  • Viviana Pensato,
  • Alberto Doretti,
  • Rosario Vasta,
  • Umberto Manera,
  • Antonio Canosa,
  • Maura Brunetti,
  • Davide Gentilini,
  • Stefano Messina,
  • Federico Verde,
  • Cristina Moglia,
  • Claudia Morelli,
  • Eleonora Dalla Bella,
  • Pamela J. Keagle,
  • John E. Landers,
  • Cinzia Gellera,
  • Giuseppe Lauria Pinter,
  • Adriano Chiò,
  • Antonia Ratti,
  • Andrea Calvo,
  • Vincenzo Silani,
  • Nicola Ticozzi

摘要

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.