Genetic and phenotype analyses of primary lateral sclerosis datasets from international cohorts

Primary lateral sclerosis (PLS) is the rarest form of motor neurone disease (MND). It is characterized by upper motor neuron degeneration, leading to progressive weakness, spasticity and functional disability. Although PLS does not typically shorten life substantially, it gradually impacts quality of life as the diseases progresses. There is no established genetic cause of PLS. One of the biggest challenges faced by people with PLS is delayed diagnosis and misdiagnosis, since the initial symptoms can be similar to amyotrophic lateral sclerosis (ALS), the most common form of MND. In the absence of a concrete genetic test that differentiates PLS from other MNDs, this delay in diagnosis is inevitable. Understanding the genetic basis of PLS might help in reducing the time from the onset of symptoms to diagnosis, and it will improve our understanding of the disease biology favouring the development of a treatment. The aim of our study is to collect a large international PLS genetic and clinical dataset to investigate its genetic and phenotypic landscapes as well as to evaluate whether genetic testing should be advised in PLS. Through Project MinE and AnswerALS, we accessed whole-genome sequencing data of 120 PLS, 7405 ALS and 2444 controls. We identified variants in several MND genes such as FIG4, FUS, SPG7, SPG11 and SQSTM1 genes among others and repeat expansions in the ATXN1 (12.2%) and NIPA1 (7.3%) genes, but none in the C9orf72 and ATXN2 genes. Overall PLS patients harboured fewer clinically actionable MND-associated variants than ALS patients (p = 0.0001), however, depending on the panel, up to 11% of people with PLS might benefit from genetic testing. By looking at the clinical characteristics of these cohorts, the age of symptom onset was not younger for people with PLS than for those with ALS in both Project MinE and AnswerALS. On such bases, we advise that the current diagnostic criteria that discourage the use of genetic testing and rely on age of onset should be reconsidered. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement M.K. and A.I. are supported by South London and Maudsley NHS Foundation Trust, MND Scotland, Motor Neurone Disease Association, National Institute for Health Research, Darby Rimmer MND Foundation, Spastic Paraplegia Foundation, Alzheimers Research UK and Rosetrees Trust. TPS is currently employed by AstraZeneca. This study represents independent research part funded by the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and Kings College London. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The whole genome sequencing data and clinical data was acquired from the Project MinE database. The ethical approval for the project MinE dataset is described in detail here Van Rheenen, W. et al. Project MinE: study design and pilot analyses of a large-scale whole-genome sequencing study in amyotrophic lateral sclerosis. Eur. J. Hum. Genet. (2018).). The AALS trial and smartphone app were approved by the Johns Hopkins institutional review board (nos. 00082277 and 00240000). The AALS program is registered at clinicaltrials.gov([NCT02574390][1]). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02574390&atom=%2Fmedrxiv%2Fearly%2F2023%2F07%2F23%2F2023.07.19.23292817.atom