{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T13:07:09Z","timestamp":1790687229910,"version":"4.1.0"},"reference-count":89,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,5,8]],"date-time":"2020-05-08T00:00:00Z","timestamp":1588896000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health","award":["#RF-2011-02351193"],"award-info":[{"award-number":["#RF-2011-02351193"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Although the genetic architecture of amyotrophic lateral sclerosis (ALS) is incompletely understood, recent findings suggest a complex model of inheritance in ALS, which is consistent with a multistep pathogenetic process. Therefore, the aim of our work is to further explore the architecture of ALS using targeted next generation sequencing (NGS) analysis, enriched in motor neuron diseases (MND)-associated genes which are also implicated in axonal hereditary motor neuropathy (HMN), in order to investigate if disease expression, including the progression rate, could be influenced by the combination of multiple rare gene variants. We analyzed 29 genes in an Italian cohort of 83 patients with both familial and sporadic ALS. Overall, we detected 43 rare variants in 17 different genes and found that 43.4% of the ALS patients harbored a variant in at least one of the investigated genes. Of note, 27.9% of the variants were identified in other MND- and HMN-associated genes. Moreover, multiple gene variants were identified in 17% of the patients. The burden of rare variants is associated with reduced survival and with the time to reach King stage 4, i.e., the time to reach the need for percutaneous endoscopic gastrostomy (PEG) positioning or non-invasive mechanical ventilation (NIMV) initiation, independently of known negative prognostic factors. Our data contribute to a better understanding of the molecular basis of ALS supporting the hypothesis that rare variant burden could play a role in the multistep model of disease and could exert a negative prognostic effect. Moreover, we further extend the genetic landscape of ALS to other MND-associated genes traditionally implicated in degenerative diseases of peripheral axons, such as HMN and CMT2.<\/jats:p>","DOI":"10.3390\/ijms21093346","type":"journal-article","created":{"date-parts":[[2020,5,11]],"date-time":"2020-05-11T10:01:18Z","timestamp":1589191278000},"page":"3346","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Burden of Rare Variants in ALS and Axonal Hereditary Neuropathy Genes Influence Survival in ALS: Insights from a Next Generation Sequencing Study of an Italian ALS Cohort"],"prefix":"10.3390","volume":"21","author":[{"given":"Stefania","family":"Scarlino","sequence":"first","affiliation":[{"name":"Experimental Neuropathology Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teuta","family":"Domi","sequence":"additional","affiliation":[{"name":"Experimental Neuropathology Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2406-0713","authenticated-orcid":false,"given":"Laura","family":"Pozzi","sequence":"additional","affiliation":[{"name":"Experimental Neuropathology Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Romano","sequence":"additional","affiliation":[{"name":"Experimental Neuropathology Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni Battista","family":"Pipitone","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Molecular Biology, Unit of Genomics for Human Disease Diagnosis, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri Matteo","family":"Falzone","sequence":"additional","affiliation":[{"name":"Experimental Neuropathology Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"Neurology Unit, San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena","family":"Mosca","sequence":"additional","affiliation":[{"name":"Medical Genetic Unit, Department of Laboratory Medicine, Niguarda Hospital, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvana","family":"Penco","sequence":"additional","affiliation":[{"name":"Medical Genetic Unit, Department of Laboratory Medicine, Niguarda Hospital, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Lunetta","sequence":"additional","affiliation":[{"name":"NEuroMuscular Omnicentre (NEMO), Fondazione Serena Onlus, Milan 20132, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Sansone","sequence":"additional","affiliation":[{"name":"NEuroMuscular Omnicentre (NEMO), Fondazione Serena Onlus, Milan 20132, Italy"},{"name":"Department Biomedical Sciences of Health, University of Milan, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucio","family":"Tremolizzo","sequence":"additional","affiliation":[{"name":"Neurology Unit, \u201cSan Gerardo\u201d Hospital and University of Milano-Bicocca, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Fazio","sequence":"additional","affiliation":[{"name":"Neurology Unit, San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Agosta","sequence":"additional","affiliation":[{"name":"Neuroimaging Research Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Filippi","sequence":"additional","affiliation":[{"name":"Neurology Unit, San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"Neuroimaging Research Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"Neurophysiology Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"Vita-Salute San Raffaele University,20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Carrera","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Molecular Biology, Unit of Genomics for Human Disease Diagnosis, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nilo","family":"Riva","sequence":"additional","affiliation":[{"name":"Experimental Neuropathology Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"Neurology Unit, San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8226-8320","authenticated-orcid":false,"given":"Angelo","family":"Quattrini","sequence":"additional","affiliation":[{"name":"Experimental 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