{ "abstract": "Neurodegenerative and neuromuscular disorders are genetically heterogeneous, and many patients remain without a genetic diagnosis after multiple rounds of clinical gene panels or exome sequencing. These approaches often fail to detect structural variants (SVs), contributing to missed diagnoses. We investigated 286 individuals with neurodegenerative or neuromuscular diseases who previously received an uninformative report from diagnostic testing. Short-read genome sequencing (srGS) was used for single nucleotide variant/indel, copy number variant, and SV calling with variant prioritisation in seqr. Findings were corroborated by long-read sequencing, orthogonal validation (PCR/MLPA/Sanger), transcriptomics, and proteomics. We also assessed the utility of Talos (an automated variant prioritisation tool) to find clinically relevant SVs. Overall, 65/286 cases (22.7%) were solved; SVs accounted for 11/65 solved cases (16.9%); four of these would not be detectable with targeted panel or exome sequencing. We describe 10 illustrative diagnoses spanning diverse SV classes: an intronic interspersed duplication disrupting SPAST (SPG4); SVs supporting phenotype expansions associated with SPG11 (neuronal ceroid lipofuscinosis), heterozygous large in-frame deletions in TTN (distal arthrogryposis), and SPTAN1 (autosomal-dominant hereditary spastic paraplegia); an intergenic balanced translocation downstream of FOXG1; and a pathogenic SVA insertion in TAF1 detected as breakends in srGS. Talos prioritised seven of these 10 SV diagnoses. Here, we show SVs contribute substantially to diagnoses in neurogenetic disease cohorts and can evade panel/exome pipelines due to intronic breakpoints, balanced rearrangements, microhomology, and partial-exon events. srGS combined with automated reanalysis can shorten diagnostic timelines and improve diagnostic equity through a single, genome-wide test, although the clinical interpretation of SVs remains a significant challenge.\n\nSupplementary Information: The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-69714-w.", "abstract_shown": true, "affiliations": [ "Centre for Medical Research, Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, Australia", "Department of Diagnostic Genomics, PathWest Laboratory Medicine, Nedlands, WA Australia", "Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, Australia", "Centre for Population Genomics, Murdoch Children’s Research Institute, Melbourne, Australia", "Neurology Department, Te Toka Tumai, Te Whatu Ora, Auckland, New Zealand", "Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, VIC Australia", "Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC Australia", "Victorian Clinical Genetics Services, Royal Children’s Hospital, Melbourne, VIC Australia", "Department of Paediatrics, The University of Melbourne, Parkville, VIC Australia", "Centre for Brain Research, The University of Auckland, Auckland, New Zealand", "Neurogenetics Research Clinic, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand", "Department of Paediatrics, Monash University, Melbourne, VIC Australia", "Department of Pathology, Beaumont Hospital, Dublin, Ireland", "The Royal College of Surgeons, Dublin, Ireland", "Genetic Health WA, King Edward Memorial Hospital, Perth, WA Australia", "Neurology Department, Perth Children’s Hospital, Nedlands, Perth, Australia", "Medical Imaging Department, Perth Children’s Hospital, Perth, Australia", "Neurology, Royal Perth Hospital, Perth, WA Australia", "Perron Institute for Neurological and Translational Science, The University of Western Australia, Nedlands, WA Australia", "Neurosciences Department, Queensland Children’s Hospital, Brisbane, QLD Australia", "Anatomical Pathology, The Alfred Hospital, Melbourne, VIC 3004 Australia", "Neurogenetics Unit, Royal Perth Hospital, Perth, WA Australia" ], "article_type": "research article", "arxiv": null, "author_total": 36, "authors": [ { "affs": [ 0 ], "name": "Gavin Monahan" }, { "affs": [ 0, 1 ], "name": "Carolin K. Scriba" }, { "affs": [ 0 ], "name": "Jasmine Chew" }, { "affs": [ 1 ], "name": "Jessica Baker" }, { "affs": [ 0 ], "name": "Christina Vo" }, { "affs": [ 0 ], "name": "Chiara Folland" }, { "affs": [ 0 ], "name": "Jevin Parmar" }, { "affs": [ 2, 3 ], "name": "Samantha Bryen" }, { "affs": [ 0 ], "name": "Lein Dofash" }, { "affs": [ 0 ], "name": "Shelby Mullin" }, { "affs": [ 0 ], "name": "Audrey V. Rick" }, { "affs": [ 0 ], "name": "Elyshia McNamara" }, { "affs": [ 4 ], "name": "Joseph Donnelly" }, { "affs": [ 5 ], "name": "Tanavi Sharma" }, { "affs": [ 5, 6, 7 ], "name": "Daniella H. Hock" }, { "affs": [ 6, 7 ], "name": "Tegan Stait" }, { "affs": [ 2, 3 ], "name": "Matthew J. Welland" }, { "affs": [ 6, 7, 8 ], "name": "David R. Thorburn" }, { "affs": [ 4 ], "name": "Harry Fraser" }, { "affs": [ 4, 9, 10 ], "name": "Miriam Rodrigues" }, { "affs": [ 11 ], "name": "Nikki Gelfand" }, { "affs": [ 1 ], "name": "Mark Davis" }, { "affs": [ 1 ], "name": "Rebecca Gooding" }, { "affs": [ 12, 13 ], "name": "Michael Farrell" }, { "affs": [ 14 ], "name": "Catherine Kiraly-Borri" }, { "affs": [ 15 ], "name": "Twinkle Ghia" }, { "affs": [ 16 ], "name": "Richard Warne" }, { "affs": [ 17 ], "name": "Carolyn F. Orr" }, { "affs": [ 5, 6, 7 ], "name": "David A. Stroud" }, { "affs": [ 18 ], "name": "Wai Yan Yau" }, { "affs": [ 19 ], "name": "Anita Cairns" }, { "affs": [ 20 ], "name": "Catriona McLean" }, { "affs": [ 11 ], "name": "Michael Fahey" }, { "affs": [ 4, 9, 10 ], "name": "Richard Roxburgh" }, { "affs": [ 21, 17 ], "name": "Phillipa J. Lamont" }, { "affs": [ 0 ], "name": "Gianina Ravenscroft" } ], "bibtex": "https://research.draconitic.com/paper/11zz5qe2y6qbs.bib", "cited_by": 0, "doi": "10.1038/s41598-026-69714-w", "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13722596/", "id": "11zz5qe2y6qbs", "issns": [ "2045-2322" ], "landing_url": "https://doi.org/10.1038/s41598-026-69714-w", "language": "en", "licence": "CC-BY-NC-ND-4.0", "licence_label": "CC BY-NC-ND 4.0", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/", "metadata_licence": null, "native_subjects": [ [ "heading", "Article" ], [ "openalex", "1311|Genomics and Rare Diseases" ] ], "openalex": "W7212224314", "pdf_url": "https://www.nature.com/articles/s41598-026-69714-w_reference.pdf", "pmcid": "PMC13722596", "pmid": null, "published": "2026-09-11", "publisher": null, "ris": "https://research.draconitic.com/paper/11zz5qe2y6qbs.ris", "sources": [ { "first_seen": "2026-11-04T12:21:23Z", "native_id": "PMC13722596", "source": "pmc", "url": "https://doi.org/10.1038/s41598-026-69714-w" } ], "subjects": [ { "field": "biology", "origin": "openalex:1311|Genomics and Rare Diseases", "subfield": "genetics-genomics" } ], "title": "The hidden burden of structural variants in neurodegenerative and neuromuscular disorders", "title_text": "The hidden burden of structural variants in neurodegenerative and neuromuscular disorders", "type": "peer-reviewed", "updated_at": "2026-11-04T12:21:23Z", "url": "https://research.draconitic.com/paper/11zz5qe2y6qbs", "venue": "Scientific Reports", "versions": [] }