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Peer-reviewedCC BY-NC-ND 4.0Scientific Reports

The hidden burden of structural variants in neurodegenerative and neuromuscular disorders

  • Gavin Monahan1
  • Carolin K. Scriba1,2
  • Jasmine Chew1
  • Jessica Baker2
  • Christina Vo1
  • Chiara Folland1
  • Jevin Parmar1
  • Samantha Bryen3,4
  • Lein Dofash1
  • Shelby Mullin1
  • Audrey V. Rick1
  • Elyshia McNamara1
24 more authors
  • Joseph Donnelly5
  • Tanavi Sharma6
  • Daniella H. Hock6,7,8
  • Tegan Stait7,8
  • Matthew J. Welland3,4
  • David R. Thorburn7,8,9
  • Harry Fraser5
  • Miriam Rodrigues5,10,11
  • Nikki Gelfand12
  • Mark Davis2
  • Rebecca Gooding2
  • Michael Farrell13,14
  • Catherine Kiraly-Borri15
  • Twinkle Ghia16
  • Richard Warne17
  • Carolyn F. Orr18
  • David A. Stroud6,7,8
  • Wai Yan Yau19
  • Anita Cairns20
  • Catriona McLean21
  • Michael Fahey12
  • Richard Roxburgh5,10,11
  • Phillipa J. Lamont22,18
  • Gianina Ravenscroft1
22 affiliations
  1. 1Centre for Medical Research, Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, Australia
  2. 2Department of Diagnostic Genomics, PathWest Laboratory Medicine, Nedlands, WA Australia
  3. 3Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, Australia
  4. 4Centre for Population Genomics, Murdoch Children’s Research Institute, Melbourne, Australia
  5. 5Neurology Department, Te Toka Tumai, Te Whatu Ora, Auckland, New Zealand
  6. 6Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, VIC Australia
  7. 7Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC Australia
  8. 8Victorian Clinical Genetics Services, Royal Children’s Hospital, Melbourne, VIC Australia
  9. 9Department of Paediatrics, The University of Melbourne, Parkville, VIC Australia
  10. 10Centre for Brain Research, The University of Auckland, Auckland, New Zealand
  11. 11Neurogenetics Research Clinic, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
  12. 12Department of Paediatrics, Monash University, Melbourne, VIC Australia
  13. 13Department of Pathology, Beaumont Hospital, Dublin, Ireland
  14. 14The Royal College of Surgeons, Dublin, Ireland
  15. 15Genetic Health WA, King Edward Memorial Hospital, Perth, WA Australia
  16. 16Neurology Department, Perth Children’s Hospital, Nedlands, Perth, Australia
  17. 17Medical Imaging Department, Perth Children’s Hospital, Perth, Australia
  18. 18Neurology, Royal Perth Hospital, Perth, WA Australia
  19. 19Perron Institute for Neurological and Translational Science, The University of Western Australia, Nedlands, WA Australia
  20. 20Neurosciences Department, Queensland Children’s Hospital, Brisbane, QLD Australia
  21. 21Anatomical Pathology, The Alfred Hospital, Melbourne, VIC 3004 Australia
  22. 22Neurogenetics Unit, Royal Perth Hospital, Perth, WA Australia
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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.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-69714-w.

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Cite

BibTeXRIS
BibTeX
@article{monahan2026hidden,
  title = {{The hidden burden of structural variants in neurodegenerative and neuromuscular disorders}},
  author = {Gavin Monahan and Carolin K. Scriba and Jasmine Chew and Jessica Baker and Christina Vo and Chiara Folland and Jevin Parmar and Samantha Bryen and Lein Dofash and Shelby Mullin and Audrey V. Rick and Elyshia McNamara and Joseph Donnelly and Tanavi Sharma and Daniella H. Hock and Tegan Stait and Matthew J. Welland and David R. Thorburn and Harry Fraser and Miriam Rodrigues and Nikki Gelfand and Mark Davis and Rebecca Gooding and Michael Farrell and Catherine Kiraly-Borri and Twinkle Ghia and Richard Warne and Carolyn F. Orr and David A. Stroud and Wai Yan Yau and Anita Cairns and Catriona McLean and Michael Fahey and Richard Roxburgh and Phillipa J. Lamont and Gianina Ravenscroft},
  journal = {Scientific Reports},
  year = {2026},
  month = sep,
  doi = {10.1038/s41598-026-69714-w},
  url = {https://doi.org/10.1038/s41598-026-69714-w},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - The hidden burden of structural variants in neurodegenerative and neuromuscular disorders
AU  - Gavin Monahan
AU  - Carolin K. Scriba
AU  - Jasmine Chew
AU  - Jessica Baker
AU  - Christina Vo
AU  - Chiara Folland
AU  - Jevin Parmar
AU  - Samantha Bryen
AU  - Lein Dofash
AU  - Shelby Mullin
AU  - Audrey V. Rick
AU  - Elyshia McNamara
AU  - Joseph Donnelly
AU  - Tanavi Sharma
AU  - Daniella H. Hock
AU  - Tegan Stait
AU  - Matthew J. Welland
AU  - David R. Thorburn
AU  - Harry Fraser
AU  - Miriam Rodrigues
AU  - Nikki Gelfand
AU  - Mark Davis
AU  - Rebecca Gooding
AU  - Michael Farrell
AU  - Catherine Kiraly-Borri
AU  - Twinkle Ghia
AU  - Richard Warne
AU  - Carolyn F. Orr
AU  - David A. Stroud
AU  - Wai Yan Yau
AU  - Anita Cairns
AU  - Catriona McLean
AU  - Michael Fahey
AU  - Richard Roxburgh
AU  - Phillipa J. Lamont
AU  - Gianina Ravenscroft
PY  - 2026
DA  - 2026/09/11
JO  - Scientific Reports
DO  - 10.1038/s41598-026-69714-w
UR  - https://doi.org/10.1038/s41598-026-69714-w
AB  - 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.  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-69714-w.
SN  - 2045-2322
ER  -