{
  "abstract": "Background The genetic myopathies are a large, clinically and genetically heterogeneous group of disorders caused by variants in >300 genes. Many patients with genetic myopathies remain undiagnosed even after use of current clinical genetic testing modalities (e.g. next-generation sequencing, etc.). Long-read sequencing (LRS) is a newer sequencing approach that has several technical advantages over existing sequencing methodologies, potentially allowing for improved diagnostic rates. We aimed to explore the diagnostic utility of Oxford Nanopore LRS in the genetic myopathies.Methods Individuals with either a genetically solved myopathy (n = 17; Group A) or a suspected genetic myopathy that remained genetically unsolved or incompletely solved following standard clinical genetic testing (n = 28; Group B) were recruited from patients referred to the Concord Hospital Neuromuscular Clinic and the NeuRA Clinics. Blood was collected and sequenced using an adaptive sampling Oxford Nanopore LRS panel targeting 333 myopathy genes/loci.Results The Oxford Nanopore LRS panel detected all previously identified causative variants in Group A and led to a new genetic diagnosis in 21.4% (6/28) of cases from Group B, with pathogenic variants identified in LAMA2, the 4q35 D4Z4 repeat array and several oculopharyngodistal myopathy (OPDM) genes (GIPC1, NOTCH2NLC, RILPL1, ABCD3).Conclusion LRS provided a streamlined approach to identifying a range of different pathogenic variants and led to resolution of a significant proportion of our previously undiagnosed genetic myopathy cohort. In particular, we identified a number of recently described pathogenic short tandem repeat expansions in OPDM genes for which clinically accredited genetic testing is not currently available in Australia.",
  "authors": [
    {
      "affiliations": [
        "Neurodegenerative Service, Prince of Wales Hospital, Sydney, NSW, Australia",
        "Neuroscience Research Australia, Sydney, NSW, Australia",
        "Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia",
        "Garvan Institute of Medical Research, Sydney, NSW, Australia",
        "Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia",
        "Molecular Medicine Laboratory, Concord Repatriation General Hospital, Sydney, NSW, Australia"
      ],
      "name": "Dennis Yeow"
    },
    {
      "affiliations": [
        "Garvan Institute of Medical Research, Sydney, NSW, Australia"
      ],
      "name": "Igor Stevanovski"
    },
    {
      "affiliations": [
        "Garvan Institute of Medical Research, Sydney, NSW, Australia",
        "Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia"
      ],
      "name": "Andre LM Reis"
    },
    {
      "affiliations": [
        "Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia",
        "Garvan Institute of Medical Research, Sydney, NSW, Australia",
        "Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia",
        "Molecular Medicine Laboratory, Concord Repatriation General Hospital, Sydney, NSW, Australia",
        "Neurofibromatosis Clinic, Department of Clinical Genetics, Royal North Shore Hospital, Sydney, NSW, Australia"
      ],
      "name": "Laura I Rudaks"
    },
    {
      "affiliations": [
        "Garvan Institute of Medical Research, Sydney, NSW, Australia"
      ],
      "name": "Sanjog R Chintalaphani"
    },
    {
      "affiliations": [
        "Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia",
        "Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney Local Health District, Sydney, NSW, Australia"
      ],
      "name": "Bianca Grosz"
    },
    {
      "affiliations": [
        "Neurodegenerative Service, Prince of Wales Hospital, Sydney, NSW, Australia",
        "Neuroscience Research Australia, Sydney, NSW, Australia",
        "Department of Neurology, Royal North Shore Hospital, Sydney, NSW, Australia"
      ],
      "name": "Christina Liang"
    },
    {
      "affiliations": [
        "Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia",
        "Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia",
        "Neurofibromatosis Clinic, Department of Clinical Genetics, Royal North Shore Hospital, Sydney, NSW, Australia"
      ],
      "name": "Katrina A Morris"
    },
    {
      "affiliations": [
        "Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia",
        "Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia"
      ],
      "name": "Stephen Reddel"
    },
    {
      "affiliations": [
        "Department of Neurology, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia",
        "University of Queensland, Brisbane, QLD, Australia"
      ],
      "name": "Pamela A McCombe"
    },
    {
      "affiliations": [
        "Molecular Medicine Laboratory, Concord Repatriation General Hospital, Sydney, NSW, Australia"
      ],
      "name": "Danqing Zhu"
    },
    {
      "affiliations": [
        "Molecular Medicine Laboratory, Concord Repatriation General Hospital, Sydney, NSW, Australia"
      ],
      "name": "Marion Stoll"
    },
    {
      "affiliations": [
        "Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia",
        "Garvan Institute of Medical Research, Sydney, NSW, Australia",
        "Neurogenetics Research Group, Kolling Institute, University of Sydney and Northern Sydney Local Health District, Sydney, NSW, Australia"
      ],
      "name": "Ryan L Davis"
    },
    {
      "affiliations": [
        "Department of Genetic Medicine, Westmead Hospital, Sydney, NSW, Australia"
      ],
      "name": "David Manser"
    },
    {
      "affiliations": [
        "Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia",
        "Department of Genetic Medicine, Westmead Hospital, Sydney, NSW, Australia"
      ],
      "name": "Michel Tchan"
    },
    {
      "affiliations": [
        "Clinical Genetics Service, Royal Prince Alfred Hospital, Sydney, NSW, Australia"
      ],
      "name": "Lisa Worgan"
    },
    {
      "affiliations": [
        "Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia",
        "Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia"
      ],
      "name": "Andrew Hannaford"
    },
    {
      "affiliations": [
        "Neurodegenerative Service, Prince of Wales Hospital, Sydney, NSW, Australia",
        "Neuroscience Research Australia, Sydney, NSW, Australia",
        "Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia"
      ],
      "name": "Carolyn M Sue"
    },
    {
      "affiliations": [
        "Department of Neurology, Toowoomba Base Hospital, Toowoomba, QLD, Australia"
      ],
      "name": "Ehsan Shandiz"
    },
    {
      "affiliations": [
        "Department of Neurology, Royal North Shore Hospital, Sydney, NSW, Australia"
      ],
      "name": "Kate E Ahmad"
    },
    {
      "affiliations": [
        "Department of Neurology, Royal Adelaide Hospital, Adelaide, SA, Australia"
      ],
      "name": "Roula Ghaoui"
    },
    {
      "affiliations": [
        "Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia",
        "Department of Neurology, Hornsby Ku-ring-gai Hospital, Sydney, NSW, Australia"
      ],
      "name": "Stephanie L Barnes"
    },
    {
      "affiliations": [
        "Central Coast Neurosciences Research, Tumbi Umbi, NSW, Australia"
      ],
      "name": "Jonathan Sturm"
    },
    {
      "affiliations": [
        "Department of Neurology, Canberra Hospital, Canberra, ACT, Australia"
      ],
      "name": "Anna Willard"
    },
    {
      "affiliations": [
        "Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia",
        "Central West Neurology and Neurosurgery, Orange, NSW, Australia"
      ],
      "name": "Simon Hawke"
    },
    {
      "affiliations": [
        "Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia",
        "Department of Neurology, Royal North Shore Hospital, Sydney, NSW, Australia"
      ],
      "name": "Karl Ng"
    },
    {
      "affiliations": [
        "Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia",
        "Institute of Precision Medicine and Bioinformatics, Sydney, NSW, Australia",
        "New South Wales Health Pathology, Royal Prince Alfred Hospital, Sydney, NSW, Australia"
      ],
      "name": "Pak Leng Cheong"
    },
    {
      "affiliations": [
        "Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia",
        "Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney Local Health District, Sydney, NSW, Australia",
        "Molecular Medicine Laboratory, Concord Repatriation General Hospital, Sydney, NSW, Australia"
      ],
      "name": "Marina L Kennerson"
    },
    {
      "affiliations": [
        "Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia",
        "Garvan Institute of Medical Research, Sydney, NSW, Australia",
        "Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia",
        "Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia",
        "Molecular Medicine Laboratory, Concord Repatriation General Hospital, Sydney, NSW, Australia"
      ],
      "name": "Kishore R Kumar"
    },
    {
      "affiliations": [
        "Garvan Institute of Medical Research, Sydney, NSW, Australia",
        "Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia"
      ],
      "name": "Ira W Deveson"
    }
  ],
  "title": "YI5 Targeted nanopore long-read sequencing improves diagnosis of genetic myopathies",
  "uid": "438aee15-9310-58e3-b791-21855447a2d2"
}