{
  "abstract": "Background Heterozygous variants in SLC12A6 have recently been shown to cause dominant Charcot-Marie-Tooth disease (CMT). We aim to characterise the phenotype of patients with previously reported and novel heterozygous variants in the gene and understand any genotype-phenotype correlation.Methods Patients were clinically and genetically assessed in sites from Europe, Australia, Brazil and the USA. All patients underwent whole exome or whole genome sequencing. Variants were classified using American College of Medical Genetics and Genomics criteria.Results Twenty-three individuals from 13 families carried nine variants classified either as pathogenic/likely pathogenic or variants of uncertain significance segregating in multiple family members, including five novel variants. Forty-eight percent (11/23) were male with a mean age of disease onset of 15.7 years (range 1–45 years). Clinical phenotype varied dramatically with genotype; Arg207His and Ser647Pro caused a severe childhood-onset, sensory and motor, conduction-slowing neuropathy, whereas Gly552Asp caused a mild, adult-onset, sensory-predominant neuropathy, Thr991Ala an infantile-onset motor neuropathy, and the Met282Lys/Gly286Cys locus a complex, axonal neuropathy.Conclusions Heterozygous variants in SLC12A6 can cause CMT of all clinical phenotypes, severity and age of onset, depending on the genotype. Such phenotypic diversity has not been described for any other CMT gene, and more work is needed to understand disease mechanisms to guide future therapeutic options.",
  "authors": [
    {
      "affiliations": [
        "Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK"
      ],
      "name": "Christopher J Record"
    },
    {
      "affiliations": [
        "Department of Neurology, University of Iowa Health Care Medical Center, Iowa City, Iowa, USA"
      ],
      "name": "Tiffany Grider"
    },
    {
      "affiliations": [
        "Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA"
      ],
      "name": "Adriana P Rebelo"
    },
    {
      "affiliations": [
        "Neuromuscular Repair Unit, Institute of Experimental Neurology (InSpe), Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy"
      ],
      "name": "Christian Laurini"
    },
    {
      "affiliations": [
        "Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK"
      ],
      "name": "Mariola Skorupinska"
    },
    {
      "affiliations": [
        "Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA"
      ],
      "name": "Matt C Danzi"
    },
    {
      "affiliations": [
        "Neurogenetics Laboratory, North Thames Genomics Laboratory Hub, National Hospital for Neurology and Neurosurgery, London, UK"
      ],
      "name": "Roy Poh"
    },
    {
      "affiliations": [
        "Department of Neurology, University of Sao Paulo Ribeirao Preto Medical School, Ribeirao Preto, Brazil"
      ],
      "name": "Pedro J Tomaselli"
    },
    {
      "affiliations": [
        "Department of Neurology, University of Sao Paulo Ribeirao Preto Medical School, Ribeirao Preto, Brazil"
      ],
      "name": "Rodrigo S Frezatti"
    },
    {
      "affiliations": [
        "Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK"
      ],
      "name": "Natalia Dominik"
    },
    {
      "affiliations": [
        "Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney Local Health District and Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia"
      ],
      "name": "Bianca Grosz"
    },
    {
      "affiliations": [
        "Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney Local Health District and Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia"
      ],
      "name": "Melina Ellis"
    },
    {
      "affiliations": [
        "Molecular Medicine Laboratory and Neurology Department, Concord Repatriation General Hospital, Concord, New South Wales, Australia",
        "Translational Neurogenomics Group, Genomic and Inherited Disease Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia"
      ],
      "name": "Kishore R Kumar"
    },
    {
      "affiliations": [
        "Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York, USA"
      ],
      "name": "Matthew B Harms"
    },
    {
      "affiliations": [
        "Department of Neurology, Washington University in Saint Louis School of Medicine, St. Louis, Missouri, USA"
      ],
      "name": "Conrad C Weihl"
    },
    {
      "affiliations": [
        "Department of Neurology, University of Sao Paulo Ribeirao Preto Medical School, Ribeirao Preto, Brazil"
      ],
      "name": "Wilson Marques Júnior"
    },
    {
      "affiliations": [
        "Department of Neurology, University Hospitals Leuven, Leuven, Belgium",
        "Laboratory for Muscle Diseases and Neuropathies, KU Leuven, Leuven, Belgium"
      ],
      "name": "Kristl G Claeys"
    },
    {
      "affiliations": [
        "Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK",
        "Department of Clinical Neurophysiology, Norfolk and Norwich University Hospital, Norwich, UK"
      ],
      "name": "Julian C Blake"
    },
    {
      "affiliations": [
        "Walton Centre for Neurology and Neurosurgery, Liverpool, UK"
      ],
      "name": "James KL Holt"
    },
    {
      "affiliations": [
        "Liverpool Centre for Genomic Medicine, Liverpool Women’s Hospital, Liverpool, UK"
      ],
      "name": "Astrid Weber"
    },
    {
      "affiliations": [
        "Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA"
      ],
      "name": "Ryan Jacobson"
    },
    {
      "affiliations": [
        "Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA"
      ],
      "name": "Richard T Dineen"
    },
    {
      "affiliations": [
        "Neuromuscular Repair Unit, Institute of Experimental Neurology (InSpe), Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy"
      ],
      "name": "Yuri M Falzone"
    },
    {
      "affiliations": [
        "Neuromuscular Repair Unit, Institute of Experimental Neurology (InSpe), Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy",
        "Vita-Salute San Raffaele University, Milan, Italy"
      ],
      "name": "Stefano C Previtali"
    },
    {
      "affiliations": [
        "TY Nelson Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, Westmead, New South Wales, Australia",
        "The Children’s Hospital of Westmead Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia"
      ],
      "name": "Manoj P Menezes"
    },
    {
      "affiliations": [
        "Brain and Nerve Research Centre, Concord Hospital, Concord Clinical School, The University of Sydney, Sydney, New South Wales, Australia"
      ],
      "name": "Steve Vucic"
    },
    {
      "affiliations": [
        "Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK"
      ],
      "name": "Matilde Laura"
    },
    {
      "affiliations": [
        "Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney Local Health District and Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia"
      ],
      "name": "Marina L Kennerson"
    },
    {
      "affiliations": [
        "Department of Neurology, University of Iowa Health Care Medical Center, Iowa City, Iowa, USA"
      ],
      "name": "Michael E Shy"
    },
    {
      "affiliations": [
        "Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA"
      ],
      "name": "Stephan Zuchner"
    },
    {
      "affiliations": [
        "Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK"
      ],
      "name": "Mary M Reilly"
    }
  ],
  "title": "Spectrum of dominant Charcot-Marie-Tooth disease due to SLC12A6 variants",
  "uid": "f7e2215d-7ede-5dc3-bdb7-045dda5ac136"
}