Journal article
Spectrum of dominant Charcot-Marie-Tooth disease due to SLC12A6 variants
Journal of neurology, neurosurgery and psychiatry
01/07/2026
DOI: 10.1136/jnnp-2025-336643
PMID: 41500801
Abstract
BackgroundHeterozygous 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.MethodsPatients 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.ResultsTwenty-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.ConclusionsHeterozygous 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.
Details
- Title: Subtitle
- Spectrum of dominant Charcot-Marie-Tooth disease due to SLC12A6 variants
- Creators
- Christopher J Record - National Hospital for Neurology and NeurosurgeryTiffany Grider - University of IowaAdriana P Rebelo - University of MiamiChristian Laurini - IRCCS Ospedale San RaffaeleMariola Skorupinska - National Hospital for Neurology and NeurosurgeryMatt C Danzi - University of MiamiRoy Poh - National Hospital for Neurology and NeurosurgeryPedro J Tomaselli - Clinics Hospital of Ribeirão PretoRodrigo S Frezatti - Clinics Hospital of Ribeirão PretoNatalia Dominik - National Hospital for Neurology and NeurosurgeryBianca Grosz - Anzac Research InstituteMelina Ellis - Anzac Research InstituteKishore R Kumar - Concord Repatriation General HospitalMatthew B Harms - Columbia UniversityConrad C Weihl - Washington University in St. LouisWilson Marques Júnior - Universidade de São PauloKristl G Claeys - KU LeuvenJulian C Blake - National Hospital for Neurology and NeurosurgeryJames KL Holt - University of LiverpoolAstrid Weber - University of LiverpoolRyan Jacobson - Rush University Medical CenterRichard T Dineen - Rush University Medical CenterYuri M Falzone - IRCCS Ospedale San RaffaeleStefano C Previtali - IRCCS Ospedale San RaffaeleManoj P Menezes - Children's Hospital at WestmeadSteve Vucic - Concord Repatriation General HospitalMatilde Laura - National Hospital for Neurology and NeurosurgeryMarina L Kennerson - Anzac Research InstituteMichael E Shy - University of IowaStephan Zuchner - Dr. John T. Macdonald FoundationMary M Reilly - National Hospital for Neurology and Neurosurgery
- Resource Type
- Journal article
- Publication Details
- Journal of neurology, neurosurgery and psychiatry
- DOI
- 10.1136/jnnp-2025-336643
- PMID
- 41500801
- NLM abbreviation
- J Neurol Neurosurg Psychiatry
- ISSN
- 0022-3050
- eISSN
- 1468-330X
- Publisher
- BMJ Publishing Group Ltd
- Grant note
- U54NS065712 / National Institute of Neurological Disorders and Stroke (http://dx.doi.org/10.13039/100000065) MR/ S005021/1 / Medical Research Council (http://dx.doi.org/10.13039/501100000265)
- Language
- English
- Electronic publication date
- 01/07/2026
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9985116064102771
Metrics
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