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Neurogenetics
Short report
De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy
  1. Joohyun Park1,2,
  2. Bianca R Flores3,
  3. Katalin Scherer4,
  4. Hanna Kuepper5,
  5. Mari Rossi6,
  6. Katrin Rupprich7,
  7. Maren Rautenberg1,
  8. Natalie Deininger1,
  9. Annette Weichselbaum5,
  10. Alexander Grimm2,
  11. Marc Sturm1,
  12. Ute Grasshoff1,
  13. Eric Delpire3,
  14. Tobias B Haack1,8
  1. 1 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
  2. 2 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
  3. 3 Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  4. 4 Neuromuscular Clinic, Children’s Clinic for Rehabilitative Services, Tucson, Arizona, USA
  5. 5 Department of Neuropediatrics, University of Tübingen, Tübingen, Germany
  6. 6 Department of Clinical Diagnostics, Ambry Genetics, Aliso Viejo, California, USA
  7. 7 Department of Neuropediatrics, Essen University Hospital, Essen, Germany
  8. 8 Centre for Rare Diseases, University of Tübingen, Tübingen, Germany
  1. Correspondence to Dr Tobias B Haack, Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Baden-Württemberg, Germany; tobias.haack{at}med.uni-tuebingen.de

Abstract

Background Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous disorder of the peripheral nervous system. Biallelic variants in SLC12A6 have been associated with autosomal-recessive hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC). We identified heterozygous de novo variants in SLC12A6 in three unrelated patients with intermediate CMT.

Methods We evaluated the clinical reports and electrophysiological data of three patients carrying de novo variants in SLC12A6 identified by diagnostic trio exome sequencing. For functional characterisation of the identified variants, potassium influx of mutated KCC3 cotransporters was measured in Xenopus oocytes.

Results We identified two different de novo missense changes (p.Arg207His and p.Tyr679Cys) in SLC12A6 in three unrelated individuals with early-onset progressive CMT. All presented with axonal/demyelinating sensorimotor neuropathy accompanied by spasticity in one patient. Cognition and brain MRI were normal. Modelling of the mutant KCC3 cotransporter in Xenopus oocytes showed a significant reduction in potassium influx for both changes.

Conclusion Our findings expand the genotypic and phenotypic spectrum associated with SLC12A6 variants from autosomal-recessive HMSN/ACC to dominant-acting de novo variants causing a milder clinical presentation with early-onset neuropathy.

  • SLC12A6
  • KCC3
  • Charcot-Marie-Tooth
  • hereditary neuropathy
  • DI-CMT

https://doi.org/10.1136/jmedgenet-2019-106273

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    Footnotes

    • Contributors JP collected and analysed clinical and genetic data and was responsible for drafting the manuscript. BRF conducted functional experiments, collected and analysed the functional data and contributed to manuscript. KS, HK, KR, AW, AG and UG contributed to phenotyping, acquisition and analysis of clinical and electrophysiological data. MR, MR, ND and MS contributed to analysis and interpretation of genetic data. TBH and ED were responsible for the conception, design and supervision of the study and writing of the manuscript. All authors revised the manuscript for intellectual content.

    • Funding This study was supported by the German Bundesministerium für Bildung und Forschung (BMBF) through the Juniorverbund in der Systemmedizin ‘mitOmics’ (FKZ 01ZX1405C to TBH), the intramural fortüne program (#2435-0-0) and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Projektnummer (418081722)

    • Competing interests None declared.

    • Patient consent for publication Obtained.

    • Provenance and peer review Not commissioned; externally peer reviewed.