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.
- hereditary neuropathy
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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.