<i>De novo</i> variants in <i>SLC12A6</i> cause sporadic early-onset progressive sensorimotor neuropathy.

Abstract

Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous disorder of the peripheral nervous system. Biallelic variants in <i>SLC12A6</i> 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 <i>SLC12A6</i> in three unrelated patients with intermediate CMT. We evaluated the clinical reports and electrophysiological data of three patients carrying de novo variants in <i>SLC12A6</i> identified by diagnostic trio exome sequencing. For functional characterisation of the identified variants, potassium influx of mutated KCC3 cotransporters was measured in <i>Xenopus</i> oocytes. We identified two different de novo missense changes (p.Arg207His and p.Tyr679Cys) in <i>SLC12A6</i> 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 <i>Xenopus</i> oocytes showed a significant reduction in potassium influx for both changes. Our findings expand the genotypic and phenotypic spectrum associated with <i>SLC12A6</i> variants from autosomal-recessive HMSN/ACC to dominant-acting de novo variants causing a milder clinical presentation with early-onset neuropathy.