Novel heterozygous variants of SLC12A6 in Japanese families with Charcot-Marie-Tooth disease

Abstract

Background: Recessive mutations in SLC12A6 have been linked to hereditary motor sensory neuropathy with agenesis of the corpus callosum. Patients with early-onset peripheral neuropathy associated with SLC12A6 heterozygous variants were reported in 2016. Only five families and three variants have been reported to date, and the spectrum is unclear. Here, we aim to describe the clinical and mutation spectra of SLC12A6-related Charcot-Marie-Tooth (CMT) disease in Japanese patients.

Methods: We extracted SLC12A6 variants from our DNA microarray and targeted resequencing data obtained from 2598 patients with clinically suspected CMT who were referred to our genetic laboratory by neurological or neuropediatric departments across Japan. And we summarized the clinical and genetic features of these patients.

Results: In seven unrelated families, we identified one previously reported and three novel likely pathogenic SLC12A6 heterozygous variants, as well as two variants of uncertain significance. The mean age of onset for these patients was 17.5 ± 16.1 years. Regarding electrophysiology, the median motor nerve conduction velocity was 39.6 ± 9.5 m/sec. For the first time, we observed intellectual disability in three patients. One patient developed epilepsy, and her brain MRI revealed frontal and temporal lobe atrophy without changes in white matter and corpus callosum.

Conclusions: Screening for the SLC12A6 gene should be considered in patients with CMT, particularly those with central nervous system lesions, such as cognitive impairment and epilepsy, regardless of the CMT subtype.

Figure 1

Flow chart of our study. Using DNA microarray and target resequencing, we analyzed 2598 patients with clinically diagnosed CMT, and extracted all SLC12A6 (NM_133647) variants from the 1800 test‐negative patients. CMT, Charcot–Marie–Tooth.

Figure 2

Genetic findings of seven families and variants review from literatures. (A) Seven families with SLC12A6 heterozygous variants in our study. Arrows indicate proband. −: wild type, +: variant positive (B) The variant residues detected in our study are highly conserved in human KCC family members and across species. (C) Location of SLC12A6 heterozygous and homozygous variants. Heterozygous variants are labeled above the protein, and variants detected in our study are underlined. Reported homozygous variants are labeled below the protein diagram.

Figure 3

Brain MRI of patient 7 with p.Tyr679Ser variant. FLAIR images show frontal (arrow) and temporal lobe atrophy (arrow head). White matter change and corpus callosum change are not observed. [Colour figure can be viewed at wileyonlinelibrary.com]