Case Report: Novel SLC9A6 Splicing Variant in a Chinese Boy With Christianson Syndrome With Electrical Status Epilepticus During Sleep.

Xiaorui Liu,Zhixu Fang,Lingling Xie,Li Jiang

doi:10.3389/fneur.2021.796283

Abstract

We investigated the existence and potential pathogenicity of a SLC9A6 splicing variant in a Chinese boy with Christianson Syndrome (CS), which was reported for the first time in China. Trio whole-exome sequencing (WES) was performed in the proband and his parents. Multiple computer prediction tools were used to evaluate the pathogenicity of the variant, and reverse transcription-polymerase chain reaction (RT-PCR) analysis and cDNA sequencing were performed to verify the RNA splicing results. The patient presented with characteristic features of CS: global developmental delay, seizures, absent speech, truncal ataxia, microcephaly, ophthalmoplegia, smiling face and hyperkinesis with electrical status epilepticus during sleep (ESES) detected in an electroencephalogram (EEG). A SLC9A6 splicing variant was identified by WES and complete skipping of exon 10 was confirmed by RT-PCR. This resulted in altered gene function and was predicted to be pathogenic. ESES observed early in the disease course is considered to be a significant feature of CS with the SLC9A6 variant. Combined genetic analysis at both the DNA and RNA levels is necessary to confirm the pathogenicity of this variant and its role in the clinical diagnosis of CS.

Highlights

The SLC9A6 gene(chrX:135098802), located on Xq26.3, encodes isoform 6 of the Na+/H+ exchanger superfamily (NHE6)
We identified a maternally-inherited SLC9A6 splicing variant in a Chinese boy who presented with global developmental delay, epilepsy and microcephaly
A Chinese boy was born at term with a birth weight of 2,950 g (25–50th centile) and head circumference of 32 cm (10–25th centile) without neonatal asphyxia at birth or aberrant family history

Summary

Introduction

The SLC9A6 gene(chrX:135098802), located on Xq26.3, encodes isoform 6 of the Na+/H+ exchanger superfamily (NHE6). NHE6 exchanges luminal H+ in early and recycling endosomes, contributing to substance transport and receptor recycling, which are essential for axonal growth, branching, synaptic maturation and neural plasticity [1]. Christianson syndrome (CS) has been associated with a SLC9A6 variant and is characterized by moderate to severe global developmental delay, epilepsy, absent or impaired speech, truncal ataxia, ophthalmoplegia, acquired microcephaly [2] and reduced life expectancy [3]. The clinical features of CS overlap with those of Angelman syndrome (AS) [4], making it hard to identify in clinical practice. We identified a maternally-inherited SLC9A6 splicing variant in a Chinese boy who presented with global developmental delay, epilepsy and microcephaly. Our findings indicate the pathogenicity of this SLC9A6 splicing variant in CS

Methods

Results

Conclusion