Missense variants in SLC9A6 cause partial epilepsy without neurodevelopmental delay.

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• The SLC9A6 gene encodes a sodium/hydrogen exchanger crucial for endosomal function.
• Variants in SLC9A6 are known to cause Christianson Syndrome, a severe neurodevelopmental disorder with seizures.
• The association of SLC9A6 variants with milder neurological phenotypes remains largely unexplored.

Purpose of the Study:

• To investigate the role of SLC9A6 variants in epilepsy beyond severe neurodevelopmental disorders.
• To explore genotype-phenotype correlations and potential sub-regional effects of SLC9A6 variants.

Main Methods:

• Whole-exome sequencing was performed on families with unexplained epilepsy.
• Analysis included previously reported SLC9A6 variants to understand phenotypic variability.
• In silico tools were used to predict the pathogenicity of identified missense variants.

Main Results:

• Five hemizygous SLC9A6 variants (3 null, 2 missense) were identified in males with epilepsy.
• Null variants correlated with refractory epilepsy and severe developmental delay.
• Missense variants showed varied outcomes, with one achieving seizure freedom, suggesting a genotype-phenotype correlation and sub-regional effects.

Conclusions:

• Missense variants in SLC9A6 are associated with milder forms of partial epilepsy.
• Genotype-phenotype correlations and molecular sub-regional effects of SLC9A6 explain phenotypic diversity.
• This study expands the known phenotypic spectrum associated with SLC9A6 variants.