SLC9A6 encodes an endosomal Na+, K+/H+ antiporter that mediates electroneutral exchange of endosomal luminal H+ for cytosolic Na+ or K+ 1234. By facilitating proton efflux, SLC9A6 counteracts vacuolar ATPase-generated acidity, thereby maintaining endosomal pH and enabling endosome maturation and recycling endosomal cargo trafficking 1234. The transporter plays critical roles in neurodevelopment, regulating synaptic development and plasticity, and maintains cell polarity through intravesicular pH modulation 5. Mutations in SLC9A6 cause ChrX syndrome, an X-linked intellectual developmental disorder characterized by global developmental delay, epilepsy, hyperkinesis, ataxia, and microcephaly 6. Frameshift variants result in loss of functional NHE6 protein, with emerging evidence suggesting mitochondrial dysfunction and lipid metabolism alterations contribute to pathogenesis 6. Female carriers exhibit variable phenotypes including learning difficulties, mild-to-moderate intellectual disability, behavioral issues, and psychiatric illness 7. SLC9A6 is increasingly recognized among X-linked epilepsy genes associated with developmental and epileptic encephalopathies 8. Gene-specific variant interpretation criteria have been established to improve diagnostic accuracy 9.