CLCN4 encodes a chloride/proton antiporter (ClC-4) that mediates electrogenic exchange of chloride ions against protons 1. The protein functions as a strongly outwardly rectifying H+/Cl- exchanger with conserved gating glutamate residues typical of antiporter family members 2. ClC-4 localizes to multiple intracellular compartments including endosomes, lysosomes, and synaptic vesicles, where it associates with other chloride-proton antiporters like CLCN3 and CLCN5 2. Pathogenic CLCN4 variants cause Raynaud-Claes syndrome, an X-linked neurodevelopmental disorder characterized by global developmental delay, intellectual disability, and drug-resistant epilepsy 3. Seizures develop in approximately 55% of patients, often within the first year of life, with myoclonic seizures being most common 4. Most variants result in loss-of-function through reduced anion exchange capacity, altered protein trafficking, or disrupted oligomerization with other ClC proteins 3. Functional analyses reveal that 25% of variants cause voltage-dependent activation shifts, while others produce toxic gain-of-function allowing inward transport at negative voltages 5. CLCN4 dysfunction impairs synaptic plasticity and dendritic development; Clcn4 knockout mice exhibit autism-spectrum behaviors with reduced dendritic branching and decreased synaptic phosphorylation markers 6. Lamotrigine shows therapeutic promise in select patients 4.