The CLCN4 gene encodes the protein CIC-4 which is a 2Cl-/H+ exchanger expressed in intracellular compartments in a wide variety of tissues, but prominently in the brain and skeletal muscle. ClC-4 is thought to be expressed within cells on endosomes and possibly the endoplasmic reticulum, and to be involved in the ion homeostasis of endosomes and intracellular trafficking. A role for CIC-4 in neuronal differentiation has been suggested by mouse studies: hippocampal neurons from Clcn4 knockout mice and wild-type neurons subjected to shRNA-mediated Clcn4 knockdown demonstrate a reduction in the total number of dendritic branches per neuron. However, the pathophysiology of CLCN4-related disorder in humans is incompletely understood.

The mutation spectrum includes frameshift, missense and splice site variants, and chromosomal microdeletions.
Pathogenic missense variants cluster within the helical trans- or intermembrane domains of the protein, or the cystathionine-β-synthase (CBS) domain which is believed to be important for gating of the antiporter. All missense variants known to date that cluster in these regions have been shown to have a functional effect on electrophysiological studies when heterologously expressed in Xenopus laevis oocytes. All affected females known to date have a missense variant in CLCN4: heterozygous female carriers in families with predicted loss of function variants have essentially normal phenotypes.