CLCN4-related condition is a syndromic form of X-chromosome linked intellectual disability/epilepsy with complete penetrance but variable expressivity in males, and incomplete penetrance and variable expressivity in females.
The clinical phenotype can include distinctive dysmorphic features, aggressive/hyperactive/autistic features, an increased risk of depression and anxiety, infantile hypotonia, progressive neurological symptoms including gait disturbance and evolving spasticity, and white matter changes on cerebral imaging.
To date clinical information is available on 53 individuals with a CLCN4 gene change, from 17 families, but it is likely more individuals will be diagnosed as genomic testing is more commonly used for undiagnosed intellectual disability.
CLCN4 encodes CIC-4 which is a2Cl-/H+ exchanger expressed in intracellular compartments. CIC-4 is widely expressed across tissues, including 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-/- 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.