Autosomal dominant and recessive variants of the CLCN3 gene cause neurodevelopmental disease. Scientists of an international research collaboration studied patients with global developmental delay/intellectual disability and neurodevelopmental phenotypes of variable severity. The majority of the patients also presented with behavioral problems and structural brain anomalies. In their study, the researchers identified 9 variants in CLCN3 as underlying cause of the disease. The variants included 8 different heterozygous missense mutations and two homozygous frameshift variants.

Neurodevelopmental disorders are known to have numerous genetic causes, among them variants in various ion channels and transporters. CIC-3, the protein encoded by CLCN3, is a member of the CLC family of voltage-gated chloride channels, which play important roles in many cellular processes. CIC-3 is predominantly localized in membranes of intracellular compartments like endosomes and functions as a chloride/proton exchanger regulating pH required, for example, to activate specific enzymes in the cell. Further experiments to electrophysiologically characterize four of the heterozygous missense mutations showed that two of the variants result in an increased ion transport by CIC-3.

The results of the study have been published in the American Journal of Human Genetics.