CLCN3-related neurodevelopmental disorder is a rare and phenotypically variable condition characterized primarily by global developmental delay (GDD) and intellectual disability (ID). Individuals have been shown to exhibit additional neurological and other clinical manifestations including mood or behavioral disorders, hypotonia, seizures, vision abnormalities, dysmorphic facial features, and structural brain anomalies.
Both homozygous loss-of-function variants and heterozygous de novo missense variants in CLCN3, the gene encoding the endosomal/lysosomal chloride-proton exchanger ClC-3, have been implicated in the disease. Homozygous variants result in more severe neurologic phenotypes that resemble Clcn3 knockout mouse models - their MRIs showing possible neurodegeneration, involving thin corpus callosum and decreased white matter volume. Conversely, heterozygous de novo missense variants present with variable clinical severity, including agenesis of the corpus callosum, pons hypoplasia, and increased gyral folding.
CLCN3