De novo CLCN3 variants affecting Gly327 cause severe neurodevelopmental syndrome with brain structural abnormalities

A recent study revealed that monoallelic missense or biallelic loss-of-function variants in the chloride voltage-gated channel 3 (CLCN3) cause neurodevelopmental disorders resulting in brain abnormalities. Functional studies suggested that some missense variants had varying gain-of-function effects on channel activity. Meanwhile, two patients with homozygous frameshift variants showed severe neuropsychiatric disorders and a range of brain structural abnormalities. Here we describe two patients with de novo CLCN3 variants affecting the same amino acid, Gly327 (p.(Gly327Ser) and p.(Gly327Asp)). They showed severe neurological phenotypes including global developmental delay, intellectual disability, hypotonia, failure to thrive, and various brain abnormalities. They also presented with characteristic brain and ophthalmological abnormalities, hippocampal and retinal degradation, which were observed in patients harboring homozygous loss-of-function variants. These findings were also observed in CLCN3-deficient mice, indicating that the monoallelic missense variant may also have a dominant negative effect. This study will expand the phenotypic spectrum of CLCN3-related disorders.