De novo missense variants in SLC32A1 cause a neurodevelopmental disorder with epilepsy due to impaired GABAergic neurotransmission

We describe four patients with a neurodevelopmental disorder and de novo missense variants in SLC32A1, the gene that encodes the vesicular GABA transporter (VGAT). The main phenotype comprises moderate to severe intellectual disability, early onset epilepsy within the first 18 months of life and a choreatic, dystonic or dyskinetic movement disorder. In silico modeling and functional analyses in cultured neurons reveal that three of these variants, which are located in helices that line the putative GABA transport pathway, result in reduced quantal size, consistent with impaired filling of synaptic vesicles with GABA. The fourth variant, located in the VGAT N-terminus, does not affect quantal size, but increases presynaptic release probability, leading to more severe synaptic depression during high frequency stimulation. Thus, variants in VGAT can impair GABAergic neurotransmission via at least two mechanisms, by affecting synaptic vesicle filling and by altering synaptic short-term plasticity. This work establishes de novo missense variants in SLC32A1 as a novel cause for a neurodevelopmental disorder with epilepsy.