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GAD2(glutamate decarboxylase 2), encodes the glutamate decarboxylase enzyme GAD65, a critical component of γ-aminobutyric acid (GABA) metabolism, as it catalyzes the decarboxylation of glutamic acid to form GABA. GAD65 is primarily localized at nerve terminals and is transiently activated to regulate GABA synthesis for vesicular release during periods of increased synaptic demand. We describe four individuals from three unrelated consanguineous families with bi-allelic loss-of-function variants in GAD2. We define a novel neurodevelopmental syndrome characterized by early-onset epilepsy, with seizures most severe in early infancy, together with developmental delay, mild to moderate intellectual disability and autism spectrum disorder. To further investigate the pathogenicity of GAD2variants, a GAD65 knockout mouse model was generated and characterized, which fully recapitulates the human phenotype. The strong concordance between clinical findings and the mouse model underscores the pivotal role of GAD2in neurodevelopment and epilepsy.